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Dapagliflozin FARXIGA® FDA DOSSIER MASTER AREIPS – MARCH 2016 G. BARRE ; A. CAILLE ; M. CAPPADORO ; O. CHANU ; S. DANIEL ; P. DESBORDES ; L. DIRSON ; C. GANDOIN ; E. GIL ; A. KAIKMAXOGLOU ; H. MHAOUCH ; M. PERNELLE ; L. PERRIAT ; C. PICARD ; M. PLEURMEAU ; S. STIRN Content Introduction Name review Pharmacology CMC Non clinical trials Clinical trials Post-marketing Conclusion 2 Introduction 3 Physiopathology of T2DM 4 Statistics on diabetes type 2 29.1 million people or 9.3% of the U.S. population have diabetes: -Diagnosed =21.0 million people -UnDiagnosed =8.1 million people Cost of diabetes : -Direct medical costs : $174 billion -Indirect medical costs (disability, wor loss, premature mortality ): $58 billion 5 Diabetes itself is a cardiovascular risk 6 Current therapies LIMITATIONS Hypoglycemia Weight gain GI side effects Injected No long-acting 7 Glycemic goal for T2DM ADA IDF AACE/ACE HbA1c (%) < 7,0 < 6,5 < 6,5 FPG (mg/dl) < 130 < 110 < 110 2 Hr PG (mg/dl) < 180 < 140 < 140 8 Unmet medical needs 62% of patients on oral therapy are not at ADA goal of HbA1c < 7% 9 SO WE NEED A NEW THERAPEUTIC OPTION! 10 Dapagliflozin MECHANISM OF ACTION (MOA) TARGETED ORGANS 11 Phlorizin Derived from apple tree bark (first isolated in 1835) Antidiabetic effect discovered (1987) But… ◦ Very poor oral bioavailability ◦ Non-selective inhibitor of both SGLT-1 and SGLT-2 ◦ Serious adverse events (diarrhea, dehydration) C-glucoside discovered = Dapagliflozin • Indications • Type 2 diabetes in adults • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 12 A novel insulin-independent approach to remove excess glucose SGLT2 inhibitors Inhibition of SGLT2 at PCT Prevention of reabsorption of glucose Excretion of glucose in urine (glycosuria) Reduction of blood glucose level 13 SGLT2 Sodium-Glucose Linked Transporter 2 = Sodium-dependent glucose co-transporters Two kinds of SGLTs ◦ SGLT1 ◦ SGLT2 SGLT2 inhibitors SGLT2 inhibitors Glycosuria Glycosuria Net calorie loss of approximately 200-300 kilocalories per day Glucose acts as osmotic diuretic Dehydratation Weight loss Blood pressure reduction 14 Targeted organs 15 Targeted organs Hypotension Genital mycotic infections Hypoglycemia Ketoacidosis 16 But what about the history? 17 First review cycle To be submitted : additional data from studies 18 & 19 ; updated analyses for CV safety, malignancy and hepatic safety July 2012 : Applicant files a formal dispute resolution request (FDRR) Nov 2011 : major amendment is submitted Dec 2010 : NDA submitted July 2011 : EMDAC vote 2008 : new guidance + rosiglitazone (2010) : CV risk Jan 2012 : FDA issues a complete response letter Sept 2012 : dispute appeal is denied Emdac voted not to support approval of dapa based on current data Do the efficacy andthe safety providecancers substantial evidence to support approval to more data are needed regarding risksdata of bladder and liver improve glycemic control injury 6 Yes 9 No 18 First review cycle July 2012 : Applicant files a formal dispute resolution request (FDRR) Nov 2011 : major amendment is submitted Dec 2010 : application submitted July 2011 : dapa application presente to EMDAC Jan 2012 : FDA issues a complete response letter Sept 2012 : dispute appeal is denied Discordance between CV safety data from initial studies vs 18-19 studies K bladder and hepatic toxicity Path forward : additional clinical trial data + analysis on K events ; hepatic safety and CV meta-analysis 19 Second review cycle Jan 2014 : July 2013 : NDA resubmission APPROVAL Dec 2013 : FDA Advisory Committee recommends the investigational SGLT2 inhibitor dapa for treatment of type 2 diabetes in adults Are data sufficient to prove an acceptable CV risk profile ? 