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MASTER 2 AREIPS February 2015 Lantier.L; Gillet.D; Marquegnies.V, Despres.C; Cumzain.M; Caminade.C; Gouy.C; Khamassi.H; Roye.C; Courvoisier.B; Tournoys.L; Jeannot.A; Hologne.P; Roselmac.C; Renaux.V 1. 2. 3. 4. 5. 6. 7. 8. 9. Introduction Regulatory procedures Pharmacology Toxicology CMC Clinical Trials Medical Device Name Review Post Marketing Studies 2 Introduction 3 December 19, 2014 approved by FDA Monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) detected by an FDA-approved test : BRACAnalysis CDx (Myriad Genetics) for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes. 4 5th cause of cancer Population estimated : 22 000 new cases diagnosed 14 270 deaths in the US in 2014 http://www.ovariancancermd.com/staging/ http://www.cdc.gov/cancer/ovarian/statistics/ 5 http://www.ovariancancermd.com/prognosis/ 6 BRCA1 and BRCA2, encode proteins involved in the DNA damage repair pathway. Deleterious mutations are : ↗ incidence several cancers (ovarian, breast…) Ovarian and breast cancer characterized by : • autosomal dominant pattern • The Majority are protein truncating → loss of function • 10-40% lifetime risk of developing ovarian cancer • 50-85% for breast cancer earlier age bilateral 7 gBRCAm = 10-15% of ovarian cancer ◦ 2 000 cases per year in the U.S. 8 Debulking surgery Chemotherapeutic regimens: • platinum agent (carboplatin or cisplatin) •taxane (paclitaxel or docetaxel) Targeted therapy: Olaparib 9 Olaparib 50 mg capsules (Lynparza®) : ◦ Monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) ◦ advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Posology : 400 mg (8 capsules) 2/ day. 10 Inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes. Including PARP-1, PARP-2, and PARP-3. 11 PARP 1, 2 and 3 DNA-dependent enzymes that are catalytically activated upon binding to DNA damage. Inhibition DNA damaged accumulation and cell death. Source : http://www.onclive.com/publications/Oncology-live/2013/August-2013/New-Life-for-PARPInhibitors-Emerging-Agents-Leave-Mark-at-ASCO 12 (HR) http://www.nature.com/nrclinonc/journal/v12/n1/full/nrclinonc.2014.163.html 13 Olaparib (HR) http://www.nature.com/nrclinonc/journal/v12/n1/full/nrclinonc.2014.163.html 14 BRACAnalysis CDx™ developped in parallel to detect variant in BRCA 1 et BRCA 2 genes to select patients for an Olaparib treatment. Regulatory procedures 17 Orphan drug status granted IND 75918 activated August 2006 Pre-submission meeting October 2012 Guidance meeting March 2013 Breakthrough therapy request Pre-NDA meeting October 2013 Approval Oncologic Drug Advisory comittee February 2014 NDA 206162 submitted June 2014 July 2014 December 2014 Major admendment 18 Companion diagnostic development Class 3 PMA CDRH Center for Device and Radiological Health Priority review: 15 oct 2014 Orphan statut: 16 oct 2013 Oncologic Drug advisory committee Drug develop Approval: 19 dec 2014 Priority review: April 2014 Accelerated approval & NDA : 19 dec 2014 19 Pharmacology 23 Goal : evaluate the PARP inhibitory activity of olaparib in SW620 human colon adenocarcinoma cell line How ? ◦ SW620 extracts (lysates) were incubated with 0 – 300 nM olaparib for 5 minutes at 30°C in the presence of deoxyribonucleic acid ◦ Immunoassay detecting formation of poly ADP-ribose (PAR), a downstream product of PARP activation 24 Immunoassay detecting formation of poly ADP-ribose (PAR), a downstream product of PARP activation PARP PAR poly ADP-ribose 25 Results : IC50 = 5,48 nM IC90 = 60,08 nM Conclusion : Olaparib inhibited formation of PAR in SW620 extracts in a dosedependent manner. 