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Afrezza®: Inhaled insulin approved by the FDA Regulatory Seminar AREIPS March 2015 Cécile CAMINADE Malika CUMZAIN Anne-Charlotte DUBUS Clémence GOUY Cécile ROSELMAC Louise TOURNOYS 2 Table of Contents Introduction - Context • Diabetes • Types of insulin Insulin therapy : unmeet needs and non-adherence History of the Inhaled Insulin & Exubera® MannKind Afrezza® : Technosphere® + Medical Device Trials Approval of Afrezza® REMS Sanofi & MannKind Partnership Markets Europe Conclusion 3 Introduction - Context Diabetes 4 Epidemiology of Diabetes Mellitus Prevalence of diabetes in adults aged 20-79 years range : 8,3 % (world, 2013) The 7th leading cause of death in 2030 (1) (WHO projection) FID Fédération International du diabète, Atlas du diabète 6ème édition 5 Diabetes Mellitus 10 % 90% FID Fédération International du diabète, Atlas du diabète 6ème édition 6 Introduction - Context Types of insulin 7 Insulin secretion in individuals without diabetes At a low, basal level in the non-fed state, With increased, stimulated levels at mealtimes 8 http://www.sanofidiabetes.in/apidra-doctor.aspx Insulins Basal IntermediateActing : NPH Long-Acting Umuline NPH Insulatard HM Lantus Levemir Tresiba NPH : Neutral Protamine Hagedorn http://www.sanofidiabetes.in/apidra-doctor.aspx 9 Insulins Bolus Short acting = Regular Insulin Rapid-acting Actrapid Umuline Rapid Humalog Novo Rapid Apidra http://www.sanofidiabetes.in/apidra-doctor.aspx 10 Insulin in Type 2 Diabetes Mellitus Healthy eating, weight control, physical activity Initial drug monotherapy: Metformin 2 then 3-drug combination: + SU/TZD/DDP4-i/GLP1 receptor agonist Initiation with basal insulin: long-acting, or intermediate-acting NPH If the HbA1c target is not met: intensification of insulin therapy: addition of bolus insulin Individualization of treatment (multiple daily doses + 1 or 2 non-insulin agents) Glycaemic Target: HbA1c < 7% American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) ; Diabetes Care; 2012 : 35 : 1364-1379 11 Insulin therapy : unmeet needs and non-adherence 12 Effective insulin therapy Four critical accomplishments: involvement of both patient and healthcare provider intensification initiation persistence adherence 13 PUBMED : M. Peyrot1,2, A. H. Barnett3 , L. F. Meneghini4 and P.-M. Schumm-Draeger5 Article: Care Delivery Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study Adherence Self reported rate of adherence ranged from 43% to 86% for insulin therapy with Type1 or Type 2 diabetes mellitus Adherence to insulin therapies is generally poor Review Article : Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review M. J. Davies1, J. J. Gagliardino2, L. J. Gray3, K. Khunti3, V. Mohan4 and R. Hughes5 14 Top 5 reasons for insulin omission/non-adherence 1 • Too busy 2 • Travelling 3 • Skipped meals 4 • Stress (needle phobia, hypoglycemia, weight gain…) 5 • Public embarrassment Review Article : Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review M. J. Davies1, J. J. Gagliardino2, L. J. Gray3, K. Khunti3, V. Mohan4 and R. Hughes5 15 Ideal insulin therapy Low number of injections No weight gain Minimize consequence of a delayed or missed insulin No risk of hypoglycemia Easy to adjust insulin doses to respond to daily changes Device who is not a burden for the daily life 16 History of the Inhaled ® Insulin & Exubera 17 History of Inhaled Insulin Since 1924 : various attempts have been made to get away from injectable insulin → upper nasal airways ; deep lungs ; stomach. Deep lungs most promising → small physiological barriers + inspired aerosol deposited on a large area + absorption through extremely thin alveolar membrane. 