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SPINRAZA READINESS KIT Please see full Prescribing Information for important safety information. MANAGEMENT OF THE REIMBURSEMENT PROCESS FOR SPINRAZA 1 SELECT TREATMENT AFTER DISCUSSING BENEFITS AND RISKS 2 CONDUCT A BENEFIT INVESTIGATION Tip: Thoroughly investigate specific payer requirements regarding • Coverage and documentation • Product acquisition • Patient cost sharing • Site of care • Coding and billing 4 IS A PRIOR AUTHORIZATION AND/OR MEDICAL EXCEPTION REQUIRED? YES 3 SCHEDULE PATIENT TREATMENT AND ORDER SPINRAZA Tip: Submit the SPINRAZA Start Form to enroll your patient in Biogen support services. Review plan requirements for a prior authorization, complete form, and submit OR Submit a medical exception request using a letter of medical necessity and supporting documentation NO 5 SUBMIT THE CLAIM 6 TRACK REIMBURSEMENT Tip: Establish an efficient claim submission process that includes Tip: Ensure appropriate payment by • Appropriate documentation • Accurate coding • Timely submissions • Monitoring payer remittance • Appealing, if necessary For more information on how to submit claims and track reimbursement, please see the Guide to SPINRAZA Reimbursement or ask your Biogen representative If the plan denies the prior authorization or medical exception request, you can appeal and resubmit the request. Please see full Prescribing Information for important safety information. 2 SPINRAZA™ (nusinersen) READINESS KIT RESOURCES SPINRAZA READINESS KIT WELCOME LETTER The welcome letter provides an overview of the kit and a summary of included items. SPINRAZA PRODUCT FACT SHEET This fact sheet provides information about SPINRAZA. In addition, this sheet also includes the relevant product and procedure codes for SPINRAZA. SPINRAZA FREQUENTLY ASKED QUESTIONS This resource includes the answers to questions that your office or facility may have about SPINRAZA. SPINRAZA CLINICAL OVERVIEW This overview provides information about the multiple clinical studies with SPINRAZA, including the trial designs and efficacy and safety results. TIPS TO SUCCESSFULLY COMPLETING THE SPINRAZA START FORM This guide explains the SPINRAZA Start Form and provides tips on how to complete each section so that your patients can enroll in Biogen support services. GUIDE TO PRIOR AUTHORIZATION SUBMISSIONS This guide provides steps and tips when submitting a prior authorization. GUIDE TO REQUESTING A MEDICAL EXCEPTION This guide provides templates and tips for submitting a medical exception. SAMPLE LETTER OF MEDICAL NECESSITY A sample letter template to use when requesting a medical exception for a patient. INSURANCE CARRIER CONTACT SHEET The Insurance Carrier Contact Sheet allows your office to record contact information for the insurance carriers that are contacted most frequently. UNDERSTANDING MEDICAL VS PHARMACY BENEFIT INSURANCE CARDS This overview provides information about distinguishing between medical and pharmacy benefit cards. Please see full Prescribing Information for important safety information. © 2016 Biogen. 3 All rights reserved. 12/16 SPZ-US-0362 WELCOME TO THE SPINRAZA READINESS KIT! The SPINRAZA Readiness Kit provides a comprehensive resource to assist your practice or facility in navigating formulary decision-making for pharmacy and therapeutics committees, as well as supporting the process to help gain access and approval of your patient’s treatment once prescribed. This kit provides various resources to help along the way with Informing your practice or facility about the use of SPINRAZA for appropriate patients. The materials included in this thumb drive will provide detailed product information, including SPINRAZA efficacy and safety nderstanding the steps to product access. U Refer to the printed piece that accompanied this thumb drive of materials to review these steps. The action item for each step in the process is included, as well as tips provided in this kit ompleting the SPINRAZA Start C Form to enroll your patient in Biogen support services ubmitting prior authorizations S and requesting medical exceptions Maintaining insurance carrier contact information Obtaining approval for your patient’s treatment for spinal muscular atrophy (SMA) often requires your practice or facility to complete several steps, including conducting a thorough Benefit Investigation to determine if an authorization and/or exception is needed prior to treatment approval. In addition, your practice or facility may need to coordinate with a specialty pharmacy to ensure all payer approvals are obtained and the medication is shipped. Biogen’s SMA360°™ support provides certain services that address nonmedical barriers to access. These include logistical assistance, product education, insurance benefits investigations, and financial assistance. A complete list of the SMA360° offerings can be found at SPINRAZA.com/support. For more information about insurance coverage for SPINRAZA, contact SMA360° at 1-844-4SPINRAZA (1-844-477-4672), Monday through Friday, 8:30 am to 8:00 pm ET, or contact your Biogen representative. SMA360° services from Biogen are available only to those who have been prescribed SPINRAZA. SMA360° is available only in the US. INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following page for additional Important Safety Information. 1 IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. © 2016 Biogen. 2 All rights reserved. 12/16 SPZ-US-0297 COMPANY: Biogen PRODUCT TRADE NAME: SPINRAZA™ GENERIC NAME: nusinersen PRODUCT AVAILABILITY (Estimate): end Q4 2016 PRODUCT DESCRIPTION: SPINRAZA is an intrathecal injection indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients and is available in 12-mg/5-mL single-dose vials. How supplied 12-mg/5-mL injection Packaging Single-dose glass vial Carton dimensions 2.28" x 3.15" x 2.56" Shipping case dimensions 11.25" x 9.5" x 8" or 11.25" x 9.5" x 10.75" NDC number 64406-058-01 Potential ICD-10 Codes G12.0 - Infantile spinal muscular atrophy, type I G12.1 - Other inherited spinal muscular atrophy G12.8 - Other spinal muscular atrophies and related syndromes G12.9 - Spinal muscular atrophy, unspecified CPT codea 96450 - C hemotherapy administration, into CNS (eg, intrathecal), requiring and including spinal puncture 62270 - Spinal puncture, lumbar, diagnostic CPT=Current Procedural Terminology; ICD-10=International Classification of Diseases, Tenth Revision; NDC=National Drug Code. a Additional codes may be needed for procedures required to properly administer SPINRAZA. DOSING: Initiate with 4 loading doses. The first 3 loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months therafter. STORAGE REQUIREMENTS: Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. See product packaging and Prescribing Information for complete list of instructions. INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following page for additional important safety information. 1 IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional important safety information. Reference: SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen; December 2016. © 2016 Biogen. 2 All rights reserved. 12/16 SPZ-US-0364 FREQUENTLY ASKED QUESTIONS Please see full Prescribing Information for additional Important Safety Information. SPINAL MUSCULAR ATROPHY WHAT IS SPINAL MUSCULAR ATROPHY (SMA)? •S MA is an autosomal recessive neuromuscular disease that has a significant impact on patients and their families1,2 •L ow levels of survival motor neuron (SMN) protein lead to progressive loss of motor neurons1-4 •S MA is characterized by progressive muscle weakness and atrophy resulting from the degeneration of motor neurons in the spinal cord1-3,5,6 HOW MANY PEOPLE ARE AFFECTED BY SMA? •S MA is a rare disease—an estimated 9000 people in the United States have the disease—and the incidence ranges from 5.1 to 16.6 per 100,000 live births across all disease severities7-9 HOW WAS SMA PREVIOUSLY TREATED? • Until the approval of SPINRAZA, there were no FDA-approved treatments indicated for SMA. Medical care has typically been palliative care, aimed at helping patients with breathing, coughing, swallowing/feeding, mobility, and other activities of daily living1,5,10 SMA is a leading genetic cause of infant mortality.2,5,6 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following pages for additional Important Safety Information. 2 ABOUT SPINRAZA WHAT IS SPINRAZA? •S PINRAZA is the first and only FDA-approved treatment indicated for SMA in pediatric and adult patients11,12 •S PINRAZA has been studied in multiple clinical trials across a range of SMA patients, including presymptomatic and symptomatic patients who had or were likely to develop Type 1, 2, or 3 SMA11 • In a pivotal controlled trial, patients with infantile-onset SMA who were treated with SPINRAZA demonstrated significant improvement in motor milestones as measured by Hammersmith Infant Neurologic Exam (HINE) Section 2 as compared to untreated patients 11 • The overall findings of the controlled trial in infantile-onset SMA and the open-label uncontrolled trials support the effectiveness of SPINRAZA across the range of SMA patients and appear to support the early initiation of treatment with SPINRAZA11 • In the open-label uncontrolled trials, some presymptomatic and symptomatic patients who had or were likely to develop Type 1, 2, or 3 SMA11 — Survived to ages unexpected considering the number of SMN2 gene copies of patients enrolled in the studies — Achieved milestones such as the ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so — Maintained milestones at ages when they would be expected to be lost WHAT IS THE MECHANISM OF ACTION FOR SPINRAZA? • SPINRAZA is an antisense oligonucleotide (ASO) targeted to SMN211 • In laboratory tests and animal studies, SPINRAZA was shown to increase full-length SMN protein by targeting the process through which it is produced by a gene called survival motor neuron 2 (SMN2)11 IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Please see following pages for additional Important Safety Information. 3 HOW IS SPINRAZA ADMINISTERED? • SPINRAZA should be administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures11 • Prior to administration, remove 5 mL of cerebrospinal fluid • Sedation may be considered based on the clinical condition of the patient • Ultrasound or other imaging techniques may help guide intrathecal administration of SPINRAZA, particularly in younger patients WHAT IS THE DOSAGE OF SPINRAZA? • The recommended dosage is 12 mg (5 mL) per administration11 •S PINRAZA treatment is initiated with 4 loading doses. The first 3 loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter11 Day 0 Day 14 days 14 Day 14 days 28 Day 30 days Every 4 months 58 LOADING DOSING (approximate days) MAINTENANCE DOSING • If a loading dose is delayed or missed, administer SPINRAZA as soon as possible with at least 14 days between doses and continue dosing as prescribed. If a maintenance dose is delayed or missed, administer SPINRAZA as soon as possible and continue dosing every 4 months11 • Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed:11 — Platelet count — Prothrombin time; activated partial thromboplastin time — Quantitative spot urine protein testing IMPORTANT SAFETY INFORMATION (continued) Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. Please see following pages for additional Important Safety Information. 4 WHAT IS THE APPROPRIATE DURATION OF USE FOR SPINRAZA? • The overall findings of the clinical trials support the early initiation of treatment with SPINRAZA1 • Patient improvement may vary and be difficult to measure quantitatively, therefore physician discretion should be used to evaluate the length of treatment11 ARE THERE ANY CONTRAINDICATIONS FOR SPINRAZA? • There are no contraindications for SPINRAZA11 ARE THERE WARNINGS AND PRECAUTIONS FOR SPINRAZA? • Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some ASOs. In a clinical study, 6 of 56 (11%) SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal, compared with 0 of 28 sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL in this study and no patient developed a sustained low platelet count despite continued drug exposure. Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed11 • Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some ASOs. SPINRAZA is present in and excreted by the kidney. In a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared with 5 of 25 (20%) sham-control patients. In a group of later-onset SMA patients (mean treatment exposure 34 months), 36 of 52 (69%) had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in these studies. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/L, consider repeat testing and further evaluation11 ARE THERE ADVERSE EVENTS WITH SPINRAZA? • In the controlled study, the most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection, upper respiratory infection, and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. The most common adverse events in the open-label studies in later-onset patients were headache, back pain, and post lumbar puncture syndrome. Most of these events occurred within 5 days of lumbar puncture11 • In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months. Two cases of rash were reported in patients treated with SPINRAZA. Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment11 IMPORTANT SAFETY INFORMATION (continued) The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see following pages for additional Important Safety Information. 5 HOW SHOULD SPINRAZA BE STORED? •S tore SPINRAZA in a refrigerator between 2°C and 8°C (36°F - 46°F)11 •K eep the vial in its original packaging to protect it from light11 • If refrigeration is not available, store SPINRAZA in its original packaging, protected from light, below 30°C (86°F) for up to 14 days11 HOW IS SPINRAZA ORDERED? • SPINRAZA is supplied as a 12-mg/5-mL (2.4 mg/mL) solution in a single-dose glass vial free of preservatives11 • SPINRAZA may be ordered through CuraScript Specialty Distributor (SD)/Accredo Specialty Pharmacy (SP). CuraScript SD/Accredo SP have extensive experience handling and distributing specialty pharmacy products for a variety of chronic and rare conditions • For SPINRAZA ordering, CuraScript SD/Accredo SP can be reached at 1-855-778-1510 (phone) or 1-866-579-4655 (fax) SPINRAZA SUPPORT SERVICES DOES BIOGEN HAVE SUPPORT SERVICES FOR SPINRAZA? • Biogen’s SMA360°™ support provides certain services that address nonmedical barriers to access.a These include logistical assistance, product education, insurance benefits investigations, and financial assistance. A complete list of the SMA360° offerings can be found at www.SPINRAZA-hcp.com/support Biogen is committed to supporting patients and those who care for them with a range of helpful services, financial assistance, and other programs. SMA360° services from Biogen are only available to those who have been prescribed SPINRAZA. SMA 360° is available only in the US. a IMPORTANT SAFETY INFORMATION (continued) Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following page for additional Important Safety Information. 6 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. 7 References: 1. Wang CH, Finkel RD, Bertini ES, et al; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8): 1027-1049. 2. Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743-766. 3. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133. 4. Tisdale S, Pellizzoni L. Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J Neurosci. 2015;35(23):8691-8700. 5. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. 6. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. 7. The Lewin Group, Inc; for Muscular Dystrophy Association. Cost of Amyotrophic Lateral Sclerosis, Muscular Dystrophy, and Spinal Muscular Atrophy in the United States: Final Report. https://www. mda.org/sites/default/files/Cost_Illness_Report.pdf. Published March 1, 2012. Accessed August 17, 2016. 8. Jones C, Zielinski D, Vinikoor L, Farwell W. Systematic review of incidence and prevalence of spinal muscular atrophy (SMA). Poster presented at: 11th European Paediatric Neurology Society Congress 2015. May 27-30, 2015; Vienna, Austria. 9. Biogen, Data on File. 10. National Institutes of Health; US Department of Health and Human Services. Spinal muscular atrophy. NIH publication 12-5597. http://www.ninds.nih.gov/disorders/sma/spinal_muscular_atrophy_FS.pdf. Published July 2012. Accessed October 6, 2016. 11. SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen; December 2016. 12. U.S. FDA approves Biogen’s SPINRAZATM (nusinersen), the first treatment for spinal muscular atrophy [news release]. Boston, MA: Biogen; December 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm534611.htm. Accessed December 23, 2016. Please see full Prescribing Information for additional Important Safety Information. © 2016 Biogen. All rights reserved. 12/16 SPZ-US-0129 SPINRAZA CLINICAL OVERVIEW Please see full Prescribing Information for additional Important Safety Information. TABLE OF CONTENTS INDICATION...........................................................................................................3 CONTROLLED STUDY (ENDEAR)...................................................................4 SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES............................7 SAFETY...............................................................................................................8 SUMMARY....................................................................................................... 11 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following pages for additional Important Safety Information. 2 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY INDICATION SPINRAZA is the first and only treatment approved by the US Food and Drug Administration indicated for spinal muscular atrophy (SMA) in pediatric and adult patients.1,2 SPINRAZA has been studied in multiple clinical trials across a range of SMA patients, including presymptomatic and symptomatic patients who had or were likely to develop SMA Type 1, 2, or 3.1 Infantile-onset SMA Later-onset SMA Infantile-onset SMA symptoms typically appear between birth and 6 months (most likely to develop SMA Type 1)3,4 Later-onset SMA symptoms typically appear between ages 6 and 18 months (most likely to develop SMA Type 2) and between 18 and 36 months (most likely to develop SMA Type 3)3,4 IMPORTANT SAFETY INFORMATION Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Please see following pages for additional Important Safety Information. 3 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY CONTROLLED STUDY IN PATIENTS WITH INFANTILE-ONSET SPINAL MUSCULAR ATROPHY (ENDEAR) STUDY DESCRIPTION • This study was a multicenter, randomized, double-blind, sham-procedure controlled study in 121 symptomatic infants ≤7 months of age at the time of first dose, diagnosed with spinal muscular atrophy (SMA) (symptom onset before 6 months of age)1 • A planned interim efficacy analysis was conducted based on patients who died, withdrew, or completed at least 183 days of treatment1 Day 183 Interim Analysis Randomized 2:1 Controlled study population (N=121) SPINRAZAtreated Sham injection Day 0 Day 14 days 15 Day 14 days Day 29 Every 4 months 64 30 days LOADING DOSING MAINTENANCE DOSING SPINRAZA (n=52) Sham injection (n=30) Day 302 Day 394 Key motor function endpoint measures • HINE • CHOP INTEND DESCRIPTION OF MEASUREMENTS IN SPINRAZA CLINICAL TRIALS Hammersmith Infant Neurological Examination (HINE) Section 2 is a measure comprising different areas of motor milestone development, with a maximum score of 2 to 4 points for each and a total maximum score of 26. The primary endpoint assessed at the time of interim analysis was the proportion of responders.1 • A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) in ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing, or walking (consistent with improvement by at least 1 milestone) • To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones than worsening1 Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) is a 64-point motor assessment that evaluates muscle strength and function in infants with SMA. Some examples of the assessments in the CHOP INTEND include spontaneous movement of the upper part of the body, such as lifting the elbow off of a surface or wrist movement; spontaneous movement of the lower part of the body, such as raising feet and knees off of a surface and ankle movement; head control; hand grip; elbow flexing; twisting the pelvis; and rolling.5 IMPORTANT SAFETY INFORMATION (continued) Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. Please see following pages for additional Important Safety Information. 4 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY KEY MOTOR FUNCTION ENDPOINTS Motor Milestone Response and CHOP INTEND Results1 Endpoint SPINRAZA-treated patients (n=52)a Sham-control patients (n=30)a 21 (40%); P<0.0001 0 (0%) 33 (63%) 1 (3%) 2 (4%) 12 (40%) Motor Milestone (HINE Section 2)a Achievement of a motor milestone response CHOP INTEND Improvement From Baselineb At least 4 points CHOP INTEND Worsening From Baseline b At least 4 points Analyses included all subjects who were alive with the opportunity for at least a 6-month (Day 183) assessment and all subjects who died or withdrew from the study at the time of the interim analysis. a Not statistically controlled for multiple comparisons at interim analysis. b • 40% (P<0.0001) of SPINRAZA-treated patients had achievement of motor milestone (HINE) response, compared with 0% in the sham-controlled group1 • 63% of SPINRAZA-treated patients had at least a 4-point CHOP INTEND improvement from baseline, compared with 3% in the sham-controlled group1 • 4% of SPINRAZA-treated patients had at least a 4-point CHOP INTEND worsening from baseline, compared with 40% in the sham-controlled group1 A significantly greater percentage of SPINRAZA-treated patients achieved a motor milestone response, as measured by HINE, compared with sham-controlled patients. 1,a IMPORTANT SAFETY INFORMATION (continued) The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see following pages for additional Important Safety Information. 5 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY KEY MOTOR FUNCTION ENDPOINTS (cont’d) Net Change From Baseline in Total Motor Milestone Score (HINE) by Percent of Subjects in the Interim Efficacy Set1,a SPINRAZA (n=52) Sham control (n=30) For subjects who were alive and ongoing in the study, the change in total motor milestone score was calculated at the later of Day 183, Day 302, or Day 394. a In a controlled study, a greater percentage of infantile-onset patients on SPINRAZA survived compared to untreated patients.1 IMPORTANT SAFETY INFORMATION (continued) Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following pages for additional Important Safety Information. 6 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES Multiple open-label uncontrolled trials were conducted across a range of patients with SMA, including presymptomatic and symptomatic patients who had or were likely to develop Type 1, 2, or 3 SMA.1 OVERALL FINDINGS • Overall findings of these open-label uncontrolled trials support the effectiveness of SPINRAZA across a range of SMA patients1 • The results of the controlled trial in infantile-onset SMA patients were supported by open-label uncontrolled trials conducted in1 • Symptomatic SMA patients who ranged in age from 30 days to 15 years at the time of first dose • Presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose • The overall findings appear to support the early initiation of treatment with SPINRAZA1 Some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so; some patients maintained milestones at ages when they would be expected to be lost and survived to ages unexpected.1 IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Please see following pages for additional Important Safety Information. 7 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY SAFETY MOST COMMON ADVERSE REACTIONS • Clinical trials are conducted under widely varying conditions; adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared with rates in clinical trials of other drugs and may not reflect the rates observed in practice1 • The data described below reflect exposure to SPINRAZA in 173 patients, including patients with presymptomatic SMA, infantile-onset SMA, and later-onset SMA1 • In the controlled study, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients; however SPINRAZA-treated patients at baseline had a higher percentage compared with sham-control patients of the following1: • Paradoxical breathing (89% vs 66%) • Pneumonia or respiratory symptoms (35% vs 22%) • Swallowing or feeding difficulties (51% vs 29%) • Requirement for respiratory support (26% vs 15%) • There was some imbalance in age at symptom onset with 88% of subjects in the SPINRAZA group and 77% in the control group experiencing symptoms within the first 12 weeks of life1 Adverse Reactions That Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or at Least 2 Times as Frequently Than in Control Patients in the Controlled Study in Infants With Symptomatic SMA1 Adverse Reactions SPINRAZA 12 mga (n=80); n (%) Sham Control (n=41); n (%) Lower respiratory infectionb 34 (43) 12 (29) Upper respiratory infectionc 31 (39) 14 (34) Constipation 24 (30) 9 (22) Teething 11 (14) 3 (7) Upper respiratory tract congestion 5 (6) 1 (2) Aspiration 4 (5) 1 (2) Ear infection 4 (5) 1 (2) Scoliosis 4 (5) 1 (2) Four loading doses followed by 12 mg (5 mL) once every 4 months. Includes pneumonia, bronchiolitis, pneumonia viral, respiratory syncytial virus bronchiolitis, lower respiratory tract infection, pneumonia bacterial, bronchitis, bronchitis viral, pneumonia moraxella, pneumonia parainfluenzae viral, lower respiratory tract infection viral, lung infection, pneumonia influenza, pneumonia pseudomonal, pneumonia respiratory syncytial viral. c Includes upper respiratory tract infection, nasopharyngitis, rhinitis, pharyngitis, or tracheitis. a b IMPORTANT SAFETY INFORMATION (continued) Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. Please see following pages for additional Important Safety Information. 8 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY MOST COMMON ADVERSE REACTIONS (cont’d) • In the controlled study, the most common adverse reactions that occurred in at least 20% of SPINRAZAtreated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection, lower respiratory infection, and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%)1 • In the open-label studies in later-onset patients, the most common adverse reactions were headache (50%), back pain (41%), and post lumbar puncture syndrome (41%), most of which occurred within 5 days following lumbar puncture1 • Other adverse events in these patients were consistent with adverse reactions observed in the controlled study1 • Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months1 • Two cases of rash were reported in patients treated with SPINRAZA. Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash1 • SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study1 LABORATORY TESTING AND MONITORING TO ASSESS SAFETY Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed1: • Platelet count • Prothrombin time; activated partial thromboplastin time • Quantitative spot urine protein testing IMPORTANT SAFETY INFORMATION (continued) The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see following pages for additional Important Safety Information. 9 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY WARNINGS AND PRECAUTIONS Thrombocytopenia and Coagulation Abnormalities • Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides1 • In a clinical study, 6 of 56 (11%) SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal, compared with 0 of 28 sham-procedure control patients. No patient had a platelet count less than 50,000 cells per microliter in this study and no patient developed a sustained low platelet count despite continued drug exposure1 • Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications1 Renal Toxicity • Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides1 • SPINRAZA is present in and excreted by the kidney. In a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared with 5 of 25 (20%) shamcontrol patients. In a group of later-onset SMA patients (mean treatment exposure 34 months), 36 of 52 (69%) had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in these studies. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/L, consider repeat testing and further evaluation1 IMPORTANT SAFETY INFORMATION (continued) Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following pages for additional Important Safety Information. 10 CONTROLLED STUDY (ENDEAR) SUPPORTIVE OPEN-LABEL UNCONTROLLED STUDIES SAFETY SUMMARY SUMMARY • Clinical trials support the effectiveness of SPINRAZA across the range of patients with SMA and appear to support the early initiation of treatment with SPINRAZA1 • In a pivotal controlled study the safety and efficacy of SPINRAZA was demonstrated in infantile-onset SMA1 • In open-label uncontrolled studies, the safety and efficacy of SPINRAZA was demonstrated in symptomatic and presymptomatic patients who had or were likely to develop Type 1, 2, or 3 SMA1 • Some patients treated with SPINRAZA — Survived to ages unexpected — Achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so — Maintained milestones at ages when they would be expected to be lost • Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides1 • Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications • Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides1 • SPINRAZA is present in and excreted by the kidney. In a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared with 5 of 25 (20%) sham-control patients • In the controlled study, the most common adverse reactions that occurred in at least 20% of SPINRAZAtreated patients and occurred at least 5% more frequently than in control patients were1 • Upper respiratory infection • Lower respiratory infection • Constipation IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Please see following page for additional Important Safety Information. 11 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. 12 References: 1. SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen; December, 2016. 2. U.S. FDA approves Biogen’s SPINRAZA™ (nusinersen), the first treatment for spinal muscular atrophy [news release]. Boston, MA: Biogen; December 23, 2016. http://media. biogen.com/press-release/neurodegenerative-diseases/ us-fda-approves-biogens-spinraza-nusinersen-first-treatment. Accessed December 23, 2016. 3. Finkel R, Bertini E, Muntoni F, et al; ENMC SMA Workshop Study Group. 209th ENMC International Workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7–9 November 2014, Heemskerk, the Netherlands. Neuromuscul Disord. 2015;25(7):593-602. 4. Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743-766. 5. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-161. Please see full Prescribing Information for additional Important Safety Information. © 2016 Biogen. All rights reserved. 12/16 SPZ-US-0128 TIPS TO SUCCESSFULLY COMPLETING A SPINRAZA START FORM Please see full Prescribing Information for additional Important Safety Information. YOUR GUIDE TO COMPLETING THE SPINRAZA™ (nusinersen) START FORM Completing the SPINRAZA Start Form provides your patient with an opportunity to join SMA360°TM, a support service from Biogen. The SPINRAZA Start Form is not a prescription and is not required for patients to begin treatment. As a reminder, Biogen’s SMA360° support provides certain services that address nonmedical barriers to access. These include logistical assistance, product education, insurance benefit investigation, and financial assistance. A complete list of the SMA360° offerings can be found at www.spinraza-hcp.com/support. SMA360° services from Biogen are available only to those who have been prescribed SPINRAZA. This guide will help you identify the key information needed to complete a SPINRAZA Start Form. SPINRAZA START FORM SECTIONS FOR YOUR PATIENTS’ PARENTS OR GUARDIANS The following sections of the SPINRAZA Start Form are reviewed and signed or checked off by the parent or guardian of your patient. Each SPINRAZA Start Form has an accompanying Patient Consent Information page that explains why this information is needed. Remember to discuss the Patient Consent Information page with the parent/guardian of your patient when he or she reviews and signs the SPINRAZA Start Form. A B C Authorization to share health information for Biogen support services and marketing/other communications Opt in for automated marketing calls and text messages Patient information INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. Please see following pages for additional Important Safety Information. 