26 Goal : Evaluate the effect of Olaparib on cell viability in a panel of 95 cells lines of colorectal, breast, ovarian, pancreatic, head and neck squamous cell carcinoma, and non-small cell lung cancer origin How ? CFA (Colony Forming Assay) Gold standard for measuring the effects of cytotoxic agents on cancer cells in vitro 27 Results : 28 Conclusion : In vitro, treatment with olaparib resulted in decreased cell viability, as measured by the colony formation assay, in cell lines from breast, ovarian, pancreatic, non-small cell lung, and colorectal cancers, and head and neck small-cell carcinoma 29 Goal : Evaluate whether cell lines and tumors which were sensitive to platinum based chemotherapies were also sensitive to olaparib How ? Anti-tumor activity was evaluated in patient derived mouse tumor models of triple negative breast cancer (any breast cancer that does not express the genes for Estrogen Receptor, Progesteron Receptor and Her2/neu) : Measure of tumoral volume of HBCx-10 (mutated BRCA2 and sensitive to cisplatin) cells 30 Results : 31 Conclusion : - In vivo, olaparib showed anti-tumor activity in breast patient-derived tumor models which were also sensitive to cisplatin treatment. - Co-treatment with olaparib and cisplatin resulted in greater anti-tumor effects when compared to either agent alone. 32 Goal : Evaluate the growth inhibitory activity of olaparib in a panel of 95 cancer cell lines : colorectal, breast, ovarian, pancreatic… How ? Colony Forming Assay 33 Results : HRR : homologous recombinant repair 34 Results : 35 Conclusion : Cell lines with BRCA1/2 mutations or low expression of homologous recombination repair (HRR) genes/proteins were more sensitive (IC50 < 1 µM) to growth inhibitory activity by olaparib 36 Pharmacokinetic A Rats, Mouse, Dogs: Cmax and biodisponibility more important F/M. D Rats, Mouse, Dogs, Human : no distribution in a particular organ & no differences between male and female. M Rats & Dogs 3 major metabolites, no unique human metabolite present at disproportionately higher levels in human than the rat identified. E Rats Approximately 92% of the dosed radioactivity was excreted 24h post-dosing & Radioactivity was excreted predominantly in the feces. What’s about the human excretion? 38 Toxicology 50 Toxicity 28 days in RATS Tested doses 0 5 mg/kg 15 mg/kg 40 mg/kg Control Active dose No adverse effect Dose expected in humans ~ 2 to 18% of human AUC MTD in rats Dose ≥ 100 mg/kg/day ◦ Hematological toxicities REVERSIBLE following a 21-day non-dosing period No apparent accumulation with repeated dose of olaparib 51 Toxicity 28 days in rats 40 mg/kg Clinical signs Salivation, paddling ↘ body weight in males (normal: end of recovery) FEMALES Hematological modifications Myelogram Histological lesions Pharmacocinetic Urinary effects Regenerative anemia (↘ red cells, Hb / ↗ reticulocytes, MCV ) Visible bone marrow /splenic hematopoiesis • • ↗platelet • ↘ white cells, lymphocytes End of recovery: leukocytes and lymphocytes slightly ↘. • • ↗ erythroid cells ↘ myelopoietic cells (female ++) during study Hemosiderin in hepatocytes (hemorrhage, ↘ red cells) ↗ X 3-8 Cmax and AUC values in females ↗ 40-50% urinary volume 52 Toxicity 26 weeks in RATS DOSES • • Males: 0; 5 mg/kg; 15 mg/kg ;30 mg/kg Females: 0; 1 mg/kg ;5 mg/kg ;15 mg/kg Systemic exposure significantly higher in female rats ≥ 15 mg/kg FEMALE Clinical signs ↘ body weight, Dose dependent Hematological modifications ↗ late myeloid cells ↗ M/E 53 Toxicity 28 days in DOGS DOSES: • 0 ; 2,5 ; 5; 15 mg/kg • 30 mg/kg: MTD in dos, significant hematological studies Lesions ≥ 2.5 mg/kg ↘ reticulocytes, platelets, leukocytes, lymphocytes Dose-dependent Bone marrow atrophy Delay in erythroid cells NO MORE DIFFERENCES AFTER RECOVERY PERIOD Minimal or slight microscopic findings ≥ 5 mg/kg Spleen GI tracts (congestion , hemorrhage), pancreas (pale) Urinary bladder (congestion, hemorrhage), parathyroid,kidney Prostate (inflammation) ORGAN LESIONS: PERSISTENCE AFTER RECOVERY PERIOD 15 mg/kg Cmax and AUC values : X 2 in female dogs 54 Toxicity 26 weeks in DOGS Results ≥ 3 mg/kg ↘ red cell mass, ↘ reticulocytes, platelets, leukocytes (all lines) Lack of regenerative response in bone marrow Inflammation: stomach, prostate 10 mg/kg Male dogs ↗ M/E ratio, ↗ myeloid cells ↘ erythroid cells Female dogs ↘ M/E ratio ↘ myeloid cells ↗ erythroid cells WEIGHT VARIATIONS: • Male dogs : ↗ ~30% at the 1 and 3 mg/kg • Female dogs: ↗ ~70% at 10 