2006 : Pfizer licensed the rights to a product that came to be known as Exubera®. http://www.lef.org/Magazine/2015/2/Vinpocetine-Brainshrinkage-Brain-Injury-and-Bioidentical-Hormones/Page-05 http://www.fool.com/investing/general/2013/09/11/will-the-new-inhaler-replace-injections-for-diabet.aspx 18 Exubera®: 1st approved inhalable insulin Co-developped by Pfizer and Sanofi-Aventis January 2006 : US/EU approval (Diabetes type 1 and 2: rapid-acting insulin) Pfizer bought from Sanofi-Aventis $1.3 billion the worldwide marketing rights Manufactured by Pfizer in collaboration with Nektar Therapeutics 18 October 2007 : Pfizer annonced that it would no longer manufacture or market Exubera® Pfizer Chairman and CEO Jeffrey Kindler : Exubera® « failed to gain acceptance among patients and physicians » 19 Exubera®: a failure 1 No clinical advantage over injected insulin 2 April 2006 : 1st appraisal from NICE : the benefits of avoiding injections did not justifiy the higher cost (x5). → June 2006 NICE : cost effectiveness only for patients with needle phobia 3 Serious risk of dosing errors : - Exubera® is prescribed in mg (UI traditionally) - 1 mg ↔ 3UI but the increment is not linear : 3 mg ↔ 8UI ! - 3 consecutive doses of 1 mg = higher dose than a single 3 mg blister ! 4 Begin working within the body faster than injected forms Type 1 and 2 diabetics will still need an injection of longer acting insulin to maintain a basal level for a 24-hour period http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1331.html 20 Exubera®: a bulky inhaler 21 http://www.nytimes.com/2007/11/16/business/16mannkind.html?pagewanted=1&_r=2&fta=y& Exubera®: lung cancer concern 9th April 2008 Pfizer announced that Exubera® may have been associated with lung cancer : total of 7 cases Clinical trials : 6 cases/4,740 patients who used Exubera® VS 1 case/4,292 in the placebo group. + 1 not in a study, once Exubera® was on the market => Not significant and all had a prior history of cigarette smoking => CHMP could not determine if related to Exubera® http://www.lepoint.fr/actualites-sante/2008-04-10/l-insuline-inhalee-exubera-liee-a-des-cancers-du-poumon-selon/1409/0/237289 22 Inhaled-insulin products in development in 2007 http://www.nature.com/nbt/journal/v25/n12/fig_tab/nbt1207-1331_T1.html 23 Main inhaled insulin in development in 2007 2008 : Eli Lilly and Novo Nordisk both shelved their current programs on inhalated insulin. AIR Insulin® AERx® iDMS 24 Inhaled-insulin products in development in 2007 Afrezza® remains one of the last inhaled insulin products in development http://www.nature.com/nbt/journal/v25/n12/fig_tab/nbt1207-1331_T1.html 25 MannKind 26 Alfred Mann M.S. degrees in physics, member of the Academy of Engineering Foundation of 14 companies 9 were acquired by high profile companies for a total of $ 8 billions In medical devices In aerospatial Eg: MiniMed Inc. Acquired by medtronic development of continous Glucodose monitoring system http://www.mannkindcorp.com/about-us-executive-management-alfred.htm 27 Biopharmaceutical company based in California Founded in 1991 by Alfred Mann Focus on: - discovery, - development, - commercialization of therapeutic products for diseases such as diabetes and cancer. 2001: Technosphere® technology purchased from Solomon Steiner 2004: IPO $70M offering CEO: Hakan Edstrom since January 2015 28 http://www.mannkindcorp.com/about-us-executive-management-alfred.htm ® Technosphere Technology Dry powder formulation for inhalation 29 ® Technosphere Technology « A versatile delivery system that mimics the pharmacokinetics of intraarterial administration » • FDKP, polysorbate 80, acetic acid, water • Formation reproducible and well controlled • Particles ideally sized for inhalation to the deep lung (2μm) 30 MannKind Corporation Technosphere® technology versatile drug delivery platform http://www.mannkindcorp.com/ FDKP : novel & inert excipient • • • • • • FDKP Matrix Hydrogen bonds and electrostatic interactions pH-linked release Uniform distribution