2 B:8.75” T:8.5” S:8” START FORM Phone: 1-844-4SPINRAZA (1-844-477-4672) Fax: 1-888-538-9781 AUTHORIZATION TO SHARE HEALTH INFORMATION FOR PATIENT SUPPORT SERVICES AND MARKETING/ OTHER COMMUNICATIONS I have read and understand the Authorization to Share Health Information for Patient Support Services and Marketing/Other Communications and agree to the terms. Signature of patient or parent/guardian (if under 18) Date In addition, I authorize the disclosure of my health information to the following designated individual(s) (optional): Name (print) Relationship OPT-IN FOR AUTOMATED MARKETING CALLS AND TEXT MESSAGES A Authorization to share health information for patient support services and marketing/other communications PATIENT INFORMATION First name Male Last name Female Date of birt CONTACT INFORMATION Email address Preferred Home telephone Cell phone Best time to contact Preferred Morning Afternoon The signature the in this section I haveof read and patient understandor the parent/guardian Opt-In for Automated Marketing Address authorizes the and Text Messages and hereby agree to receive these healthcareCalls providers, insurance company, and pharmacy providers to share types of communications from Biogen (optional). City State the patient’s confidential health information with Biogen. This allows Biogen Signatures/information required in order to receive Biogen services. Spanish is my primary language to forward the patient’s prescription to the dedicated specialty pharmacy, THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RECEIVE BIOGEN and will authorize the specialty pharmacy to share information with Biogen, This form is not a prescription. Please completeyour this form and fax directly to Biogen. if necessary. It also authorizes patient’s confidential health information toPRESCRIBER be shared for purposes of SMA360° support services, including financial INFORMATION FACILITY/SITE OF CARE/PLACE OF S Please complete this section if different from pres assistance. First name Last name Check box if you desire support in locating a facility/s Please note that Biogen may use this information for internal and Facility planning name City State ZIP code research. Address Address Telephone Email City The patient or parent/guardian will sign and date this section. Guardians NPI # license # ID # Facility contact name should explain theirState authority to act onTaxthe patient’s behalf. Clinic/Hospital affiliation Facility fax number Is this where the appointment/administration will take place? Site of care/POS code YES NO Physician office (11) State Facility conta NPI # Outpatien If no, please complete Facility/Site of Care/Place of Service Information section. Inpatient (21) Observation a possibility in lieu of inpa Any procedural requirements? (eg, anesthesia, sedation, etc) Ambulatory surgical center (24) Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12 Last name Date of symptom onset: Office contact name Signing Section A of the SPINRAZASpecialty Start Form enrolls your patient in SMA360°, which provides extra Group #to those support services and resources, asOffice needed. SMA360° services from Biogen are only available contact telephone Office fax number Preferred method of contact Telephone Email Fax who have been prescribed SPINRAZA. Policyholder’s first name Primary insurance Best time to contact Morning Other MEDICAL INSURANCE INFORMATIO Who is the physician administering treatment? First name Outpatient on campus (ie. infusion, short stay, surgica Afternoon ADMINISTRATION PLAN Please provide all details concerning dosing schedule (ie, number of loading doses, maintenance doses). IMPORTANT SAFETY INFORMATION (continued) Date(s) of Loading Dose(s) Policy # Insurance co Policyholder Secondary insurance Policy/group Medicaid/governmental payer *Please reme of insurance PRESCRIBER AUTHORIZATION I authorize as my designated agent on behalf o In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels atBiogen baseline information on this form to his/her insurer. 1st loading dose 2nd loading dose 3rd loading dose 4th loading dose developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. I will either administer treatment or supervise the treatme Date(s) of Maintenance Dose(s) (if applicable) No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count Prescriber signature despite continued drug exposure. Next scheduled maintenance dose Previous maintenance dose Signature stamps not acceptable. Special instructions Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some 12/16 SPZ-US-0169 antisense oligonucleotides. SPINRAZA is present in and excretedSMUS16CDNY6408_SPINRAZA_Start_Form_r32.indd by the kidney. In a clinical 1study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. Please see following pages for additional Important Safety Information. 3 OTHER COMMUNICATIONS First name I have read and understand the Authorization to Share Health Information for Patient Support Services and Marketing/Other Communications and agree to the terms. Signature of patient or parent/guardian (if under 18) Male CONTACT INFORMATION Date In addition, I authorize the disclosure of my health information to the following designated individual(s) (optional): Name (print) Email address Home telephone Relationship Cell phone OPT-IN FOR AUTOMATED MARKETING CALLS AND TEXT MESSAGES Best time to contact I have read and understand the Opt-In for Automated Marketing Calls and Text Messages and hereby agree to receive these types of communications from Biogen (optional). Opt in for automated marketing calls and text messages Phone: 1-888-4-SPINRAZA (477-4672) Fax: 1-888-538-9781 AUTHORIZATION TO SHARE HEALTH INFORMATION FOR PATIENT SUPPORT SERVICES AND MARKETING/ OTHER COMMUNICATIONS I have read and understand the Authorization to Share Health Information for Patient Support Services and Marketing/Other Communications and agree to the terms. Signature of patient or parent/guardian (if under 18) Date In addition, I authorize the disclosure of my health information to the following designated individual(s) (optional): Parent/guardian (print name) City Relationship OPT-IN FOR AUTOMATED MARKETING CALLS AND TEXT MESSAGES I have read and understand the Opt-In for Automated Marketing Calls and Text Messages and hereby agree to receive these types of communications from Biogen (optional). C Signatures/information required in order to receive Biogen services. Patient information Spanish is my primary language THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RE The patient’s parent/guardian should check the optional box in Section B This form is not a prescription. Please complete this form and fax directly to Biogen. ifT:8.5” they consent to receive auto dialed and prerecorded marketing calls and S:8”PRESCRIBER INFORMATION text messages from SMA360°, Biogen, and companies working FACILITY/SITE with Biogen. OF CARE/P B:8.75” Please complete this section if differ First name TART FORM Morning Address Signatures/information required in order to receive Biogen services. B Female Last name Check box if you desire support in loc Address Facility name City PATIENT INFORMATION Telephone ZIP code Address Email First name NPI # Male State City Last name State license # Female Tax ID # Date of birth Facility contact name CONTACT INFORMATION Clinic/Hospital affiliation Facility fax number Is this where the appointment/administration will take place? Site of care/POS code Email address YES Physician office (11) NO Preferred number OK to leave message Home telephone If no, please complete Facility/Site of Care/Place of Service Information section. Preferred number OK to leave message phone AnyCell procedural requirements? (eg, anesthesia, sedation, etc) Best time to contact Morning Afternoon Inpatient (21) Observation a possibil Outpatient on campus (ie. infusion, sh Ambulatory surgical center (24) Evening MEDICAL INSURANCE INF Address Who is the physician administering treatment? City State First name Spanish is my primary language Specialty Last name Primary diagnosis: ICD-10 G12.0, G12.1 ZIP code Date of symptom onset: Primary insurance Office contact name THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RECEIVE BIOGEN SERVICES. section includes Office contact telephone s form is not a prescription. Please complete this form and fax directly to Biogen. This RESCRIBER INFORMATION t name Last name ADMINISTRATION PLAN dress Medicaid/governmental payer Please provide all details concerning dosing schedule (ie, number of loading Email # State license # Tax ID # 1st loading dose Facility contact name 2nd loading dose 3rd loading dose Facility contact telephone 4th loading dose Date(s) of Maintenance Dose(s) (if applicable) Facility fax(continued) number IMPORTANT SAFETY INFORMATION T:11” ephone ZIP code B:11.25” State Facility name The patient’s parent/guardian completes this section. Your practice or doses, maintenance doses). Address facility should review what the parent/guardian completed with PRESCRIBER him or her AUTHORIZAT Date(s) of Loading Dose(s) to ensure accuracy. I authorize Biogen as my designated ag City State ZIP code S:10.5” y nic/Hospital affiliation Group # basic information that will familiarize Biogen with Office fax number your patient. gender, of birth, name, address, email address, Preferred methodItofincludes contact Telephone Email Fax Policyholder’s first name FACILITY/SITE OF CARE /PLACEdate OF SERVICE (POS) Besttelephone time tocomplete contact numbers, Afternoon Please this section ifMorning different fromas prescriber information. and as well preference for the best time to reach Secondary insurance Check box ifparent/guardian. you desire support in locating a facility/site of care /place of service. the patient’s information on this form to his/her insur I will either administer treatment or supe NPI # Prescriber signature NextSite scheduled maintenance dose Previous maintenance dose of C care/POS code or cystatin were observed in studies with SPINRAZA. Conduct quantitative Signature stamps not acceptable. office (11) Outpatient off-campus clinic (19) YES NO SpecialPhysician instructions spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of Inpatient (21) Observation a possibility in lieu of inpatient admission? Yes No o, please complete Facility/Site of Care /Place of Service Information section. SPINRAZA. For urinary protein concentration >0.2 repeat testing 12/16 SPZ-US-0169 Outpatient on g/L, campusconsider (ie. infusion, short stay, surgical suite) (22) and further evaluation. No elevations inwillserum creatinine his where the appointment/administration take place? y procedural requirements? (eg, anesthesia, sedation, etc) Ambulatory surgical center (24) Other Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for MEDICAL INSURANCE INFORMATION 14 months. SMUS16CDNY6408_SPINRAZA_Start_Form_r32.indd 1 o is the physician administering treatment? t name Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12.9 Date of symptom onset: Cases of rash were reported in patients treated with SPINRAZA. Last name Primary insurance Policy # Secondary insurance Policy/group # Office contact name SPINRAZA may cause a reduction in growth as measured by height when # tofaxinfants, as suggested byGroup observations from the Insurance company telephone fice contact telephoneadministered Office number controlled Policyholder’s first name Policyholder’s last name ferred method of contact Telephone studyEmail Fax ecialty t time to contact Morning Afternoon DMINISTRATION PLAN see following pages for additional Important Safety Information. Please ase provide all details concerning dosing schedule (ie, number of loading ses, maintenance doses). 4 Dose(s) te(s) of Loading Medicaid/governmental payer PRESCRIBER AUTHORIZATION I authorize Biogen as my designated agent and on behalf of my patient to forward the above statement of medical necessity and furnish any information on this form to the insurer of the above-named patient. Patient Section Quick Tips Here is a checklist of the key sections of the SPINRAZA Start Form to be signed or checked off by patients’ parents or guardians Section A ignature for sharing of the patient’s confidential health information between your office, the S insurance company, SMA360°, Biogen, and other companies working with Biogen (such as a specialty pharmacy) Section B Check to opt in for automated marketing calls and text messages Section C Complete contact information to familiarize Biogen with the patient SPINRAZA START FORM SECTIONS FOR PRACTICES OR FACILITIES TO COMPLETE The following sections of the SPINRAZA Start Form should be completed by your practice or facility: 1 2 3 4 5 Prescriber information Administration plan Facility/site of care/place of service (POS) Medical insurance information Prescriber authorization IMPORTANT SAFETY INFORMATION (continued) The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see following pages for additional Important Safety Information. 5 OPT-IN FOR AUTOMATED MARKETING CALLS AND TEXT MESSAGES I have read and understand the Opt-In for Automated Marketing Calls and Text Messages and hereby agree to receive these types of communications from Biogen (optional). Signatures/information required in order to receive Biogen services. Cell phone Best time to contact Morning Afternoon Address City State Spanish is my primary language THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RECEIVE BIOGEN This form is not a prescription. Please complete this form and fax directly to Biogen. PRESCRIBER INFORMATION First name FACILITY/SITE OF CARE /PLACE OF S Please complete this section if different from pres Last name Check box if you desire support in locating a facility/s Address Facility name City State Telephone Email ZIP code City State Facility contact name Facility conta Clinic/Hospital affiliation Facility fax number NPI # Is this where the appointment/administration will take place? Site of care/POS code NPI # YES State license # Tax ID # NO If no, please complete Facility/Site of Care /Place of Service Information section. Any procedural requirements? (eg, anesthesia, sedation, etc) Prescriber information Outpatient on campus (ie. infusion, short stay, surgica Other Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12 Last name Specialty Office contact name Office contact telephone Office fax number Best time to contact Outpatien Inpatient (21) Observation a possibility in lieu of inpa MEDICAL INSURANCE INFORMATIO First name Preferred method of contact Physician office (11) Ambulatory surgical center (24) Who is the physician administering treatment? 1 Address Telephone Email Morning Afternoon Date of symptom onset: Fax ADMINISTRATION PLAN Primary insurance Policy # Group # Insurance co Policyholder’s first name Policyholder Secondary insurance Policy/group Medicaid/governmental payer Please provide all details concerning dosing schedule (ie, number of loading The prescribing physician completes this section. This may or may not be the doses, maintenance doses). PRESCRIBER AUTHORIZATION same person who administers the injection. Please include your email address Date(s) of Loading Dose(s) I authorize Biogen as my designated agent and on beh and all information requested. the above statement of medical necessity and furnish an 1st loading dose 2nd loading dose 3rd loading dose 4th loading dose to the insurer of the above-named patient. I will either administer treatment or supervise the treatme If “yes” is checked for the question that asks if the appointment/administration Date(s) of Maintenance Dose(s) (if applicable) will take place at the prescriber’s practice or facility, the prescriber information Prescriber signature scheduled maintenance dose location Previous maintenance dose is Next assumed to be the where the treatment will beSignature administered. If you stamps not acceptable. Special plan toinstructions administer treatment at a location other than the information provided, 11/16 SPZ-US-0169 please check “no” and complete the section Facility/Site of Care/Place of Service on the top right portion of the Start Form (see page 7 of this guide for more information). SMUS16CDNY6408_SPINRAZA_Start_Form_r18.indd 1 At the bottom of the Prescriber Information section, please provide information about the healthcare professional who will administer treatment. Even if you are both the prescriber and administering physician, please complete the form. IMPORTANT SAFETY INFORMATION (continued) Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see following pages for additional Important Safety Information. 