mg/kg Without change in food consumption End of study: no microscopic correlates in the bone marrow or lymphoid organs 55 Ames test: negative ◦ Not mutagenic at concentrations up to 5000 μg/plate under the conditions tested Cytogenetic analysis on Chinese Hamster ovarian cells ◦ Olaparid is clastogenic ◦ Dose dependent effect Micronucleus test (in vivo) ◦ Doses: 100; 200; 400 mg/kg ◦ Bone marrow toxicity all doses: clastogenic 56 NO STUDY « Consistent with recommendations in ICH S9, these studies are not essential to support an NDA for the proposed patient population. » 57 Fertility and early embryonic development FEMALE RATS Doses: 0; 0,05 (NOEL); 0,5 ; 15 mg/kg Modifications 15 mg/kg ( ~11% of human AUC) After 15 mg/kg + 4 weeks recovery • • • • Minimal maternal toxicity :↓ ~ 5% body weight ↗ pre-implantation loss ↗ early intrauterine deaths ↗ post-implantation loss No effects on mating, fertility, or embryo-fetal survival. 58 Fertility and early embryonic development MALE RATS Doses: 0; 5; 15 ; 40 mg/kg Modifications 40 mg/kg ≤40 mg/kg + 4 weeks recovery (7% of human AUC) • • • ↘ or ↗ body weight Salivation Hair loss No effects on mating and fertility rates compared to controls 59 Embryonic fetal development Dose Effect ≥ 5 mg/kg/day (2% of human AUC) EMBRYOTOXIC no viable offspring Major fetal malformations During organogenesis 0.05 and 0.5 mg/kg (≤ 0.3% of human AUC) • • Eye , anophthalmia, microphthalmia Vertebra/ribs, limbs, skull,diaphragm: ossification disorders Minor malformations: • • Skeletal Visceral abnormalities (kinked, dilated ureter, additional liver lobe…) 60 Chemistry Manufacturing Control 61 Olaparib Formule C24 H23FN4O3 Chemical name 4-[(3-{[4- (cyclopropylcarbonyl) piperazin-1-yl]carbonyl}-4fluorophenyl)methyl]phthalazin1(2H) one Molecular weight 434.46 g/mol Appearance White, crystalline solid Solubility Low solubility, pH-independent characters Not hygroscopic, Non-chiral center Free base, BCS Class 4 (low solubility, low permeability) ICH S2 classified as genotoxic 62 Manufacturing site and analysis for release: Patheon Pharmaceuticals Inc. Cincinnati, OH 45237 Packaging : AstraZeneca Pharmaceuticals LP USA 63 Presentation Olaparib 50 mg capsules Excipient lauroyl polyoxylglycerides Hard Capsules are white, opaque, composed of hypromellose, titanium dioxide, gellan gum, potassium acetate Capsule printing ink shellac, ferrosoferric oxide Mark “OLAPARIB 50 mg” and the AstraZeneca logo printed in black ink 64 Test procedure Drug substance Test procedure Drug product Description Description identification identification Assay Assay Organic impurities Degradation product any individual unspecified largest individual unspecified Total Total Particule size Dissolution Residual solvents Uniformity of dosage units 65 FDA demand: Change of maximal content of degradant Addition of a release test Stability: ◦ Appearance testing: thermal failure for several batches capsule leakage and printing ink smudged Consequences ◦ Post Marketing commitment: conduct stability study of commercial product : minimum of 3 batches Shelf-life: 18 months 66 Storage condition : 20°C to 25°C Excursion permitted : 15°C to 30°C should not be exposed: >40ºC Container closure system: Bottle of HDPE with cap and seal aluminium foil 112 capsules per bottle 4 bottles per carton 67 Clinical Trials 68 Trial 19: Indication: Maintenance treatment in patients with platinum sensitive relapsed ovarian cancer with germline BRCA mutation who are in response to platinum based chemotherapy Accelerated Approval? 