Biologically inert Renally excreted Crystallline and amorphous particles Characterized in a full panel of toxicology studies • Chronic inhalation toxicology in 2 species (rat 6 months; dog 9 months) • 2-year carcinogenicity by the inhalation route in rats • Reproductive toxicology • Safety pharmacology • Genetic toxicology 31 http://www.mannkindcorp.com/ Technosphere® Technology Advantages Applicability to a wide variety of API Molecular weight from 500 Da to 150 KDa (proteins, peptides, small molecules) Anionic and cationic drugs Hydrophobic and hydrophilic drugs • Rapid drug absorption Dissolve extremely fast after inhalation and deliver the API directly into the arterial circulation • Excellent bioavailability • Improved convenience with patient-friendly, needle-free devices, self-adminitered medicines 32 MannKind Corporation Technosphere® technology versatile drug delivery platform http://www.mannkindcorp.com/ ® Afrezza Technosphere® Insulin Inhalation Powder (TI) 33 Technosphere® Insulin Inhalation Powder (TI) Dry powder form, administered with an inhaler (Oral inhalation route) Microparticles : fumaryl diketopiperazine (FDKP) + recombinant human insulin (monomeric) • Human insulin produced by recombinant deoxyribonucleic acid (rDNA) : a non-pathogenic laboratory strain of E.Coli (K12) • FDKP carries the insulin to the lung 34 20140401-EMDAC-B1-02-MannKind_Backgrounder ® Technosphere Insulin 35 20140401-EMDAC-S1-02-MannKind_Slides An inhaled formulation Advantages Painless Discrete Convenient Non invasive Very fast absorption of insulin 36 20140401-EMDAC-B1-02-MannKind_Backgrounder ® Afrezza Medical Device 37 Regulatory history of Afrezza® program 2009 Complete Response Letter 1: Original NDA MedTone 2010 Complete Response Letter 2: 2013 Request: Resubmission Request: Resubmission Gen2 Device T2DM: 2 trials Safety data One trial with safety comparison with MedTone Gen2 inhaler T1DM: 1 trial Additionnal data for clinical utility Duration of 6 months or greater Comparability between 2 types of MedTone Clinical trials with Gen2 device for T1DM and T2DM 2 new Phase III trials in T1DM and T2DM MedTone Model C and D No major clinical trials, only bioequivalence study Medtone comparison 38 Afrezza® inhaler device The Afrezza® Inhaler is breath-powered by the patient, when the patient inhales through The device, the powder is aerosolized and delivered to the lung. MannKind initially filed for marketing approval based on data from the MedTone device 39 www.mannkindcorp.com Regulatory history of Afrezza® program 2009 Original NDA MedTone T1DM: 1 trial T2DM: 2 trials Duration of 6 months or greater Complete Response Letter 1: Request: 2010 Additionnal data for clinical utility Resubmission Inadequate titration No major clinical trials, only bioequivalence study Safety data Comparability between 2 types of MedTone Gen2 Device Complete Response Letter 2: 2013 Request: Resubmission One trial with safety comparison with MedTone Gen2 inhaler Clinical trials with Gen2 device for T1DM and T2DM Medtone comparison 2 new Phase III trials in T1DM and T2DM 40 Afrezza® inhaler device In 2009, switch to the 2nd generation inhaler Dreamboat (Gen2) Gen2 device Dreamboat Medtone 41 www.mannkindcorp.com Reason of the change Designed to be smaller, easier to load, handle and low-cost 42 www.mannkindcorp.com Reason of the change Need of less inspiratory flow pressure and duration Only one inspiration Very little change in performance over a wide range of relevant pressure drops (flow rates) and particule size 43 MannKind Corp Innovation in drug delivery by inhalation Reason of the change Medtone Gen2 device Dreamboat Less cartridge load to deliver the same dosage of insulin as from MedTone Inhaler • Bioequivalence 20U delivered by Gen2 = 30U delivered by MedTone • 90% of the powder is delivered to the patient, • almost 70% is