6 MEDICAL INSURANCE INFORMATIO B:8.75” T:8.5” S:8” RT FORM Phone: 1-888-4-SPINRAZA (477-4672) Fax: 1-888-538-9781 THORIZATION TO SHARE HEALTH INFORMATION R PATIENT SUPPORT SERVICES AND MARKETING/ HER COMMUNICATIONS ve read and understand the Authorization to Share Health Information Patient Support Services and Marketing/Other Communications and ee to the terms. ature of patient or parent/guardian (if under 18) Date ddition, I authorize the disclosure of my health information to the owing designated individual(s) (optional): 2 nt/guardian (print name) Relationship PT-IN FOR AUTOMATED MARKETING CALLS AND XT MESSAGES Administration have read and understand the Opt-In for Automated Marketing alls and Text Messages and hereby agreeplan to receive these types of ommunications from Biogen (optional). natures/information required in order to receive Biogen services. Who is the physician administering treatment? Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12 First name Last name Date of symptom onset: Specialty Office contact name Primary insurance Policy # Group # Insurance co Office contact telephone Office fax number Preferred method of contact Best time to contact Telephone Email Morning Fax Afternoon PATIENT INFORMATION ADMINISTRATION PLAN First name Last name Please provide all details concerning dosing schedule (ie, number of loading doses, maintenance doses). Male Female Date(s) of Loading Dose(s) CONTACT INFORMATION 1st loading dose 2nd loading dose Special instructions Cell phone Best time to contact 12/16 SPZ-US-0169 Morning Policyholder Secondary insurance Policy/group Medicaid/governmental payer *Please reme of insurance PRESCRIBER AUTHORIZATION Date of birth 3rd loading dose 4th loading dose I authorize Biogen as my designated agent on behalf o information on this form to his/her insurer. I will either administer treatment or supervise the treatme Date(s) of Maintenance Dose(s) (if applicable) Email address Home telephonemaintenance dose Next scheduled Policyholder’s first name Preferred number OK to leave message Previous maintenance dose Preferred number OK to leave message Afternoon Evening Prescriber signature Signature stamps not acceptable. Address Administration of SPINRAZA1 requires 4 loading doses followed by SMUS16CDNY6408_SPINRAZA_Start_Form_r32.indd City State ZIP code maintenance doses every 4 months. Please provide information about Spanish is my primary language the proposed dates of future doses. THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RECEIVE BIOGEN SERVICES. m is not a prescription. Please complete this form and fax directly to Biogen. CRIBER INFORMATION me FACILITY/SITE OF CARE /PLACE OF SERVICE (POS) Please complete this section if different from prescriber information. Last name Check box if you desire support in locating a facility/site of care /place of service. s Facility name State Tax ID # ospital affiliation where the appointment/administration will take place? NO ease complete Facility/Site of Care /Place of Service Information section. 3 cedural requirements? (eg, anesthesia, sedation, etc) Facility/ site of care/POS he physician administering treatment? me Last name y Office contact name ontact telephone Office fax number Telephone d method of contact Morning e to contact INISTRATION PLAN Email Afternoon Fax provide all details concerning dosing schedule (ie, number of loading maintenance doses). State ZIP code Facility contact name Facility contact telephone Facility fax number NPI # T:11” State license # City B:11.25” Email Address S:10.5” ne ZIP code Site of care/POS code Physician office (11) Outpatient off-campus clinic (19) Inpatient (21) Observation a possibility in lieu of inpatient admission? Yes No Outpatient on campus (ie. infusion, short stay, surgical suite) (22) Ambulatory surgical center (24) Other MEDICAL INSURANCE INFORMATION Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12.9 Date of symptom onset: the facility/site of care/POS information if your contact Please complete details are different from the prescriber information. It is important to Primary insurance Policy # provide a contact name and number for the facility where SPINRAZA should Group # Insurance company telephone be delivered. Policyholder’s first name Policyholder’s last name In addition, please provide details about your facility by checking the box Secondary insurance the POS code. Policy/group # that indicates It is also important to note if observation of your patient is apayer possibility in lieu of inpatient admission. Medicaid/governmental PRESCRIBER AUTHORIZATION I authorize Biogen as my designated agent and on behalf of my patient to forward IMPORTANT SAFETY INFORMATION (continued) the above statement of medical necessity and furnish any information on this form ) of Loading Dose(s) to the insurer of the above-named patient. 3rd loading dose 4th loading dose Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some I will either administer treatment or supervise the treatment accordingly. antisense oligonucleotides. ) of Maintenance Dose(s) (if applicable) ing dose 2nd loading dose Prescriber signature Date maintenancein dose SPINRAZAPrevious is present and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had Signature stamps not acceptable. elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. heduled maintenance dose instructions PZ-US-0169 No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose NY6408_SPINRAZA_Start_Form_r18.indd 1 11/9/16 1:22 PM of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Please see following pages for additional Important Safety Information. 7 Facility fax number NPI # OF SERVICE (POS) FACILITY/SITE OF CARE/PLACE where the appointment/administration will take place? me Last name NO ease complete Facility/Site of Care/Place of Service Information section. State sedation, etc) ZIP code ocedural requirements? (eg, anesthesia, State license # me Please complete this section if different from prescriber information. Site of care/POS code Check box if you desire support in locating a facility/site of care/place of service. Physician office (11) Outpatient off-campus clinic (19) Inpatient (21) Observation a possibility in lieu of inpatient admission? Yes Facility name Outpatient on campus (ie. infusion, short stay, surgical suite) (22) Ambulatory surgical center (24) Address MEDICAL INSURANCE City Email the physician administering treatment? Tax ID # Last name Facility contact telephone Other INFORMATION* State ZIP code Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12.9 Facility contact name Facility contact telephone Date of symptom onset: ospital affiliation y Office contact name Facility fax number Primary insurance NPI # Policy # ontact NOtelephone Office fax number Group # Physician office (11) Insurance company telephone Outpatient off-campus clinic (19) where the appointment/administration will take place? d method of contact Email Information Faxsection. ease complete Facility/SiteTelephone of Care/Place of Service e to contact Morning Afternoon ocedural requirements? (eg, anesthesia, sedation, etc) 4 INISTRATION PLAN provide all details concerning dosing schedule (ie, number of loading the physician administering treatment? maintenance doses). ) of Loading Dose(s) me y dose ing 2nd loading dose Medical insurance Office contactdose name 3rd loading 4th loading dose information Last name )ontact of Maintenance telephone Dose(s) (if applicable) Office fax number d method of contact Telephone heduled maintenance dose e to contact Morning instructions Email Fax Previous maintenance dose Afternoon INISTRATION PLAN PZ-US-0169 provide all details concerning dosing schedule (ie, number of loading maintenance doses). )NY6408_SPINRAZA_Start_Form_r32.indd of Loading Dose(s) 1 ing dose 3rd loading dose 2nd loading dose 4th loading dose Previous maintenance dose nstructions 5 PZ-US-0169 Prescriber authorization NY6408_SPINRAZA_Start_Form_r32.indd 1 Site of care/POS code Inpatient (21) Observation a possibility in lieu of inpatient admission? Yes Policyholder’s first name Policyholder’s last name Outpatient on campus (ie. infusion, short stay, surgical suite) (22) Secondary insurance Ambulatory surgical center (24) No Policy/group # Other *Please remember to fax front and back copy Medicaid/governmental payer of insurance card(s) along with this Start Form. MEDICAL INSURANCE INFORMATION* Primary diagnosis: ICD-10 G12.0, G12.1, G12.8, or G12.9 Date of symptom onset: PRESCRIBER AUTHORIZATION I authorize Biogen as my designated agent on behalf of my patient to furnish any This section beinsurer. completed in addition to sending a faxed copy of information on thisshould form to his/her Primary insurance Policy # the front and back oforthe covered patient’s I will either administer treatment supervise the treatment accordingly. insurance card along with the Group # Insurance company telephone SPINRAZA Start Form. Please be sure to include all forms of the patient’s Prescriber signature Policyholder’s first name insurance inname this section. Policyholder’s lastDate Signature stamps not acceptable. Secondary insurance Policy/group # Medicaid/governmental payer *Please remember to fax front and back copy of insurance card(s) along with this Start Form. PRESCRIBER AUTHORIZATION 12/22/16 5:00 PM I authorize Biogen as my designated agent on behalf of my patient to furnish any information on this form to his/her insurer. I will either administer treatment or supervise the treatment accordingly. ) of Maintenance Dose(s) (if applicable) heduled maintenance dose No S:10.5” ne T:11” CRIBER INFORMATION ospital affiliation B:11.25” Facility contact name 25” license # # m is not a prescription.State Please complete this form andTax faxIDdirectly to Biogen. 1” Email City State ZIP code THE FOLLOWING INFORMATION MUST BE FILLED OUT BY YOUR HEALTHCARE PROVIDER IN ORDER TO RECEIVE BIOGEN SERVICES. 0.5” ne Prescriber signature Signature stamps not acceptable. Date The Prescriber Authorization section is important because you will be 12/22/16 5:00 PM sharing private information with Biogen as a designated agent on behalf of the patient or parent/guardian. It further acknowledges that you are the prescriber and/or that you will supervise the administration of treatment. IMPORTANT SAFETY INFORMATION (continued) Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. Please see following pages for additional Important Safety Information. 8 START FORM SECTION CHECKLIST Here is a checklist of the key sections of the SPINRAZA Start Form to be completed Patient information that is verified by your patients’ parents or guardians Prescriber information including the physician’s information who will be administering the treatment Administration plan including date(s) of loading dose(s) and maintenance dose(s) Facility/site of care/POS, if different than your practice or facility location M edical insurance Information should include all insurance information (eg, primary/secondary insurance) completed as requested Prescriber authorization with physician signature If you have any questions about how to fill out the SPINRAZA Start Form, call SMA360° at 1-844-4SPINRAZA (1-844-477-4672), Monday through Friday, 8:30 AM to 8 PM ET, or contact your Biogen representative. IMPORTANT SAFETY INFORMATION (continued) The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see following page for additional Important Safety Information. 9 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. 10 Please see full Prescribing Information for additional Important Safety Information. © 2016 Biogen. All rights reserved. 12/16 SPZ-US-0298 Guide to Prior Authorization Submissions 1 and proprietary to Biogen. Confidential and proprietary toConfidential Biogen. Introduction to prior authorizations In certain instances, your practice or facility may need to obtain prior approval from an insurance carrier before the insurer will cover a specific drug for a patient. This request for approval is referred to as prior authorization (PA), precertification, or coverage determination. PAs are very common for orphan drugs that treat rare diseases, such as spinal muscular atrophy (SMA), because they enable insurance carriers to monitor costs and ensure that drugs are being used for appropriate patients only. For many drugs that treat rare diseases, insurance carriers may require a PA renewal after a certain period (typically 1 year). This is true regardless of whether the patient is remaining on the same treatment or transitioning to another treatment. Biogen can help your practice or facility understand the PA requirements for individual insurance carriers in your area. Call SMA360°™ at 1-844-4SPINRAZA (1-844-477-4672), or contact your Biogen representative. As a reminder, Biogen’s SMA360° support provides certain services that address nonmedical barriers to access. These include logistical assistance, product education, insurance benefit investigation, and financial assistance. A complete list of the SMA360° offerings can be found at www.spinraza-hcp.com/support. SMA360° services from Biogen are available only to those who have been prescribed SPINRAZA. SMA360° is available only in the US. INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see page 12 for additional Important Safety Information. Confidential and proprietary to Biogen. 2 Prior Authorization vs Medical Exception In situations when a drug is not on an insurance carrier’s formulary, the physician may still prescribe it if he or she requests a medical exception, or ME. These requests are typically more complex than PAs and require specific documentation, including a letter of medical necessity and more information about the patient’s medical history. Guide to Requesting a Medical Exception Guide to Requesting a Medical Exception For more information about the ME process and its requirements, refer to the Guide to Requesting a Medical Exception and the sample Letter of Medical Necessity included in this kit. Site of care for injected therapies It is important to determine the insurance carrier’s rules regarding the site of care for injected drugs. For injected therapies, determine whether the insurance carrier imposes restrictions as to where it may be administered (eg, the hospital, a separate ambulatory surgical center, or a physician’s office). How this guide can help with PA submissions To help you in understanding the submission process for a PA for a Biogen therapy, this guide will provide information on Key steps to submitting a PA Fields to complete on a PA form Confidential and proprietary to Biogen. Supporting documentation that may be required 3 Steps to completing a PA The following steps illustrate how to complete a PA. Step 1 Complete the Benefit Investigation. You will need to first complete a Benefit Investigation to determine whether your patient has insurance coverage for the prescribed drug. You will need to find out if there are any restrictions in place, determine if the insurance carrier has restrictions on where the drug can be administered or which specialty pharmacy can ship the drug, and identify patient cost-sharing requirements. Refer to the remaining steps and tips found in this guide to complete the PA process. Step 2 Complete the PA form. Review page 6 to see how supplemental documentation may increase your PA success. ake sure you have the proper PA form for that payer. PAs can be denied M simply because the wrong form has been submitted emember to fill out the form completely. PAs are often denied because R the form is missing information Confidential and proprietary to Biogen. 