10 Yes ; 4 No Does the benefits of dapa outweigh the identified risks (K bladder ; infection ; CV event) to control glycemic in DBT2 13 Yes ; 1 No Consensus : post-marketing studies 20 Name review 21 Name Approval Players Office of Prescription Drug Promotion CDER Division of Medication Error Prevention and Analysis (DMEPA) 1. Promotional Assessment 2. Safety Assessment Evaluate the proposed proprietary name (PPN) from a safety and promotional perspective 22 Name Review • Submission of the PPN (Proposed Proprietary Name) : FORXIGA® Sept 2011 • ACCEPTANCE OF FORXIGA® by OPDP and DMEPA Dec 2011 • Resubmission of PPN July 2013 • Re-review of PPN by FDA « fo » is reserved for phosphoro-derivatives not acceptable • Proposition of FARXIGA® by the DMEPA August 2013 • review by OPDP for promotional assessment ACCEPTANCE FARXIGA® 23 Pharmacology P HA R MACOKI NETICS P HA R MACODYNAM ICS I N T RINSIC/ EXTRINSIC FAC TORS 24 Pharmacokinetics Absorption ◦ Tmax : 1 hour (PO, 10 mg) ◦ F% : 77,8 Distribution ◦ Protein Binding : 91% High fixation Metabolism ◦ Primary metabolite in human = dapagliflozin 3-O-glucuronide ◦ UGT1A9 is the major enzyme ◦ T1/2 : 12,9 hour Excretion ◦ 96% of the administered dose recovered in the urine (75%) and feces (21%) ◦ In urine 61% of primary metabolite ◦ 1,2% of dose as parent drug Dose-proportionality 25 Pharmacodynamics Healthy subjects ◦ Wide dose range (2,5 mg to 500 mg) in single dose (120 h) ◦ Wide dose range (2,5 mg to 100 mg) in multiple dose (14 days) T2DM ◦ 25 mg or 100 mg for Day 1 and Day 14 T2DM = Type 2 Diabetes Mellitus Dose-response relationship for effectiveness supports the proposed dose of 10 mg QD For doses > 10 mg, increased incidence of genitourinary infection, hyperphosphatemia and increases in haematocrit 26 Intrinsic factors Renal impairment ◦ ◦ ◦ ◦ ◦ Healthy subjects with normal renal function Subjects with T2DM and normal renal function Subjects with T2DM and mild renal impairment Subjects with T2DM and moderate renal impairment Subjects with T2DM and severe renal impairment 27 Intrinsic factors • Hepatic impairment • Age • Weight • Gender • Race/Ethnicity • Paediatric patients No dose adjustment based on intrinsic factors 28 Extrinsic factors Co-administered drugs Diet ◦ In presence of high fat meal no change in AUC Not evaluated : ◦ Herbal products ◦ Smoking ◦ Alcohol use No dose adjustment based on extrinsic factors 29 Chemistry, Manufacturing & Control CMC 30 Active Pharmaceutical Ingredient (API) Dapagliflozin propanediol monohydrate Formule C21H25ClO6 . C3H8O2 . H2O Chemical name (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,(2S)propane-1,2-diol (1:1) monohydrate Molecular weight Dapagliflozin propanediol monohydrate: 502,98 g/mol : Dapagliflozin: 408,87 g/mol Biopharmaceutics Classification System (BCS) Class 3 (low permeability, high solubility) 31 Active Pharmaceutical Ingredient (API) Dapagliflozin propanediol monohydrate The development of the manufacturing process Stability On 30 batches Quality by Design (QbD) - Long-term conditions 25°C/60% RH - Intermediate conditions 30°C/65% RH - Accelerated conditions (40°C/75% RH) →during 6months - Diverse stress conditions Manufacturer: BMS Facility in Swords, Ireland 32 API specifications at release Characters: ◦ Appearance ◦ Color Identification: ◦ IR or Raman, and HPLC Assay: ◦ Dapaglifozin content by HPLC These specifications were identified by the applicant as critical quality attributes established for the drug substance linked to patient safety. Test: ◦ Water content ◦ Residual solvents ◦ Purity ◦ … 33 Finished Product Farxiga®, Tablets for immediate release Strengths - 5 mg - 10 mg Rx/OTC Dispensed Rx Container closure systems - HDPE bottles, 95-cc (30-count) and 200-cc (90-count) Blister - Active ingredient:Dapagliflozin - Excipients: Anhydrous lactose, microcristalline cellulose, silicon dioxide, crospovidone, magnesium stearate Composition 34 Finished Product Farxiga®, Tablets for immediate release The development of the manufacturing process Quality by Design (QbD) - Long-term conditions 25°C/60% RH On-going (available results at 24 Stability On 6 batches (3 for 5mg and 3 for 10mg) months) - Intermediate conditions 30°C/65% RH - Accelerated conditions 40°C/75% RH during 6 months → The stability protocol includes matrix testing design. Shelf-life and Storage condition - 24 months - Store at 25°C, excursions permitted 15°C to 30°C into HDPE bottles or into blisters Manufacturers: - BMS manufacturing company in Humacao, US - BMS manufacturing company in Mount Vernon, US 35 FP specifications at release and at shelf-life Specifications at release Specifications at shelf-life Characters: ◦ Appearance (visual examination) Identification: Idem + Impurities ◦ IR ◦ HPLC Assay: ◦ Dapaglifozin content by HPLC Other tests: ◦ Disintegration (surrogate of dissolution) ◦ Content uniformity These specifications were based on the drug product critical attributes indentified by risk assessment and developmental studies. 36 Excipient specifications According to the US pharmacopoeia 37 Recommendations Recommendation and Conclusion on Approvability ◦ From CMC point of view this application is recommended for Approval. ◦ The recommendation for the acceptability of the manufacturing sites is still outstanding. ◦ The CMC recommendation does not incorporate any potential facility inspection issues. Recommendation on Phase 4 (Post-Marketing) Commitments and Risk Management Steps ◦ None 38 Non clinical trials 39 MRHD - Maximum Recommended Human Dose Selectivity – in vitro studies 436 fold 207 fold 130 fold In vivo testing with X MRHD 40 Toxicology MRHD Mecanism related ( x dose) Non mecanism related High dose (mortality) Toxicity 41 Distribution Steady state volume of distribution > total body water → Extravascular distribution Concentration : 1% at 48 hours in tissues → no drug accumulating 42 Excretion Mean Concentration of Radioactivity in rat Blood, Plasma and Milk Following a Single Oral Administration of [14C]Dapagliflozin at 5 mg/kg Dapagliflozin not recommended for nursing women 43 General toxicology Single-Dose Oral Toxicity Study •Multilple mortality at HD Rats 6 months DAPA 85-3097x MRHD • Major target organs : kidneys, heard, bones, liver • Dose-dependent : DAPA 128-3269x MRHD ↗ weights :kidneys, adrenal, liver Dogs 12 months ↗ urinary volume ↗glucose, ↗ calcium, phosphorus, protein •Urothelial hyperplasia of the bladder and/or lining of the renal pelvis In addition, a 3 month toxicity study was conducted in mice 44 Reproductive toxicity FERTILITY EARLY EMBRYONIC DEVELOPMENT PRE & POST-NATAL DEVELOPMENT JUVENIL ANIMALS Recommended against the use during the second and third trimesters of pregnancy and during nursing 45 Carcinogenicity • Exploring whether dapagliflozin had activity that may contribute to bladder cancer development Tumor Promotion Investigations in vitro studies study of a bladder tumor xenograft implanted in the flank of immunodeficient mice Dapagliflozin did not increase the incidence of any tumor in rats and mice at drug exposures reaching 131x and 72x the clinical dose Dapagliflozin had not been found to be a direct carcinogen/tumor promoter, after review of the