delivered in the respirable range Low maintenance (discarded and replaced every 15 days) of the device 44 www.mannkindcorp.com Regulatory history of Afrezza® program 2009 Original NDA MedTone T1DM: 1 trial T2DM: 2 trials Duration of 6 months or greater Complete Response Letter 1: Request: Complete Response Letter 2: 2013 Resubmission Gen2 inhaler Additionnal data for clinical utility 2010 Request: Resubmission Inadequate titration Gen2 Device Safety data Bioequivalence study One trial with safety comparison with MedTone Comparability between 2 types of MedTone Clinical trials with Gen2 device for T1DM and T2DM Medtone comparison 2 new Phase III trials in T1DM and T2DM 45 Strategy of bridging Issue of the 1st NDA: ECLIA method used for BE studies is not compliant du FDA guideline: Bioanalytical Method Validation 1-Show correlation of serum insulin concentrations between ECLIA and RIA method The Relationship Between Two Insulin Assays Used to Determine Bioequivalence and Dose Proportionality of AFREZZA® Insulin Administered Using a Gen2 46 Inhaler Compared to a MedTone® Inhaler: Simulation of Clinical Trials and Actual Data »Mark » T. Marino, MD and James P. Cassidy, MS MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda 2-Show bioequivalence between MedTone et Gen2 device device « Bioequivalence and Dose Proportionality of AFREZZA® Inhalation Powder Administered Using a Gen2 Inhaler Compared to the MedTone® Inhaler » Mark T. Marino, MD; James P. Cassidy, MS; Chad C. Smutney, BSME; Michael Zupon, PhD; Joseph Kocinski, PhD MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda, MD 47 3-Show dose linearity of Gen2 device « Bioequivalence and Dose Proportionality of AFREZZA® Inhalation Powder Administered Using a Gen2 Inhaler Compared to the MedTone® Inhaler » Mark T. Marino, MD; James P. Cassidy, MS; Chad C. Smutney, BSME; Michael Zupon, PhD; Joseph Kocinski, PhD MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda, MD 48 Regulatory history of Afrezza® program 2009 Complete Response Letter 1: Original NDA Request: MedTone Complete Response Letter 2: 2013 2010 Request: Resubmission Resubmission T2DM: 2 trials Safety data Duration of 6 months or greater Comparability between 2 types of MedTone Bioequivalence study One trial with safety comparison with MedTone Gen2 inhaler T1DM: 1 trial Additionnal data for clinical utility Clinical trials with Gen2 device for T1DM and T2DM 2 new Phase III trials in T1DM and T2DM Gen2 Device Medtone comparison 49 4-Head to head comparison between Medtone and Gen2 requested by FDA Aim: Bridging pulmonary safety data Gen2 vs Medtone in phase 3 studies No significant difference in mean change in FEV1 (Forced expiratory volume in 1 sec) Similar rate of pulmonary AE 50 Briefing Document Afrezza- Mannkind EMDAC Device - Conclusion BE not performed with golden standard method Show dose linerarity of of 2x10U cartridge VS 20U cartridge of Gen2 Resubmision with a new version of the device BE performed between MedTone and Gen 2 Need of clinical trials 51 Trials 52 PK: Phase I in healthy subjects Dose ranging study of Afrezza® with Gen2 inhaler : 10 U ; 30 U ; 60 U and 80 U Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 53 PK: Phase I in healthy subjects Bolus Short acting = Regular Insulin Rapid-acting Technosphere® insulin Peak : 1h- 3h Duration : 5-8 h Peak : 30-90 min Duration : 3-5 h Peak : 10-15 min Duration : 3h Actrapid Umuline Rapid Humalog Novo Rapid Apidra Afrezza® 54 PD: Phase I in healthy and T1DM subjects with Gen2 inhaler Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 55 Regulatory history of Afrezza® program 2009 Complete Response Letter 1: Original NDA MedTone 2010 Complete Response Letter 2: 2013 Request: Resubmission Request: Resubmission Gen2 Device T2DM: 2 trials Safety data One trial with safety comparison with MedTone Gen2 inhaler T1DM: 1 trial