4 Step 3 Submit the PA form. etermine whether the information should be phoned in, faxed, emailed, or D submitted via the website to the insurance carrier. This information is often listed on the actual form F or future reference, you may want to add the insurance carrier contact information, proper submission requirements, and other tips to the Insurance Carrier Contact Sheet included in this kit eep a copy of everything your practice or facility submits with K the request. You may need to reference these documents for many reasons, including if your patient needs financial assistance services from SMA360° later on Step 4 Track the status of the PA request. It is important to keep a thorough log of the PA submissions and denials for each patient as this information will be needed if the patient wishes to apply for financial support services from SMA360° Step 5 Send additional documentation, if required. If additional documentation is requested at any point, make sure to provide it as soon as possible Did You Know? The PA process can sometimes take longer than expected. If you have questions about how long the insurance approval process is taking, contact your Biogen representative. Confidential and proprietary to Biogen. 5 Providing supplemental documentation can help to increase the chance that your patient can start therapy efficiently Each insurance carrier is unique in its requirements, so it is essential to identify the specific documents you will need before submitting a PA request. While the preferred forms of documentation may vary, here is a list of items that may be required with your submission: Completed PA form (forms vary per insurance carrier) Relevant literature Clinical patient notes and relevant patient medical history that substantiates therapy recommendation TIP Make sure to keep copies of all PA request documents and correspondence for your records. A successful PA begins with an accurate and complete form This sample form is meant to guide you as you complete a PA form. It cannot be submitted. PA forms vary by insurance carrier and may require more documentation than what is listed on this sample. Please contact the specific insurance carrier to obtain the correct PA form. Remember to fill out the insurance carrier’s PA form(s) properly and completely. Failure to do so could delay your patient’s treatment. Confidential and proprietary to Biogen. 6 This is a sample PA form for illustrative purposes only. How to fill out a PA form 123 Park Ave. • Hometown, IA • 55555 | Phone: 1-888-555-1234 Fax: 1-888-555-5678 ABC The first part of Health the PA Plan form (Section A) is typically where the sender includes relevant For Medicare Partall B— Fax: 1-888-555-9191 contact information. Multiple Sclerosis Therapy Prior Authorization Request Form All fields must be completed in their entirety and legible. Section A: Requestor Information Patient and insurance information First Name: Phone: Last Name: Fax: E-mail: Last Name: Member ID: Section B: Patient Information First Name: Address: City: State: Zip: Phone: DOB: Allergies: Is the requested medication NEW or a CONTINUATION OF THERAPY ? Start Date: / / Section C: Insurance Information Member ID #: Does patient have other coverage? Group #: If yes, provide ID#: Insured: Yes No Carrier Name: Insured: Yes Medicare: No If yes, provide ID #: Medicaid: Yes No If yes, provide ID #: Section D: Physician Information Physician Name: ABC Health Plan NPI #: 123 Park Ave. • Hometown, IA • 55555 Specialty: OR MA Provider ID #: Phone: 1-888-555-1234 Fax: 1-888-555-5678 For Medicare Part B— Fax: 1-888-555-9191 | State License: Multiple Sclerosis Therapy Prior Authorization Request Form All fields must be completed in their entirety and legible. Section A: Requestor Information First Name: Prescriber Address: City/State/Zip Suite #: Phone: ( Last Name: Phone: Fax: Section B: Patient Information E-mail: Last Name: Address: City: State: Phone: DOB: Member ID #: Group #: Diagnosis (Please be specific & provide as much information as possible): Zip: ? Start Date: / / E L P M SA Does patient have other coverage? Comorbidities Yes If yes, provide ID #: Medicaid: Carrier Name: Yes No Physician Name: Specialty: Medication: OR MA Provider ID #: NPI #: Prescriber Address: City/State/Zip Phone: ( State License: Suite #: ) Directions for use: Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): Comorbidities If yes, provide ID #: Section F: Product Information Section D: Physician Information Fax: ( ) ICD-10-CODE: – Some therapies may be covered under the medical Section G: Dispensing Provider/Administration Information benefit (ie, the same card you would use to charge Place of Administration: Dispensing Provider/Pharmacy: Patient selected choice Self Administered Physician’s for Office the office visit) Physician’s Office Retail Pharmacy Section F: Product Information Medication: No If yes, provide ID#: No ICD-10-CODE: Make sure to include all relevant patient information and ensure you are using the correct insurance card. Please note that in some instances, the patient may Strength: have separate medical and pharmacy benefit cards Allergies: or a CONTINUATION OF THERAPY Insured: Yes Medicare: ) Member ID: Section C: Insurance Information Insured: Fax: ( Section E: Diagnosis Information First Name: Is the requested medication NEW ) Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Self Administered Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Dispensing Provider/Pharmacy: Patient selected choice Physician’s Office Phone: Phone: Section H: Clinical Information Physician’s Office Specialty Office Other Name: Phone: TIN: Retail Pharmacy Mail Order Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Fax: PIN: Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History Medications Section J: Physician Signature Physician Signature: Strength Phone: Specialty Office Other Name: Phone: TIN: Phone: Mail Order Fax: Make sure to list the patient’s name exactly as it PIN: appears on the insurance card. It is important to Section H: Clinical Information Explanation of why the preferred medication(s) would not meet your patient’s needs: check for possible name changes and make sure all the documents match Dates of Therapy Reason for failure/discontinuation Date / / Section I: Patient Treatment History Medications of Therapy Reason for failure/discontinuation Check theDates appropriate box to distinguish between a new medication and a continuation of therapy Strength Section J: Physician Signature Physician Signature: Confidential and proprietary to Biogen. Date / / 7 All fields must be completed in their entirety and legible. Section A: Requestor Information First Name: Last Name: Phone: Fax: E-mail: This is a sample PA form for illustrative purposes only. Section B: Patient Information First Name: Last Name: Member ID: Address: City: State: Zip: Phone: DOB: Allergies: Is the requested medication NEW or a CONTINUATION OF THERAPY ? Start Date: / / Prescribing physician, diagnosis, and product information Section C: Insurance Information Member ID #: Does patient have other coverage? Group #: If yes, provide ID#: Insured: Yes No Carrier Name: Insured: Medicare: Yes No If yes, provide ID #: Medicaid: Yes No If yes, provide ID #: Section D: Physician Information Physician Name: Specialty: OR MA Provider ID #: NPI #: State License: Prescriber Address: Suite #: City/State/Zip Phone: ( ) Fax: ( ) Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): ICD-10-CODE: Comorbidities Section F: Product Information Medication: Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Dispensing Provider/Pharmacy: Patient selected choice Self Administered Outpatient Infusion Center Multiple Sclerosis Therapy Prior Authorization Request Form Center Name: Section A: Requestor Information Home Infusion Center Agency Name: Section B: Patient Information Administration code(s) (CPT): ABC Health Plan 123 Park Ave. • Hometown, IA • 55555 Physician’s Office Phone: Phone: 1-888-555-1234 Fax: 1-888-555-5678 For Medicare Part B— Fax: 1-888-555-9191 | All fields must be completed in their entirety and legible. First Name: Last Name: Phone: Fax: E-mail: First Name: Last Name: Member ID: Address: Phone: Section H: Clinical Information City: State: Phone: Member ID #: Allergies: ? Start Date: / Complete the physician information section. Be sure to include all identification and/or licensing information / E L P M A S Yes Does patient have other coverage? If yes, provide ID#: No Carrier Name: Insured: Yes Medicare: No If yes, provide ID #: Medicaid: Yes No If yes, provide ID #: Section D: Physician Information Physician Name: Specialty: Section I: Patient Treatment History OR MA Provider ID #: NPI #: Prescriber Address: City/State/Zip State License: Suite #: Phone: ( Medications ) Fax: ( Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): Comorbidities ) Strength Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Self Administered Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Dispensing Provider/Pharmacy: Patient selected choice Physician’s Office Phone: Section H: Clinical Information Physician’s Office Specialty Office Other Name: Phone: TIN: Retail Pharmacy Mail Order Section J: Physician Signature Phone: Fax: PIN: Physician Signature: Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History Medications Strength Dates of Therapy Reason for failure/discontinuation Provide a detailed diagnosis and ICD-10 code so the insurance carrier understands why a medication is being requested. Ensure the ICD-10 code and the language used to describe matches Date the /diagnosis / the FDA-approved indications for the drug Reason for failure/discontinuation Section J: Physician Signature Physician Signature: Dates of Therapy ICD-10-CODE: Section F: Product Information Medication: Fax: PIN: Explanation of why the preferred medication(s) would not meet your patient’s needs: or a CONTINUATION OF THERAPY Section C: Insurance Information Group #: Insured: Retail Pharmacy Mail Order Zip: DOB: Is the requested medication NEW Physician’s Office Specialty Office Other Name: Phone: TIN: Date / / It is important to list any comorbidities, as this may help provide medical rationale for the prescribed medication vs an alternate medication Include the name and dosage of the medication you want to prescribe for your patient FDA=US Food and Drug Administration; ICD-10=International Classification of Diseases, Tenth Revision. Confidential and proprietary to Biogen. 8 Medicare: Yes No If yes, provide ID #: Medicaid: Yes No If yes, provide ID #: Section D: Physician Information Physician Name: Specialty: OR MA Provider ID #: NPI #: Prescriber Address: City/State/Zip Phone: ( State License: This is a sample PA form Suite #: for illustrative purposes only. ) Fax: ( ) Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): ICD-10-CODE: Comorbidities Place ofSection administration, dispensing provider/pharmacy, F: Product Information and clinical information Medication: Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Dispensing Provider/Pharmacy: Patient selected choice Self Administered Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Physician’s Office Phone: Phone: Physician’s Office Specialty Office Other Name: Phone: TIN: Retail Pharmacy Mail Order Fax: PIN: Section H: Clinical Information Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History ABC Health Plan 123 Park Ave. • Hometown, IA • 55555 Phone: 1-888-555-1234 Fax: 1-888-555-5678 For Medicare Part B— Fax: 1-888-555-9191 | Multiple Sclerosis Therapy Prior Authorization Request Form Medications All fields must be completed in their entirety and legible. Strength Dates of Therapy Reason for failure/discontinuation Section A: Requestor Information First Name: Last Name: Phone: Fax: E-mail: Section B: Patient Information First Name: Last Name: Member ID: Address: City: State: Zip: Phone: DOB: Allergies: Is the requested medication NEW or a CONTINUATION OF THERAPY ? Start Date: / / E L P M A S Section C: Insurance Information Member ID #: Yes Does patient have other coverage? No Section J: Physician Signature Group #: If yes, provide ID#: Insured: Carrier Name: Insured: Yes Medicare: No If yes, provide ID #: Yes Physician Signature: Section D: Physician Information Physician Name: Medicaid: Suite #: Phone: ( ) Fax: ( ) Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): Comorbidities ICD-10-CODE: Section F: Product Information Medication: Date / / State License: Prescriber Address: City/State/Zip If yes, provide ID #: Specialty: OR MA Provider ID #: NPI #: No T he Place of Administration is the site of care. If your site of care is not listed, you should write it in Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Self Administered Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Dispensing Provider/Pharmacy: Patient selected choice Physician’s Office Phone: Phone: Physician’s Office Specialty Office Other Name: Phone: TIN: Retail Pharmacy Mail Order Fax: PIN: Section H: Clinical Information Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History Medications Strength Dates of Therapy Reason for failure/discontinuation F or the Dispensing Provider/Pharmacy section, make sure to use the information found from the Benefit Investigation to ensure you are listing a specialty pharmacy that is in-network Section J: Physician Signature Physician Signature: Date / / If the prescribed medication is not Preferred or Not Covered on the insurance carrier’s formulary, provide a detailed explanation describing why the preferred formulary medications are not appropriate for your patient. Use the sample Letter of Medical Necessity template included in this kit to help with your explanation. You may need to provide additional documentation, such as medical literature and the patient’s medical history Confidential and proprietary to Biogen. 9 Prescriber Address: Suite #: City/State/Zip Phone: ( ) Fax: ( ) Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): ICD-10-CODE: This is a sample PA form for illustrative purposes only. Comorbidities Section F: Product Information Medication: Strength: Directions for use: Patient treatment history and physician signature Section G: Dispensing Provider/Administration Information List any medications the patient has used for treatment. If there are no prior Dispensing Provider/Pharmacy: Patient selected choice Self Administered Physician’s Office Physician’s Office Retail Pharmacy treatments, write Phone: “none.” Review the patient’s Benefit Investigation. If the request is Outpatient Infusion Center Specialty Office Mail Order Center Name: Other of the insurance carrier’s policy, aName: letter of medical necessity may be required Phone: Homeoutside Infusion Center Place of Administration: Agency Name: Administration code(s) (CPT): Phone: TIN: Fax: PIN: Section H: Clinical Information Ensure that you sign all documentation where required Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History Medications Strength Dates of Therapy Reason for failure/discontinuation Section J: Physician Signature Physician Signature: ABC Health Plan Date 123 Park Ave. • Hometown, IA • 55555 / / Phone: 1-888-555-1234 Fax: 1-888-555-5678 For Medicare Part B— Fax: 1-888-555-9191 | Multiple Sclerosis Therapy Prior Authorization Request Form All fields must be completed in their entirety and legible. Section A: Requestor Information First Name: Last Name: Phone: Fax: E-mail: Section B: Patient Information First Name: Last Name: Member ID: Address: City: State: Zip: Phone: DOB: Allergies: E L P M A S Is the requested medication NEW or a CONTINUATION OF THERAPY ? Start Date: / / Section C: Insurance Information Member ID #: Group #: Does patient have other coverage? Yes If yes, provide ID#: Insured: No Carrier Name: Insured: Yes Medicare: No If yes, provide ID #: Medicaid: Yes No If yes, provide ID #: Section D: Physician Information Physician Name: Specialty: OR MA Provider ID #: NPI #: State License: Prescriber Address: City/State/Zip Suite #: Phone: ( ) Fax: ( ) Section E: Diagnosis Information Diagnosis (Please be specific & provide as much information as possible): Comorbidities ICD-10-CODE: Section F: Product Information Medication: Strength: Directions for use: Section G: Dispensing Provider/Administration Information Place of Administration: Self Administered Outpatient Infusion Center Center Name: Home Infusion Center Agency Name: Administration code(s) (CPT): Dispensing Provider/Pharmacy: Patient selected choice Physician’s Office Phone: Phone: Physician’s Office Specialty Office Other Name: Phone: TIN: Retail Pharmacy Mail Order Fax: PIN: Section H: Clinical Information Explanation of why the preferred medication(s) would not meet your patient’s needs: Section I: Patient Treatment History Medications Strength Dates of Therapy Reason for failure/discontinuation Section J: Physician Signature Physician Signature: Date / / Submission of improperly completed or incomplete forms is the primary reason denials occur. Make sure to read and complete the PA form carefully before submitting. Confidential and proprietary to Biogen. 