25/06/2014: meeting of the committee ◦ 11 answered NO ◦ 2 answered YES New indication: use data trial 42 + supportive trials (2, 9, 12, 20, 24) 69 Single, open-label, non-randomized trial Phase II Non-comparative, multicenter Aim: to assess efficacy and safety of olaparib (400 mg x2/day) Patients with advanced cancers who have a confirmed genetic BRCA1/2 mutation N=317 patients 94% caucasian Median age : 58 years old 70 ≥ 18 years of age Confirmed documented deleterious or suspected deleterious BRCA mutation Histologically or, cytologically confirmed malignant solid tumor refractory to standard therapy and for which no suitable effective standard therapy exists For the ovarian cancer : progressive or recurrent disease according to RECIST 1.1 The analysis of all primary and secondary objectives occurred 6 months after the last patient has commenced study treatment 71 19 patients excluded No treatment 317 patients all cancer 298 patients received the treatment 105 patients with others cancers 193 patients had an ovarian cancer 56 patients with less than 3 chemotherapy 137 patients treated with 3 or more chemotherapy 72 D-28 : DO : Baseline radiological tumor assessment Start of the treatment Every 8 weeks : Assessment of the tumor Stop treatment when there is a disease progression or intolerance 73 Primary endpoints Secondary endpoints CR ORR Complete response Objective response rate PR PFS Partial response Progression free survival OS Overall survival DOR Duration of response DCS Disease control rate 74 Many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes Tumour lesions/lymph nodes ◦ Measurable ◦ Non-measurable Target lesions : into measurable lesions ◦ Maximum 5 lesions, maximum 2 per organ Non target lesions : all the other lesions 75 Complete response : CR ◦ Disappearance of all target lesions ◦ Reduction of any pathological lymph nodes (<10 mm) ◦ Disappearance of all nontarget lesions and normalisation of tumour marker level Partial response : PR ◦ 30% decrease in the sum of diameters of target lesions 76 77 78 Design Objectives of Study Endpoint gBRCAm (n) ≥3 lines chemotherapy Study 2 Phase I Expansion cohort Safety tolerability ORR 5 3 Study 9 Phase II Single Arm Study, multicenter, noncomparative Assess efficacy of 2 dose levels ORR 33 26 Study 12 Phase II Randomized Open-label Compare efficacy of 2 dosage PFS 32 16 Study 20 Phase II Single arm study Non-comparative Determine response rate and correlative markers of repsonse ORR 17 12 Study 24 Phase I Randomized Bioavailability for different FP ORR 20 11 79 205 patients: 137 from Trial 42 and 68 from 5 supportive trials 80 Most common adverse reactions : ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Anemia Nausea Fatigue (asthenia) Vomiting diarrhea dysgeusia dyspepsia headache decreased appetite ◦ nasopharyngitis/phary ngitis/URI ◦ Cough ◦ arthralgia/musculoske letal pain ◦ myalgia ◦ back pain ◦ dermatitis/rash ◦ abdominal pain/discomfort ◦ Perturbation of NFS 81 Including in warning and precautions : ◦ Myelodysplastic syndrome/Acute Myeloid Leukemia (2%) ◦ Pneumonitis (<1% ) ◦ Embryo-fetal toxicity 82 Data available from 13 phase 1 & 2 trials. No food effect Eliminaton by metabolism (CYP3A4) +++ Elimination by Renal route + ◦ No dose adjustement for IR but monitoring Mean-half time: 12 hours at the 400 mg dose Plasma protein binding of 89% Drug interaction with CYP3A4: Inhibitor Inducer Itraconazole [olaparib] Rifampicin [olaparib] Fluconazole [olaparib] Efavirenz [olaparib] 83 84 Parameters after Single Dose Olaparib in Trial 24 85 Medical Device 86 In vitro diagnostic device intended for the qualitative detection and classification of variants of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA 2 methods of DNA sequencing: ◦ BRACAnalysis CDx Sanger sequencing: senquencing and PCR to detect single nucleotide variants and small insertions and deletions ◦ BRACAnalysis CDx Large Rearrangement Test (BART® CDx): multiplex PCR detects large daletions and duplications 87 Samples from: ◦ Ovarian cancer patients ◦ Breast cancer patients ◦ People from families with or without a high risk for hereditary breast an ovarian cancer Samples selected to represent a range of variants detected by the device 89 Sanger sequencing: comparison with a validated next-generation sequencing ◦ 100 samples ◦ Overall agreement = 100% BART®: comparison to a validated microarraybased test ◦ 100 samples ◦ Overall agreement = 94% (95% CI: 87.4%-97.8%) Good accuracy of BRACAnalysis CDx 90 Sanger sequencing ◦ 5 samples to evaluate 6 DNA input