Additionnal data for clinical utility Duration of 6 months or greater Comparability between 2 types of MedTone Clinical trials with Gen2 device for T1DM and T2DM 2 new Phase III trials in T1DM and T2DM No major clinical trials, only bioequivalence study Medtone comparison 56 Endpoints for clinical trials Efficacy Primary endpoint: - Change in HbA1c - Non inferiority margin for insulin 0.4% of difference in HbA1c Secondary endpoint: - Percent achieving HbA1c ≤7% - Body weight change Safety Pulmonary: - FEV1 - Asthma - Lung cancer Non pulmonary: - Hypoglycemia - Diabetic ketoacidosis 57 Efficacy Type 1 diabetes 58 Phase 3 trials in the 2013 resubmission T1DM on a basal/bolus insulin regimen: • One trial (009) with MedTone: • basal insulin + TI (n=277) vs basal insulin + aspart insulin (n=262) • 52 weeks 59 First submission (009): primary efficacy endpoint (change in HbA1c) Afrezza Comparator Non inferiority margin of 0.4% Afrezza® doesn’t meet the non inferiority criteria Primary analysis results MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 60 Regulatory history of Afrezza® program 2009 Original NDA MedTone T1DM: 1 trial T2DM: 2 trials Duration of 6 months or greater Complete Response Letter 1: Request: 2010 Additionnal data for clinical utility Resubmission Inadequate titration No major clinical trials, only bioequivalence study Safety data Comparability between 2 types of MedTone Gen2 Device Complete Response Letter 2: 2013 Request: Resubmission One trial with safety comparison with MedTone Gen2 inhaler Clinical trials with Gen2 device for T1DM and T2DM Medtone comparison 2 new Phase III trials in T1DM and T2DM 61 Phase 3 trials in the 2013 resubmission T1DM on a basal/bolus insulin regimen: • One trial (171) with MedTone and Gen2: • basal insulin + TI (n=174) vs basal + aspart insulin (n=170) • 24 weeks 20140401-EMDAC-S1-01-FDA_Slides_508 62 Resubmission: Study 171 design 7.5 % ≤ HbA1c ≤ 10% 63 Basal and Prandial Insulin Titration in T1DM Titration during 12 weeks Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 64 Resubmission (171): primary efficacy endpoint (change in HbA1c) Afrezza Comparator Non inferiority margin of 0.4% Non inferiority of Afrezza® vs. comparator 65 MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 Secondary endpoint: HbA1c ≤ 7% Greater achievement No significant with comparator vs. difference between Afrezza® Afrezza® and comparator MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 66 Secondary endpoint: Body weight change Significant difference in weight gain in favor of comparator Significant difference in weight gain in favor of comparator 67 MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 Efficacy T1DM: Conclusion With Gen2 inhaler (new device): • Non inferiority in HbA1c reduction for Afrezza® • Lesser achievement of HbA1c ≤ 7% target with Afrezza® • No gain weight with Afrezza® FDA: Less effective insulin ? 68 Efficacy Type 2 diabetes 69 Phase 3 trials For the 2013 resubmission, data from trials: • One trial (102) with MedTone: subjects on prior insulin therapy : basal + TI (n=302) vs premixed biphasic Rapid Acting Analog 70/30 (n=316), 52 weeks 70 First submission (102): primary efficacy endpoint (change in HbA1c) Afrezza Comparator Non inferiority margin of 0.4% Non inferiority of Afrezza® vs. comparator 71 Clinical trial MKC-TI-102 MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 Phase 3 trials For the 2013 resubmission, data from trials: • One trial (102) with Medtone: subjects on prior insulin therapy : basal + TI (n=302) vs premixed biphasic Rapid Acting Analog 70/30 (n=316), 52 weeks • One trial (175) with Gen2: insulin-naive failing Oral Anti-Diabetic (OAD) therapy: OAD + TI (n=177) vs OAD + TP (technospere placebo) (n=176), 24 weeks 72 Resubmission (175): primary efficacy endpoint (change in HbA1c) Afrezza Comparator Superior