10 In the case of a denial There are many reasons why an authorization may be denied. One of the main reasons PA requests are denied is incomplete or inaccurate information on the PA form. Check to ensure all information is complete and accurate. Resubmit the form if necessary. In some cases, a letter of medical necessity may be required when the PA is being resubmitted. Review the sample Letter of Medical Necessity template included in this kit. In the event that the PA request has been denied, the physician can appeal the decision by contacting the insurance carrier directly to have a peer-to-peer discussion regarding the patient, the clinical issues, and the reasons for requesting a specific drug. If a phone call is not possible, you may submit an ME request. Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier Name Phone Email For infusible products, please see the Payer Summary Reference Guide resource available from Biogen. Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links ME=medical exception; PA=prior authorization. If you work with a specific individual at the insurance carrier to handle denials of PA requests, you may want to include that individual’s contact information on the Insurance Carrier Contact Sheet in this kit for future reference Biogen can help your practice or facility understand the PA requirements for individual insurance carriers in your area. Call SMA360°™ at 1-844-4SPINRAZA (1-844-477-4672), or contact your Biogen representative. Please see the following page for additional Important Safety Information. Confidential and proprietary to Biogen. 11 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZAtreated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. Confidential and proprietary to Biogen. © 2016 Biogen. Confidential and proprietary to Biogen. All rights reserved. 12/16 SPZ-US-0299 12 Guide to Requesting a Medical Exception Confidential and proprietary to Biogen. 1 Reviewing the steps to a medical exception approval There are occasions when a treatment is not on an insurance carrier’s formulary but the physician can still prescribe it. This request for approval is called a medical exception (ME). A medical exception communicates a physician’s request to use medication due to the patient’s individual circumstances that is nonpreferred or not covered by the insurance carrier. This guide provides information and considerations for preparing a comprehensive ME package—from submitting the ME request and additional documentation to tracking the process. Steps to completing a medical exception — Benefit Investigation Complete a Benefit Investigation. STEP 1 Know what will be required for your patient to receive treatment, such as –If there is a prior authorization or other restrictions in place Guide to Prior Authorization Submissions Guide to Prior Authorization Submissions • If you have a prior authorization, refer to the Guide to Prior Authorization Submissions resource in this kit – The patient’s medical history and any related documentation – If there are restrictions around where the treatment can be administered –The patient’s copay, co-insurance, or other out-of-pocket costs Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier Name Phone Email Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links Consider recording contact information for health plans in the Insurance Carrier Contact Sheet on the flash drive in this kit for future reference For infusible products, please see the Payer Summary Reference Guide resource available from Biogen. ME=medical exception; PA=prior authorization. Confidential and proprietary to Biogen. 2 Steps to completing a medical exception — letter of medical necessity Complete the medical exception request with a letter of medical necessity, as needed. STEP 2 Completing the ME request may include a form from the insurance carrier or a separate letter from your office A common reason that MEs are denied is because there is missing or incorrect information on the form. This may delay treatment for your patient. Remember to carefully and accurately complete the ME request form. TEMPLATE Letter of Medical Necessity The Use of SPINRAZA™ (nusinersen) for Spinal Muscular Atrophy E L P M Date: [Insert Name of Medical Director] [Insurance Company] [Address] RE: Patient Name [ Policy Number [ Claim Number [ ] ] ] SA [City, State, Zip] Dear [Insurance Company]: I am writing this letter of medical necessity to provide information related to the treatment of [insert patient name] with SPINRAZA™ (nusinersen), the only US Food and Drug Administration (FDA)–approved treatment for spinal muscular atrophy (SMA). Provide any additional information and documentation. Use the sample Letter of Medical Necessity on the flash drive in this kit for support and information you may want to include with the ME request I would like to provide the following information about the potential benefits of SPINRAZA in patients with SMA: 1. SMA Pathophysiology SMA is a genetic neuromuscular disease characterized by degeneration of motor neurons in the anterior horn of the spinal cord. SMA is characterized by progressive symmetrical weakness and atrophy of the proximal voluntary muscles of legs, arms, and eventually of the entire trunk during disease progression. Infants and SPZ-US-0309 12/16 Refer to the SPINRAZA™ (nusinersen) Clinical Overview in this kit for efficacy and safety information to include in your letter of medical necessity INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Please see page 7 for additional Important Safety Information. Confidential and proprietary to Biogen. 3 An effective letter of medical necessity is tailored to your patient’s needs Be clear about your patient’s individual circumstance. The following are key considerations when writing a letter of medical necessity. Provide a background on your patient’s condition Summarize his or her clinical status citing diagnostic evidence of spinal muscular atrophy (SMA), including genetic testing If appropriate, list current supportive care management, and provide clinical evidence of the patient’s inadequate response Explain why the treatment you recommend is, in your opinion, the appropriate choice for your patient Provide a clinical justification supporting the treatment you have chosen for your patient State any patient-specific reasons for the treatment choice, such as efficacy Cite relevant literature Providing additional documentation that supports your decision may strengthen your request Details from the patient’s medical record If appropriate, general medical history listing comorbidities and any medication history Other relevant patient information may also be included, as appropriate Other documentation Letters from consultants or other healthcare professionals that support your treatment choice Clinical information regarding your treatment choice, such as the product prescribing information Confidential and proprietary to Biogen. 4 Steps to completing a medical exception— submission and tracking Determine how to submit the medical exception. STEP 3 Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier Name Phone Email Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links Determine whether the ME needs to be phoned in, faxed, emailed, or submitted via website to the insurance carrier Determine the appropriate individual to contact regarding the medical exception request For infusible products, please see the Payer Summary Reference Guide resource available from Biogen. ME=medical exception; PA=prior authorization. Consider updating the Insurance Carrier Contact Sheet with specific information related to submitting an ME for the individual insurance carrier, such as submission format (fax or email). This is included with this kit Some states have legislation that requires insurance carriers to respond to medical exception requests within a certain period of time. Contact your Biogen representative to learn whether this applies in your state. Confidential and proprietary to Biogen. 5 If the medical exception is denied There are many reasons why an ME may be denied. The most common reason is that there is inaccurate or incomplete information on the request. Carefully review the request to ensure that the information is correct and that no information has been omitted. Resubmit the request if necessary. Your Biogen representative can help you understand the process for handling an ME denial. Make sure to provide the denial number so he or she can help more quickly. If all information was complete but the ME was denied due to clinical reasons, the prescribing physician in your office may also contact the insurance carrier directly to speak with a clinical representative. This individual is typically someone with a medical background and may be called a Medical Director. A peer-to-peer discussion regarding the patient can take place that includes more detailed information about the patient’s medical history and clinical considerations as well as the reason for the requested treatment. This discussion may help the insurance carrier understand the concerns for your patient and why there is an ME request for your treatment of choice. If the healthcare provider is able to obtain the direct contact information for the clinical representative for future peer-to-peer discussion, consider tracking that information in the Insurance Carrier Contact Sheet. If you have questions about the ME process for a Biogen product, call SMA 360°™ at 1-844-4SPINRAZA (1-844-477-4672), Monday through Friday, 8:30 AM to 8 PM ET, or contact your Biogen representative. As a reminder, Biogen’s SMA360° support provides certain services that address nonmedical barriers to access. These include logistical assistance, product education, insurance benefit investigation, and financial assistance. A complete list of the SMA360° offerings can be found at www.spinraza-hcp.com/support. SMA360° services from Biogen are available only to those who have been prescribed SPINRAZA. SMA360° is available only in the US. Please see following page for additional Important Safety Information. Confidential and proprietary to Biogen. 6 INDICATION SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study, 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients, 69% had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZAtreated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Please see full Prescribing Information for additional Important Safety Information. Confidential and proprietary to Biogen. © 2016 Biogen. Confidential and proprietary to Biogen. All rights reserved. 12/16 SPZ-US-0300 7 TEMPLATE Letter of Medical Necessity The Use of SPINRAZA™ (nusinersen) for Spinal Muscular Atrophy Date: [Insert Name of Medical Director] RE: Patient Name [ ] [Insurance Company] Policy Number [ ] [Address] Claim Number [ ] [City, State, Zip] Dear [Insurance Company]: I am writing this letter of medical necessity to provide information related to the treatment of [insert patient name] with SPINRAZA™ (nusinersen), the only US Food and Drug Administration (FDA)–approved treatment for spinal muscular atrophy (SMA). I would like to provide the following information about the potential benefits of SPINRAZA in patients with SMA: 1. SMA Pathophysiology SMA is a genetic neuromuscular disease characterized by degeneration of motor neurons in the anterior horn of the spinal cord. SMA is characterized by progressive symmetrical weakness and atrophy of the proximal voluntary muscles of legs, arms, and eventually of the entire trunk during disease progression. Infants and children affected by SMA develop profound deficits in motor function and miss several 12/16 developmental milestones. SMA is among the leading genetic causes of infant mortality. 2. About SPINRAZA SPINRAZA is the first and only treatment approved by the FDA indicated for SMA in pediatric and adult patients. SPINRAZA has been studied across multiple clinical trials in patients with varying types of SMA, including presymptomatic and symptomatic infantileonset and later-onset SMA. The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. The overall findings of the controlled trial in infantile-onset SMA and the open-label uncontrolled trials support the effectiveness of SPINRAZA across the range of patients with SMA and appear to support the early initiation of treatment with SPINRAZA. 3. Rationale for Treatment [Note: Exercise your medical judgment and discretion when providing a diagnosis and characterization of the patient’s medical conditions.] In brief, based on the clinical data available to date, it is my medical opinion that initiating treatment of [patient name] with SPINRAZA is medically appropriate and necessary and the procedures required for its administration should be a covered and reimbursed service. Below, this letter outlines [patient name’s] medical history, prognoses, and the rationale for treatment with SPINRAZA (to be completed by physician based on patient medical history and prognosis). 4. Summary of Patient’s History [You may want to include]: • Patient’s diagnosis, condition, and history • Previous therapies the patient has undergone for the symptoms associated with their condition • Patient’s response to these therapies • Brief description of the patient’s recent symptoms and conditions 5. Patient’s Prognosis • Summary of your professional opinion of the patient’s likely prognosis without SPINRAZA treatment 12/16 6. Dosing Schedule SPINRAZA is administered by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Treatment begins with 4 loading doses; the first 3 loading doses should be administered at 14-day intervals, and the fourth loading dose should be administered 30 days after the third dose. A maintenance dose is administered once every 4 months thereafter. Approximate Dosing Regimen Illustration Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed: Platelet count Prothrombin time; activated partial thromboplastin time Quantitative spot urine protein testing 7. Administration of SPINRAZA In clinical trials, SPINRAZA has been administered in a hospital outpatient setting by or under the direction of a healthcare professional with experience in the lumbar puncture procedure. Administration of SPINRAZA may require additional medical procedures including sedation/anesthesia and/or imaging to aid in the lumbar puncture (eg, ultrasound). [Insert more detail lower in the letter when discussing individual patient needs as appropriate; fill in relevant services with rationale about why the services are clinically appropriate for each patient]. 8. SPINRAZA Clinical Trial Program The efficacy of SPINRAZA was demonstrated in a double-blind, shamprocedure controlled phase 3 clinical trial (ENDEAR) in 121 symptomatic infantileonset patients with SMA (symptom onset before 6 months of age). Patients were aged ≤7 months at the time of first dose, and 98% of patients had 2 copies of the SMN2 gene, mostly consistent with a clinical diagnosis of Type 1 SMA. The efficacy of 12/16 SPINRAZA was also supported by open-label clinical trials conducted in patients with presymptomatic and symptomatic infantile SMA as well as later-onset SMA. The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. 