concentrations ◦ Protocol: Optimal DNA input concentration: 20 ng ◦ Tolerance range from 1 ng to 100 ng BART® ◦ Protocol: optimal concentration of 8 ng ◦ DNA input levels from 2 ng to 12 ng generate similar results than with 8 ng Good sensitivity 91 Sanger sequencing: ◦ In silico analysis ◦ No non-specific sequence were predicted for any primer pair combinations BART® test: ◦ Bioinformatic program ◦ Non-specific products were not predicted for any of the primer pairs Highly specific 92 Assessment of interfering effects of : ◦ Endogenous substances in human: Hemoglobin, Albumin, IgG, Bilirubin ◦ Exogenous substance: K3EDTA ◦ Substance used in standard process of the device: ethanol bleach Interfering substances did not affect the performance of tests, except IgG at 60 g/L At 9,5 g/L of IgG, the acceptance criterial were met 93 Reproductibility: Test of 20 samples over 3 independant runs ◦ Overall agreement = 100% Repeatability: reproductible results across replicates of the same sample ◦ Sanger sequencing: one batch = 100% concordant results, an other 8 of 9 reactions were concordant ◦ BART®test: concordant results Good reproductibility and repeatability 94 To evaluate if the performance of the tests is robust to withstand process variations Sanger sequencing: ◦ PCR annealing temperature: +/- 1, 2, 3°C: positive for all T° ◦ Sequencing annealing temperature: +/- 1, 2, 3°C: positive for all T° Robustness of BART®: -3° -2° -1° 0 +1° +2°C +3°C ◦ PCR annealing temperature: ◦ Injection time: all conditions were concordant: except 20s Optimal: 6s, acceptable range from 2 to 10s Miscalled deletion results 95 DNA extraction ◦ No cross contamination were detected during extraction BART®test ◦ 10 samples ◦ Callable results and concordant with the expected results 96 Blood specimen: ◦ Blood samples stored at 2 different temperatures: 4°C (standard) 14, 30, 37 days 30°C 3, 5 and 7 days 30 days at 4°C and 5 days at 30°C Reagent stability: different reagents used in assays, stored under different temperatures and tested at defined time points Intermediate product stability 97 High specificity for all targeted regions in the BRCA1 and BRCA2 genes Good accuracy, sensitivity and specificity However, a limited range of variant types was included in some of the studies CDRH request additional testing 98 ● ● BRACAnalysis Cdx = in vitro medical device for the detection of gBRCAm The aim of BRACAnalysis clinical studies is to compare the results obtained with ● « local test » ● BRACAnalysis Cdx For a positive approval : BRACAnalysis Cdx results ≥ local test results ● 10 0 Retrospective study Non randomized Objective: ◦ To demonstrate clinical utility of BRACAnalysis CDx ◦ To analyse efficacy and safety data obtained with BRACAnalysis CDx to assess efficacy and safety olaparib Endpoints: ◦ Subjects with response ◦ Objective response rate ◦ Duration of response 10 1 Design 317 patients Advanced cancer 193 patients with ovarian cancer and gBRCAm + 61 patients available for Retrospective testing with BRACAnalysis CDx -2 false positives 137 patients had received 3 lines of chemotherapy Tested with local test 59 patients with confimed gBRCAm with BRACAnalysis CDx 78 patients tested with local test (samples not available) 10 2 137 patients had received 3 lines of chemotherapy tested with local test 59 patients with confimed gBRCAm with BRACAnalysis CDx • • • • • • Subjects with response : 33.6% ORR: 0.34 (0.26-0.42) DoR: 7.9 (5.6 - 9.6) 78 patients tested with local test (samples not available) Subjects with response: 40.7% ORR: 0.41 (0.28-0.54) DoR: 8.0 (3.8 - NC) 10 3 59 patients with confimed gBRCAm with BRACAnalysis CDx • • • Subjects with response: 40.7% ORR: 0.41 (0.28-0.54) DoR: 8.0 (3.8 - NC) = • • • 137 patients had received 3 lines of chemotherapy tested with local test Subjects with response : 33.6% ORR: 0.34 (0.26-0.42) DoR: 7.9 (5.6 - 9.6) Non significative difference between the results Results are similar to those observed in the overall population which supports effectiveness of the device 10 4 Risks