HbA1c reduction when compared to placebo as add-on to oral anti-diabetics in insulin naive subjects Clinical trial MKC-TI-175 73 Secondary endpoint: HbA1c ≤ 7% Greater achievement with No signicative difference Afrezza® vs. placebo between the 2 arms MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 74 Secondary endpoint: Body weight mean change Significant difference in weight gain in favor of Afrezza® Small weight gain in Afrezza® arm MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 75 Efficacy T2DM: Conclusion Vs. Active comparator: • Non inferiority of Afrezza® • Same achievement of HbA1c ≤ 7% target • Less increase of body weight FDA: Afrezza® less effective than comparator Vs. Placebo, in add on to OADs: • Superiority of Afrezza® • More achievement of HbA1c ≤ 7% target • Small weight gain Therapeutic strategy ? 76 Safety Pulmonary Safety 77 FEV1 FEV1 decline over duration of treatment with TI in T1DM and T2DM MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 78 Bronchospasm Original submission with MedTone : Bronchospasm in patients with asthma and chronic obstructive pulmonary disease • Trial with Medtone in non-diabetic subjects : 17 asthmatics and 13 non-asthmatics : • 2 serious adverse events (SAEs) of bronchospasm in asthmatics • Bronchospasm and wheezing AEs (29%; 5/17) compared to no events in non-asthmatics MannKind data 79 Incidence of Common TEAEs (≥2%) Combined Type 1 & 2 DM Safety Population Trials with MedTone and Gen2 devices TEAE = Treatment Emergent Adverse Event Reason for discontinuation: 2,8 % for cough MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 80 Lung cancer Observed incidence: 0.8 cases [95% CI (0.09-2.8)] per 1,000 patient-years In diabetic population : 1 – 2 cases per 1,000 patient-years (Gillian et al., 2005) MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014 81 Safety Non-pulmonary safety 82 Incidence of hypoglycemia T1DM T2DM *p<0.05 for difference between TI and comparator (favoring the TI in all cases). Incidence of hypoglycemia in studies vs. active insulin comparator Less incidence of hypoglycemia in Afrezza® arm FDA : consistent with the finding that Afrezza® is less effective no clear, consistent evidence of Afrezza® benefit on hypoglycemia MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 83 Diabetic ketoacidosis For the 2013 Resubmission Safety Population : SYE = Subject-year exposure Imbalance may be consistent with lesser efficacy of Afrezza® Related to concurrent infection and treatment interruption and/or reduced dosing MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014 84 Approval of Afrezza® 85 Approval Afrezza® was approved on June 27, 2014 Indication: Rapid-acting inhaled insulin to improve glycemic control in adults with type 1 and type 2 diabetes mellitus Dosage and administration • • • • • Oral inhalation A single inhalation per cartridge (4 or 8 units) At the beginning of the meal Before initiating, medical history, physical examination, spirometry Dosage adjustment is needed when switching from another insulin to Afrezza® Prescribing Information Afrezza® MannKind 86 Equivalence between Dose of Cartridge and SC Insulin 4units injected 10U inhaled A Cartridge labeled : - 4 units contains 0,35 mg of Insulin = 10 U of insulin - 8 units contains 0,70 mg of Insulin = 20 UI of insulin Prescribing Information Afrezza® MannKind 87 Approval Limitation of use • Used in combination with long-acting insulin in patients with T1DM • Not recommended for diabetic ketoacidosis • Not recommended in patients who smoke or recently stopped Contraindications • During episodes of hypoglycemia • Chronic lung disease: asthma, chronic obstructive pulmonary disease, risk of acute bronchospasm • Hypersensitivity to regular human insulin or Afrezza® excipients Prescribing Information Afrezza® MannKind 88 Storage conditions Inhaler