9. Summary of Clinical Trials for SPINRAZA Information about the following clinical trials for SPINRAZA is available on clinicaltrials.gov. Study ENDEAR (NCT02193074) CHERISH (NCT02292537) Phase Description 3 Randomized, sham-controlled trial in infants with SMA 3 Randomized, sham-controlled trial in children with SMA Status Positive Interim Results* Positive Interim Results* Supporting Open-Label Studies SHINE (NCT02594124) EMBRACE (NCT02462759) NURTURE (NCT02386553) CS3A (NCT01839656) CS12 (NCT02052791) CS10 (NCT01780246) CS2 (NCT01703988) CS1 (NCT01494701) 3 Open-label extension for participants in ENDEAR and CHERISH studies On-going 2 Open-label, multi-dose trial in infants and children who did not qualify for ENDEAR or CHERISH On-going 2 Open-label study in genetically diagnosed pre-symptomatic infants with SMA On-going 2 Open-label, multi-dose trial in infants with SMA to assess tolerability and pharmacokinetics Completed 2 Open-label safety and tolerability study in patients with SMA who previously participated in the CS2 or CS10 studies Completed 1 Open-label safety and tolerability study in patients with SMA who previously participated in the CS1 study Completed 1 Open-label safety, tolerability and dose-range finding study of multiple doses in patient with spinal muscular atrophy Completed 1 Open-label safety, tolerability, and dose-range finding study in patients with SMA Completed *Study stopped based on positive pre-specified interim analysis 12/16 10. Top Level Interim Efficacy Data From ENDEAR and Supportive Open-Label Studies In the interim analysis of the controlled, Phase 3 ENDEAR study in infantile-onset SMA, infants treated with SPINRAZA demonstrated a statistically and clinically significant improvement in the primary endpoint (P<0.0001), defined as the proportion of motor milestone responders as measured by the Hammersmith Infant Neurological Examination (HINE) Section 2. This endpoint evaluates 7 different areas of motor milestone development, with a maximum score between 2 and 4 points for each, depending on the milestone, and a total maximum score of 26. A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) in the ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing, or walking (consistent with improvement by at least 1 milestone). To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones than worsening. Although not statistically controlled for multiple comparisons at the interim analysis, the study also assessed treatment effects on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), which is an evaluation of motor skills in patients with infantile-onset SMA. Supportive Open-Label Studies The results of the controlled trial in infantile-onset patients with SMA (ENDEAR) were supported by open-label uncontrolled trials conducted in symptomatic patients with SMA (infantile onset and later onset) who ranged in age from 30 days to 15 years at the time of first dose, and in presymptomatic patients with SMA (infantile onset), who ranged in age from 8 days to 42 days at the time of first dose. The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. Some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so, maintained milestones at ages when they would be expected to be lost, and survived to ages unexpected, considering the number of SMN2 gene copies of patients enrolled in the studies. 11. Safety Results for ENDEAR and Supportive Open-Label Studies Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Because of the risk of thrombocytopenia and coagulation 12/16 abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared to 5 of 25 (20%) sham-control patients. The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients in ENDEAR were lower respiratory infection, upper respiratory infection, and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months. The most common adverse events in the open-label studies in later-onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Most of these events occurred within 5 days of lumbar puncture. Other adverse events in these patients were consistent with adverse reactions observed in the controlled study. Adverse reactions that occurred in at least 5% of patients treated with SPINRAZA and occurred at least 5% more frequently, or at least 2 times as frequently than in control patients, in the controlled study in infants with symptomatic SMA included Lower respiratory infection Upper respiratory infection Constipation Teething Upper respiratory tract congestion Aspiration Ear infection Scoliosis 12/16 12. Concluding Remarks [HCP to insert information relevant to particular case (eg, Given the patient’s history, his/her current condition, lack of treatment options for SMA and the emerging data of the effects of SPINRAZA in patients with SMA, I believe treatment of [insert patient name] with this product is warranted, appropriate, and medically necessary. The totality of the data available to date support the potential benefit of treatment with SPINRAZA).] Please call my office at [insert telephone number] if I can provide you with any additional information. I look forward to receiving your timely response and approval of this claim. Sincerely, [Insert Doctor name and Participating provider number] 13. References 1. Prior TW. Spinal muscular atrophy: a time for screening. Curr Opin Pediatr. 2010; 22(6):696-702. 2. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810-817. 3. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86(10):890-897. 4. Haché M, Swoboda KJ, Sethna N, et al. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J Child Neurol. 2016;31(7):899-906. 12/16 5. Finkel RS, Chiriboga CA, Vajsar J, et al. Interim results of a phase 2 clinical study of nusinersen in patients with infantile-onset spinal muscular atrophy. Lancet. 2016;688(10063):3017-3026. 6. Darras BT, Chiriboga CA, Montes J, et al. Nusinersen in treatment-naive patients with later-onset spinal muscular atrophy (SMA): efficacy results from a phase 1b/2a multicentre study (CS2) and its open-label extension (CS12). World Muscle Society Meeting, Granada Spain, October 2016. 7. Bertini E, Hwu W-L, Reyna SP, et al. Nusinersen in pre-symptomatic infants with spinal muscular atrophy (SMA): interim efficacy and safety results from the phase 2 nurture study. World Muscle Society Meeting, Granada Spain, October 2016. 8. Kuntz N, Farwell W, Zhong ZJ, et al. Nusinersen treatment of infantile-onset spinal muscular atrophy (SMA): study design and initial interim efficacy and safety findings from the phase 3 ENDEAR study. World Muscle Society Meeting, Granada Spain, October 2016. 9. SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen; December 2016. 12/16 Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier Name Phone Email Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links ME=medical exception; PA=prior authorization. Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier Name Phone Email Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links ME=medical exception; PA=prior authorization. Insurance Carrier Contact Sheet The Insurance Carrier Contact Sheet resource will enable you to capture key contact information and related processes for payers. Insurance Carrier © 2016 Biogen. Name All rights reserved. Phone 12/16 Email SMA-US-0183 Contact Role Dept. Additional Notes Preference for PA and/or ME Submissions Phone Fax Email Other Relevant Web Links ME=medical exception; PA=prior authorization. UNDERSTANDING MEDICAL BENEFIT AND PHARMACY BENEFIT INSURANCE CARDS Knowing which insurance card to use on Biogen patient start forms may help patients receive Biogen support services quickly If you are prescribing a specialty drug, you may be required to fill out a Biogen patient start form to allow your patients to access services. Correctly completing the patient insurance information on the form can help ensure the request is processed by the specialty distributor/pharmacy and the insurance company in a timely manner so that patients can receive Biogen support services more quickly. It’s important to know that prior authorizations may be denied due to incomplete or insufficient prescription information, not because the patient does not have coverage for the drug. A specialty drug may be covered by a medical or a pharmacy benefit, depending on the type of medication and how it’s administered1 edical benefits generally cover drugs that are injected or infused by a healthcare professional in the M doctor’s office, infusion center, or hospital outpatient center P harmacy benefits generally cover drugs that are self-administered orally, by injection, or inhaled 1 card vs 2 cards Pharmacy vs medical benefits can be determined based on the insurance cards. Here’s how: card for both medical and pharmacy benefits. Health plans may combine the medical and pharmacy 1 benefit into 1 program. The patient will have 1 insurance card that includes member identification information (eg, group number and member “ID”) for both the medical and pharmacy benefit. The card may also include copay or coinsurance costs for doctor office, specialist, and emergency room (ER) visits. Insurance cards for both benefits typically note the pharmacy benefit with terms such as “prescription” or “Rx” •2 cards—1 card for the medical benefit and 1 card for the pharmacy benefit. Health plans may use a third-party provider for the pharmacy benefit, such as a pharmacy-benefit manager or PBM. In this instance, the patient will have 1 card for the medical benefit that does not include pharmacy benefit information. The patient will have a different insurance card for the pharmacy benefit information Biogen patient start forms for specialty drugs may ask for medical and pharmacy benefit information. It is important to complete Biogen patient start forms with information for both benefits when required. This will provide the specialty distributor/pharmacy that is supplying the drug with the information needed to verify the benefit. Before a patient leaves the office, check the medical insurance card information to determine if you also need to obtain the pharmacy benefit information from a different card. It is important to review the patient’s insurance cards carefully to confirm that you are using the proper card (medical or pharmacy) when completing Biogen patient start forms or applying for claim reimbursement. COMMERCIAL INSURANCE CARDS If your patient has commercial insurance, they will most likely be covered in one of the following ways: Medical and pharmacy benefits with one carrier: 1 card Health Star Insurance Comet Employer Group Member Name John Doe Dependent Name Jane Doe Copays/Coinsurance Primary Care $20 Specialist $40 Urgent Care $40 ER $100 Member ID EXP000099900 Group No. 32155-000 Effective Date 11/01/11 Plan STANDARD/OPTION Patient copays for office and ER visits indicate the medical benefit The Rx symbol indicates that the pharmacy benefit is included on this card Rx For illustrative purposes only. Medical benefits with a health plan, pharmacy benefits with a PBM: 2 cards ProVantage Health Insurance Preferred Provider Network MEMBER NAME John Q Proof MEMBER ID ABC101202303 GROUP Plan PBMJ63 123456 Benefit Rx Prevention Primary Care Specialist $0 $25 $45 Prescription Card JOHN Q PROOF ID 123456789 RXBIN:610029 RXPCN:CRK RXGRP: CMCDX Issuer:80840 Patient copays indicate the medical benefit There is no prescription information on this card, which means that the patient has a separate pharmacy benefit card Card is labeled for prescription, so it’s a pharmacy benefit card 10000 Rx identification numbers indicate the pharmacy benefit information For illustrative purposes only. Before your patient leaves the office, remember to obtain all of the benefit information from both the medical and pharmacy cards so that Biogen patient start forms can be filled out completely and quickly. If you do not see “prescription” or “Rx” indicated on a patient’s insurance card, it’s a medical-benefit–only card. USING THE APPROPRIATE INSURANCE CARD MAY HELP PATIENTS START THERAPY MORE EFFICIENTLY Tips to help your office For commercial and Medicaid patients, some patients have 1 card and some patients have 2 cards If the patient’s medical insurance card does not have “prescription,” “Rx,” or other similar terms that indicate that the pharmacy benefit is included, you will need to gather the pharmacy benefit information from a separate card emember to check the Biogen patient start form before the patient leaves the office to confirm R that you have the required insurance information (medical and pharmacy) on file onfirming that the prescription information on the Biogen patient start form is correct at the C beginning may eliminate unnecessary administrative work or callbacks rior authorizations may be denied due to incomplete or insufficient information, not because P the patient does not have coverage for the drug Reference: 1. Midwest Business Group on Health. Managing the rising costs of specialty pharmacy. January 29, 2014. http://ehcark.org/site/1747ehca/EHC_Arkansas_FINAL_012914.ppt. Accessed November 17, 2016. © 2016 Biogen. All rights reserved. 12/16 SMA-US-0181 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SPINRAZA™ safely and effectively. See full prescribing information for SPINRAZA. SPINRAZA (nusinersen) injection, for intrathecal use Initial U.S. Approval: 2016 __________________ INDICATIONS AND USAGE _________________ SPINRAZA is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients (1) Laboratory Testing and Monitoring to Assess Safety (2.3) • At baseline and prior to each dose, obtain a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing _____________ DOSAGE FORMS AND STRENGTHS ______________ Injection: 12 mg/5 mL (2.4 mg/mL) in a single-dose vial (3) ___________________ CONTRAINDICATIONS ___________________ None. _______________ WARNINGS AND PRECAUTIONS _______________ • _______________DOSAGE AND ADMINISTRATION ______________ SPINRAZA is administered intrathecally (2.1) • Dosing Information (2.1) • The recommended dosage is 12 mg (5 mL) per administration • Initiate SPINRAZA treatment with 4 loading doses; the first three loading doses should be administered at 14-day intervals; the 4th loading dose should be administered 30 days after the 3rd dose; a maintenance dose should be administered once every 4 months thereafter Important Preparation and Administration Instructions (2.2) • Allow to warm to room temperature prior to administration • Administer within 4 hours of removal from vial • Prior to administration, remove 5 mL of cerebrospinal fluid • Administer as intrathecal bolus injection over 1 to 3 minutes Thrombocytopenia and Coagulation Abnormalities: Increased risk for bleeding complications; testing required at baseline and before each dose (5.1, 2.3) Renal Toxicity: Quantitative spot urine protein testing required at baseline and prior to each dose (5.2, 2.3) ___________________ ADVERSE REACTIONS ___________________ The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection, upper respiratory infection, and constipation (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 2 3 4 5 6 8 INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Important Administration Instructions 2.3 Laboratory Testing and Monitoring to Assess Safety DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Thrombocytopenia and Coagulation Abnormalities 5.2 Renal Toxicity ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 11 12 13 14 16 17 8.5 Geriatric Use DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1 Clinical Trial in Infantile-Onset SMA HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Recommended Dosage The recommended dosage is 12 mg (5 mL) per administration. Initiate SPINRAZA treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter. Missed Dose If a loading dose is delayed or missed, administer SPINRAZA as soon as possible, with at least 14-days between doses and continue dosing as prescribed. If a maintenance dose is delayed or missed, administer SPINRAZA as soon as possible and continue dosing every 4 months. 