are associated with the interpretation of result testing: False + => Not clinical benefit => Adverse reactions of olaparid False – => not obtain olaparid therapy Delayed results => delayed in treatment 10 5 ● ● ● Benefit/Risk is favorable BRACAnalysis Cdx is an aid in selecting patients BRACAnalysis Cdx + Olaparib ● – Improvement in ORR and DoR PMA accelerated approval on December, 19, 2014 with the drug Lynparza® – Additionnal testing of samples – Bridging study with ongoing clinical trial assay 10 6 Name Review 10 7 Office of Prescription Drug Promotion CDER Division of Medication Error Prevention and Analysis (DMEPA) Evaluate the proposed proprietary name (PPN) : from a safety and promotional perspective 1. Promotional Assessment 2. Safety Assessment LYNPARZA® 10 8 OPDP evaluates PPN to determine if they are overly fanciful : - misleadingly imply unique effectiveness or composition - contribute to overstatement of product efficacy, minimization of risk - broadening of product indications, or making of unsubstantiated superiority claims. OPDP determined the PPN is acceptable from a promotional perspective. NB : DMEPA concurred with the findings of OPDP's promotional assessment of the proposed name. 10 9 No United States Adopted Names (USAN) stem present in the proprietary name A single word with no derivation or intended meaning → Does not contain any components that are misleading or can contribute to medication error Two studies : - FDA Name Simulation Studies - Phonetic and Orthographic Computer Analysis (POCA) 11 0 No United States Adopted Names (USAN) stem present in the proprietary name A single word with no derivation or intended meaning → Does not contain any components that are misleading or can contribute to medication error Two studies : - FDA Name Simulation Studies - Phonetic and Orthographic Computer Analysis (POCA) 11 1 The orthographic appearance of the PPN is evaluated using a number of different handwriting samples. 93 practitioners participated in the prescription studies 22 interpreted the name correctly as LYNPARZA® 11 2 Common misinterpretations : - letter « i » for « y » (n=10) - letter « Z » for « L » (n=16) These other interpretations did not overlap, sound or look similar to any currently marketed products 11 3 No United States Adopted Names (USAN) stem present in the proprietary name A single word with no derivation or intended meaning → Does not contain any components that are misleading or can contribute to medication error Two studies : - FDA Name Simulation Studies - Phonetic and Orthographic Computer Analysis (POCA) 11 4 POCA = system designed by the FDA. Used to evaluate proposed names via phonetic and orthographic algorithm. LYNPARZA® POCA score = 100% 11 5 Moderately Similar Names with overlap or numerical similarity in Strength and/or Dose LYNPARZA® LENTARD® POCA No. Proposed name : Proposed name : Score LYNPARZA® LYNPARZA® (%) Strength : 50 mg Strength : 50 mg The infix and suffix of this Usual Dose : 8 capsules Usual Dose : 8 capsules name pair have sufficient (400 mg) by mouth twice (400 mg) by mouth twice orthographic differences. daily daily The second syllabe of this Clinpro 5000 52 pair has phonetic 7. Lokara name differences and Lynparza Flanders 52 8. Lovaza contains an extra syllable. POCA Score (%) 3. Lemtrada 57 9. Lysteda 52 4. Lentard 66 10. ****** 50 No. 1. 2. 5. 6. 52 50 Lentard MC of the 24 names54contained 11. in Synera 50 Analysis this table determined none of the names will pose a 52 risk for confusion. Linjeta 12. Translarna 50 11 6 1. Promotional Assessment 2. Safety Assessment The proposed proprietary name is acceptable from both a promotional and safety perspective. 11 7 Post Marketing Studies REMS ? 11 8 Drug Safety and Risk Management Advisory Committee Advises on : ◦ risk management, ◦ risk communication, ◦ quantitative evaluation of spontaneous reports for drugs 11 9 1. In pivotal study : 223 patients treated Adverse reaction reported in 20% or more of patients: ◦ ◦ ◦ ◦ ◦ ◦ 2. 3. 4. anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, … Adverse events in the clinical trial program are similar to those seen in clinical practice with other chemotherapies Laboratory abnormalities : 25% (Increase in creatinine, decreases in hemoglobin,lymphocytes, absolute neutrophil count, and platelets) Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. Fatal cases of pneumonitis occurred in <1% of patients treated addressed in Warnings and Precautions (similar to other drugs used in the treatment of ovarian cancer) 12 0 Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) The development of MDS/AML in recurrent ovarian cancer Linked with the use of other DNA damaging chemotherapies such as alkylating agents and platinum-based chemotherapies. The rate of MDS in the general population according to data from the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (Seer) program is approximately 3.3 per 100,000 12 1 When there are fewer healthy blood cells, infection, anemia , or easy bleeding may occur. 1/3 changes in AML 12 2 In the overall clinical development program, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with olaparib, and of these cases, 17/22 were fatal. FDA reviewers note that the reported incidence of MDS/AML in the olaparib database is higher than the expected incidence in the general population and in an ovarian cancer population treated with prior platinum-based therapies 12 3 Safety signal that warrants further investigation as a postmarketing requirement that may provide a better characterization of this risk. Provide annual summaries of all cases of AML/MDS identified in patients treated with Lynparza (olaparib). These reports should ◦ summarize all cases identified up until that reporting date (new cases and those reported in previous years), ◦ include patients treated with Lynparza on clinical trials and outside of clinical trials (including spontaneous safety reports) 12 4 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Study 02, SOLO-2): randomized doubleblind, placebocontrolled, multi-center trial to assess the efficacy of olaparib maintenance monotherapy in : -relapsed high grade serous ovarian cancer (HGSOC) patients -or high grade endometrioid cancer with BRCA mutations who have responded following platinum based chemotherapy To provide information on the effect of olaparib on these patients Ongoing Study 10 a randomized trial To establishg the superiority of olaparib over physician’s choice single agent chemotherapy in the treatment of platinum sensitive relapsed ovarian cancer in patients carrying deleterious or suspected deleterious germline BRCA1/2 mutations To provide information on the superiority of olaparib compared with single agent chemotherapy Planned 12 5 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Study 06 To assess the pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Renal Function or Renal Impairment To provide information on the use of olaparib in patients with reduced liver function. Ongoing (Submit the final report) Study 05 An Open-label, Nonrandomized, Multicenter, Comparative, Phase I Study to determine the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Hepatic Function or Mild or Moderate Hepatic Impairment. To provide information on the use of olaparib in patients with reduced hepatic function. Ongoing (Submit the final report) An Open-label, Nonrandomized, Multicenter, Comparative, and Phase I Study 12 6 REMS is not necessary to ensure the benefits of olaparib outweigh the risks in patients •Accelerated approval procedure •Since these risks are not uncommon or unknown to this prescribing population, these risks can be communicated through professional labeling. 12 7 Conclusion 12 8 Date of approval : december 2014 (first-in-class) Indicated for monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy Companion diagnostic for BRCA mutation detection Safety concerns : acute myelogenous leukemia and myelodysplastic syndrome ► post-approval safety studies Futur other indications (breast, pancreas, prostate cancers…) ? Any questions?