must be discarded after 15 days of use and replaced with a new inhaler Prescribing Information Afrezza® MannKind 89 FDA requirements Four post marketing studies: • Paediatric trials: 4 to 17 years old • Part 1: Open-label PK, and multiple-dose safety and tolerability dosetitration trial in T1DM patients • Part 2: Prospective, multicenter, open-label, randomized, controlled trial comparing the efficacy and safety of prandial Afrezza® to prandial SC insulin aspart + SC basal insulin in T1DM and T2DM patients • 5-year, randomized, controlled trial in 8 000-10 000 patients with T2DM, to assess the serious potential risk of pulmonary malignancy • 2 PK/PD trials: to characterize the dose response relative to SC insulin and assess within-subjects variability 90 Afrezza® letter of approval FDA REMS FDA REMS 91 Risk Evaluation and Mitigation Strategy (REMS) Approved in June 2014 Goal: To mitigate the risk of acute bronchospasm 1. Communication Plan - REMS Letters - REMS Factsheet - REMS website 2. Submission of Assessments to the FDA 92 1. REMS Communication Plan To inform healthcare providers and professional societies of: 93 1. REMS Communication Plan By Letters for Healthcare Providers and Professional Societies: - Within 60 days and again after 1 year after REMS approval - If the commercial launch of Afrezza® occurs later than 90 days following REMS approval, an additionnal issuance of REMS Letters will be sent within 30 days of product launch - Letters distributed by email. If an email is marked as unopened, a 2nd email will be sent within 14 days. 94 Letter for Healthcare Providers 95 1. REMS Communication Plan By Factsheet: - Distributed with the REMS Letter for Healthcare Providers - Made available to HCP through MannKind’s sales and medical representatives during initial discussion during the first 12 months after approval of this REMS - Will be prominently displayed at relevant scientific meetings where MannKind has a presence for the duration of the REMS 96 Factsheet Distributed with the REMS Letter for Healthcare Providers 97 1. REMS Communication Plan By Website: - The Afrezza REMS website (www.AfrezzaREMS.com) include a prominent REMS – specific link - Include the option to print versions of the PI, REMS Letter for HCP and the REMS factsheet - Will continue for the duration of the REMS 98 2. Submission of Assessments MannKind will submit REMS Assessments to FDA at 18 months, 3 years, and 7 years from the date of the initial REMS approval The reporting interval covered by each assessment should conclude no earlier than 60 days before the submission date, to facilitate inclusion of as much information as possible while allowing time to prepare the submission MannKind wills submit each assessment so that it will be received by the FDA on or before the due date. 99 Sanofi & MannKind Partnership 100 « The best case scenario partner » Sanofi is looking for ways to buttress revenue and fend off competition from Novo Nordisk A/S when its top-selling product, the insulin Lantus, loses patent in February 2015. Sanofi has a complementary product portfolio, a large presence on the insulin market and one of the first commercial infrastructure in the world. Afrezza will help Sanofi compete with shortacting insulins in which Novo and Eli Lilly & Co. are the market leaders. VS 101 MannKind Corp. / Sanofi partnership August 2014 Worldwide exclusive licensing agreement for development and commercialization of Afrezza®. Sanofi is responsible for: • Global commercial • Regulatory • Development activities MannKind will manufacture Afrezza at its manufacturing facility in Danbury, Connecticut. Plan to collaborate to expand manufacturing capacity to meet global demand as necessary. Sanofi and MannKind will share profits and loses on a global basis, retaining 65% receiving 35%. 