2.2 Important Preparation and Administration Instructions SPINRAZA is for intrathecal use only. Prepare and use SPINRAZA according to the following steps using aseptic technique. Each vial is intended for single dose only. Preparation • • • • • Store SPINRAZA in the carton in a refrigerator until time of use. Allow the SPINRAZA vial to warm to room temperature (25o C/77o F) prior to administration. Do not use external heat sources. Inspect the SPINRAZA vial for particulate matter and discoloration prior to administration. Do not administer SPINRAZA if visible particulates are observed or if the liquid in the vial is discolored. Withdraw 12 mg (5 mL) of SPINRAZA from the single-dose vial into a syringe and discard unused contents of the vial. Administer SPINRAZA within 4 hours of removal from vial. Administration • Consider sedation as indicated by the clinical condition of the patient. • • • 2.3 Consider ultrasound or other imaging techniques to guide intrathecal administration of SPINRAZA, particularly in younger patients. Prior to administration, remove 5 mL of cerebrospinal fluid. Administer SPINRAZA as an intrathecal bolus injection over 1 to 3 minutes using a spinal anesthesia needle [see Dosage and Administration (2.1)]. Do not administer SPINRAZA in areas of the skin where there are signs of infection or inflammation. Laboratory Testing and Monitoring to Assess Safety Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed [see Warnings and Precautions (5.1, 5.2)]: • Platelet count • Prothrombin time; activated partial thromboplastin time • Quantitative spot urine protein testing 3 DOSAGE FORMS AND STRENGTHS Injection: 12 mg/5 mL (2.4 mg/mL) nusinersen as a clear and colorless solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Thrombocytopenia and Coagulation Abnormalities Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. In a clinical study, 6 of 56 (11%) SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal, compared to 0 of 28 sham-procedure control patients. No patient had a platelet count less than 50,000 cells per microliter in this study and no patient developed a sustained low platelet count despite continued drug exposure. Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. 5.2 Renal Toxicity Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney [see Clinical Pharmacology (12.3)]. In a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared to 5 of 25 (20%) sham-control patients. In a group of lateronset SMA patients (mean treatment exposure 34 months), 36 of 52 (69%) had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in these studies. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/L, consider repeat testing and further evaluation. 6 ADVERSE REACTIONS The following serious adverse reactions are described in detail in other sections of the labeling: 6.1 • Thrombocytopenia and Coagulation Abnormalities [see Warnings and Precautions (5.1)] • Renal Toxicity [see Warnings and Precautions (5.2)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. The data described below reflect exposure to SPINRAZA in 173 patients (50% male, 82% Caucasian), including 120 exposed for at least 6 months and 83 exposed for at least 1 year. The safety of SPINRAZA was studied in infants with symptomatic SMA, approximately 1 month to 8 months of age at study entry; in a sham-controlled trial (n=80 for SPINRAZA, n=41 for control); in open-label studies in presymptomatic and symptomatic infants (n=37), and in openlabel studies in later onset patients (n=56, 2 to 15 years of age at study entry). In the controlled study in symptomatic infants, 41 patients were exposed for at least 6 months and 19 patients were exposed for at least 12 months. In the controlled study, baseline disease characteristics were largely similar in the SPINRAZAtreated patients and sham-control patients except that SPINRAZA-treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%) and requirement for respiratory support (26% vs 15%). In the controlled study, the most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection, upper respiratory infection, and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. Table 1. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients in the Controlled Study in Infants with Symptomatic SMA SPINRAZA 12 mg1 Sham-Procedure Control N=80 N=41 % % Lower respiratory infection2 43 29 Upper respiratory infection3 39 34 Constipation 30 22 Teething 14 7 Upper respiratory tract congestion 6 2 Aspiration 5 2 Ear infection 5 2 Scoliosis 5 2 Adverse Reactions 1 Four loading doses followed by 12 mg (5 mL) once every 4 months Includes pneumonia, bronchiolitis, pneumonia viral, respiratory syncytial virus bronchiolitis, lower respiratory tract infection, pneumonia bacterial, bronchitis, bronchitis viral, pneumonia moraxella, pneumonia parainfluenzae viral, lower respiratory tract infection viral, lung infection, pneumonia influenza, pneumonia pseudomonal, pneumonia respiratory syncytial viral 3 Includes upper respiratory tract infection, nasopharyngitis, rhinitis, pharyngitis, or tracheitis 2 In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. One patient, 8 months after starting SPINRAZA treatment, developed painless red macular lesions on the forearm, leg, and foot over an 8-week period. The lesions ulcerated and scabbed over within 4 weeks, and resolved over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of SPINRAZA treatment, which resolved over 3 months. Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment. The most common adverse events in the open-label studies in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%). Most of these events occurred within 5 days of lumbar puncture. Other adverse events in these patients were consistent with adverse reactions observed in the controlled study. 6.2 Immunogenicity The immunogenic response to nusinersen was determined in 126 patients with baseline and postbaseline plasma samples evaluated for anti-drug antibodies (ADAs). Five (4%) patients developed treatment-emergent ADAs, of which 3 were transient and 2 were considered to be persistent. There are insufficient data to evaluate an effect of ADAs on clinical response, adverse events, or the pharmacokinetic profile of nusinersen. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to SPINRAZA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of SPINRAZA in pregnant women. No adverse effects on embryofetal development were observed in animal studies in which nusinersen was administered by subcutaneous injection to mice and rabbits during pregnancy (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When nusinersen (0, 3, 10, or 25 mg/kg) was administered subcutaneously to male and female mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on embryofetal development were observed. Subcutaneous administration of nusinersen (0, 6, 12.6, or 25 mg/kg) to pregnant rabbits every other day throughout organogenesis produced no evidence of embryofetal developmental toxicity. 8.2 Lactation Risk Summary There are no data on the presence of nusinersen in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SPINRAZA and any potential adverse effects on the breastfed infant from SPINRAZA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SPINRAZA in pediatric patients from newborn to 17 years have been established [see Clinical Studies (14.1)]. Juvenile Animal Toxicity Data In intrathecal toxicity studies in juvenile monkeys, administration of nusinersen (0, 0.3, 1, or 3 mg/dose for 14 weeks and 0, 0.3, 1, or 4 mg/dose for 53 weeks) resulted in brain histopathology (neuronal vacuolation and necrosis/cellular debris in the hippocampus) at the mid and high doses and acute, transient deficits in lower spinal reflexes at the high dose in each study. In addition, possible neurobehavioral deficits were observed on a learning and memory test at the high dose in the 53-week monkey study. The no-effect dose for neurohistopathology in monkeys (0.3 mg/dose) is approximately equivalent to the human dose when calculated on a yearly basis and corrected for the species difference in CSF volume. 8.5 Geriatric Use SMA is largely a disease of children and young adults; therefore, there is no geriatric experience with SPINRAZA. 11 DESCRIPTION SPINRAZA contains nusinersen, which is a modified antisense oligonucleotide, where the 2’hydroxy groups of the ribofuranosyl rings are replaced with 2’-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript. The structural formula is: SPINRAZA is supplied as a sterile, preservative-free, colorless solution for intrathecal use in a single-dose glass vial. Each 1 mL solution contains 2.4 mg of nusinersen (equivalent to 2.53 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.77 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP. The product may contain hydrochloric acid or sodium hydroxide to adjust pH. The pH is ~7.2. The molecular formula of SPINRAZA is C234H323N61O128P17S17Na17 and the molecular weight is 7501.0 daltons. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SPINRAZA is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, SPINRAZA was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. 12.2 Pharmacodynamics Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants. Cardiac Electrophysiology In 121 patients with spinal muscular atrophy who received either SPINRAZA or sham-control, QTcF values >500 ms and change from baseline values >60 ms were observed in 5% of patients receiving SPINRAZA. Compared to the sham-control, there was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization in patients treated with SPINRAZA. 12.3 Pharmacokinetics Absorption Intrathecal injection of SPINRAZA into the cerebrospinal fluid (CSF) allows nusinersen to be distributed from the CSF to the target central nervous system (CNS) tissues. Following intrathecal administration, trough plasma concentrations of nusinersen were relatively low, compared to the trough CSF concentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours. Mean plasma Cmax and AUC values increased approximately dose-proportionally up to a dose of 12 mg. Distribution Autopsy data from patients (n=3) showed that SPINRAZA administered intrathecally was distributed within the CNS and peripheral tissues, such as skeletal muscle, liver, and kidney. Elimination Metabolism Nusinersen is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes. Excretion The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma. The primary route of elimination is likely by urinary excretion for nusinersen and its chain-shortened metabolites. At 24 hours, only 0.5% of the administered dose was recovered in the urine. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of nusinersen have not been performed. Mutagenesis Nusinersen demonstrated no evidence of genotoxicity in in vitro (Ames and chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays. Impairment of Fertility When nusinersen (0, 3, 10, or 25 mg/kg) was administered by subcutaneous injection to mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on male or female fertility were observed. 14 CLINICAL STUDIES The efficacy of SPINRAZA was demonstrated in a double-blind, sham-procedure controlled clinical trial in symptomatic infantile-onset SMA patients and was supported by open-label clinical trials conducted in presymptomatic and symptomatic SMA patients. 14.1 Clinical Trial in Infantile-Onset SMA This study was a multicenter, randomized, double-blind, sham-procedure controlled study in 121 symptomatic infants ≤ 7 months of age at the time of first dose, diagnosed with SMA (symptom onset before 6 months of age). Patients were randomized 2:1 to receive either SPINRAZA or sham injection. A planned interim efficacy analysis was conducted based on patients who died, withdrew, or completed at least 183 days of treatment. Of the 82 patients included in the interim analysis, 44% were male and 56% were female. Age at first treatment ranged from 30 to 262 days (median 181). Eighty-seven (87%) of subjects were Caucasian, 2% were Black, and 4% were Asian. Length of treatment ranged from 6 to 442 days (median 261 days). Baseline demographics were balanced between the SPINRAZA and control groups with the exception of age at first treatment (median age 175 vs. 206 days, respectively). The SPINRAZA and control groups were balanced with respect to gestational age, birth weight, disease duration, and SMN2 copy number (2 copies in 98% of subjects in boths groups). Median disease duration was 14 weeks. There was some imbalance in age at symptom onset with 88% of subjects in the SPINRAZA group and 77% in the control group experiencing symptoms within the first 12 weeks of life. The primary endpoint assessed at the time of interim analysis was the proportion of responders: patients with an improvement in motor milestones according to Section 2 of the Hammersmith Infant Neurologic Exam (HINE). This endpoint evaluates seven different areas of motor milestone development, with a maximum score between 2-4 points for each, depending on the milestone, and a total maximum score of 26. A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) in ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking (consistent with improvement by at least 1 milestone). To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones than worsening. Of the 82 patients who were eligible for the interim analysis, a statistically significantly greater percentage of patients achieved a motor milestone response in the SPINRAZA group compared to the sham-control group (see Table 2). Figure 1 is a descriptive display of the distribution of net change from baseline in the total motor milestone score for Section 2 of the HINE. Although not statistically controlled for multiple comparisons at the interim analysis, the study also assessed treatment effects on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), which is an evaluation of motor skills in patients with infantile-onset SMA. The CHOP-INTEND results are displayed in Table 2. Table 2. Motor Milestone Response and CHOP-INTEND Results Endpoint Motor Milestone (HINE Section 2) Achievement of a motor milestone response SPINRAZA-treated patients (n=52)1 21 (40%) p<0.0001 CHOP-INTEND Improvement from Baseline2 At least 4-points 33 (63%) CHOP-INTEND Worsening from Baseline2 At least 4-points 2 (4%) Sham-control patients (n=30)1 0 (0%) 1 (3%) 12 (40%) 1 Analyses included all subjects who were alive with the opportunity for at least a 6-month (Day 183) assessment and all subjects who died or withdrew from the study at the time of the interim analysis 2 Not statistically controlled for multiple comparisons at interim analysis Figure 1. Net Change from Baseline in Total Motor Milestone Score (HINE) by Percent of Subjects in the Interim Efficacy Set* *For subjects who were alive and ongoing in the study, the change in total motor milestone score was calculated at the later of Day 183, Day 302, or Day 394. The results of the controlled trial in infantile-onset SMA patients were supported by open-label uncontrolled trials conducted in symptomatic SMA patients who ranged in age from 30 days to 15 years at the time of first dose, and in presymptomatic patients, who ranged in age from 8 days to 42 days at the time of first dose. The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. Some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so, maintained milestones at ages when they would be expected to be lost, and survived to ages unexpected considering the number of SMN2 gene copies of patients enrolled in the studies. The overall findings of the controlled trial in infantile-onset SMA and the open-label uncontrolled trials support the effectiveness of SPINRAZA across the range of SMA patients, and appear to support the early initiation of treatment with SPINRAZA. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SPINRAZA injection is a sterile, clear and colorless solution supplied as a 12 mg/5 mL (2.4 mg/mL) solution in a single-dose glass vial free of preservatives. The NDC is 64406-058-01. 16.2 Storage and Handling Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. SPINRAZA should be protected from light and kept in the original carton until time of use. If no refrigeration is available, SPINRAZA may be stored in its original carton, protected from light at or below 30oC (86oF) for up to 14 days. Prior to administration, unopened vials of SPINRAZA can be removed from and returned to the refrigerator, if necessary. If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25oC (77oF). 17 PATIENT COUNSELING INFORMATION Thrombocytopenia and Coagulation Abnormalities Inform patients and caregivers that SPINRAZA could increase the risk of bleeding. Inform patients and caregivers of the importance of obtaining blood laboratory testing at baseline and prior to each dose to monitor for signs of increased potential for bleeding. Instruct patients and caregivers to seek medical attention if unexpected bleeding occurs [see Warnings and Precautions (5.1)]. Renal Toxicity Inform patients and caregivers that SPINRAZA could cause renal toxicity. Inform patients and caregivers of the importance of obtaining urine testing at baseline and prior to each dose to monitor for signs of potential renal toxicity [see Warnings and Precautions (5.2)]. Manufactured for: Biogen Inc. Cambridge, MA 02142 SPINRAZA is a trademark of Biogen. © 2016 Biogen