102 MannKind Corp. / Sanofi partnership August 2014 Sanofi paid $150 million up front and as much as $775 million if the drug, Afrezza, meets certain sales and development targets January 2015 MannKind just received a $50M milestone payment from Sanofi 103 Markets 104 Acceptance of inhaled insulin Among physicians 105 Acceptance of inhaled insulin Among patients Both for patients and physicians: ready to accept inhaled insulin For insulin intensification: increase percentage of « no preference » 106 Sanofi’s Target population National diabetes statistic report, 2014, CDC Excluded population : - Asthma 8%* - COPD 3,75%** - Smoker 18,1%*** http://www.cdc.gov/asthma/asthmadata.htm http://www.cdc.gov/copd/ http://www.cdc.gov/tobacco/campaign/tips/resources/data/cigarette-smoking-in-united-states.html 107 Estimation of Target population Excluded population Black box We assess this product as : Niche market product DT2 with OADs +/- GLP1 with uncontrolled HbA1c : 2 millions And Needle phobia (8,5% of population*) Target : 170 000 people Estimated Sales : 450 millions USD a year *YAEL NIR, ALONA PAZ, EDMOND SABO, AND ISRAEL POTASMAN FEAR OF INJECTIONS IN YOUNG ADULTS: PREVALENCE AND ASSOCIATIONS Am. J. Trop. Med. Hyg., 68(3), 2003, pp. 341–344 108 Sanofi’s Launch Strategy Launch 3rd February 2015 Pricing similar to rapid insulin in pen Copayment for patient depends on health inssurance Comparison of price for 600UI of insuline: Afrezza versus Sanofi rapid acting insulin http://rxusa.com/cgibin2/db/db.cgi?name2=Insulin 109 Sanofi’s Launch Strategy Recruit early users thanks to copayment reduction https://www.activatethecard.com/7055/ 110 Europe 111 Strategy 1. Obtain EC certificate for the device : not mandatory 2. MA application : the centralised authorisation procedure • Guidelines : diabetes, inhaled products, insulin • Scientific Advice 112 Application for MA The centralised authorisation procedure medicines derived from biotechnology processes human medicines for the treatment of diabetes Submitted directly to the Agency Evaluation by CHMP : 210 days + clock stops Opinion The EC grants MA in the EU : 67 days 113 http://www.ema.europa.eu/ema/ European specificities The applicant submits a risk management plan (RMP) in its marketing authorisation application. • A safety specification and a PV plan • A RMP describes activities to minimize risks Risk Management Plan (from Exubera®) • To obtain further data on cardiovascular risk as well as possible correlation with decline in FEV1. • Perform an epidemiologic study to assess the hypothetical risk of lung cancer associated with inhaled insulin. 114 EPAR Exubera® European specificities Paediatric investigation plan Pharmacovigilance system • A detailed description of the system of pharmacovigilance • A qualified person responsible • The notification of any adverse reaction occurring either in the Community or in a third country has been provided 115 http://www.ema.europa.eu/ema/ European specificities Concerning CMC : Additionnal requirements EU inspection of manufacturing site Analyses to perform according to European Pharmacopoeia Have an approved release and analyse site in Europe 116 http://www.ema.europa.eu/ema/ Chances of approval in the EU The similar inhaled insulin has already been approved by the EMA Scientific Advice Management of the application to the EMA by Sanofi which has expertise in diabetes Safety management 117 Conclusion 118 Strengths Faster action Weaknesses No injection Cough and small decrease in air flow Small device Easy to use Less hypoglycemia and less weight gain trend Opportunities Change in therapeutic strategy (treatment line, subpopulation preference) Early users could promote Afrezza® Long term safety (lung cancer) Threats Competitors in phase I (inhaled) and Phase II (oral) Need of phase IV study for European approval? 119 Thank you for your attention Any questions ? 120