applicant’s standard 2-year rodent carcinogenicity study 46 Genetic toxicity in vitro and in vivo AMES assay Micronucleus → Dapagliflozin was not mutagenic or clastogenic → Dapagliflozin and its identified metabolites are unlikely to be clastogenic in human subjects Chromosomal aberation assay 47 Conclusion . Data from additional animal studies is not likely to supplant conclusions about the risk of bladder cancer derived from human clinical trial and postmarketing data 48 Clinical trials 49 Overview of Clinical Studies 50 Choice of Primary end-points : - Change from baseline to week 24 in HbA1c (%) Why ? - Surrogate measure of glycemia that correlates blood glucose over the preceding 3 months Standardized methodology reduce inter-laboratory measures Reliable & predictive Reduce microvascular complications (and may lower macrovascular complications) → Decrease 1% of Hb1Ac => Decrease 21% complications 51 EFFICACY 52 Overview of Efficacy ● Placebo-controlled studies - Glycemic efficacy - Weight - Blood pressure ● Active-controlled studies - Vs Metformin - Vs Glipizide ● Long-term extension data - 52 weeks 53 Glycemic Efficacy Significant HbA1c Reduction across studies at week 24 54 Overview of Efficacy ● Placebo-controlled studies, double-blind - Glycemic efficacy - Weight - Blood pressure ● Active-controlled studies, double-blind - Vs Metformin - Vs Glipizide ● Long-term extension data - 52 weeks 55 Effects on weight and SPB Body Weight Reduction vs Placebo observed across studies at Week 24 LDL (mg/dL) Significant systolic blood pressure reduction at Week 12 56 Overview of Efficacy ● Placebo-controlled studies - Glycemic efficacy - Weight - Blood pressure ● Active-controlled studies - Vs Metformin - Vs Glipizide ● Long-term extension data - 52 weeks 57 Results : Dapagliflozin vs Metformin Combination therapy was superior to both dapa and metformin monotherapy treatment arms the both the dapa 5mg and 10mg dose groups. Dapa + Metformin superior to individual monotherapies 58 Overview of Efficacy ● Placebo-controlled studies, double-blind - Glycemic efficacy - Weight - Blood pressure ● Active-controlled studies, double-blind - Vs Metformin - Vs Glipizide ● Long-term extension data - 52 weeks 59 Results : Dapagliflozin vs Glipizide HbA1c reductions with Dapa equivalent to Glipizide at Week 52 60 Overview of Efficacy ● Placebo-controlled studies - Glycemic efficacy - Weight - Blood pressure ● Active-controlled studies - ● Vs Metformin Vs Glipizide Long-term extension data - 52 weeks 61 Results : Dapagliflozin + Metformine VS. Metformine + Glipizide 62 Dapagliflozin Efficacy Conclusion ● Glycemic Efficacy – HbA1c lowering with 10mg equivalent to Metformin and to Glipizide – Demonstrated in a broad range of patients with T2DM – Sustained over 2 years ● Consistent reductions in body weight ● Reductions in SBP in hypertensive patients with T2DM 63 SAFETY 64 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 65 AEs reported & deaths 66 Summary of Adverse Events ★ Significant adverse events: ★ Specific Primary Safety Concerns: - - - Bladder cancer Malignant or unspecified tumors (including Breast Cancer) Hepatic safety CV Safety → Major Adverse Cardiac Events (MACE) - Hypoglycemia Genital infections Urinary tract infections Renal impairment and volume depletion events Bone safety focused primarily on, which were identified as significant safety concerns during the first review. 67 ★ Common Adverse Events (>1%) 68 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 69 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 70 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 71 Impact on renal function 72 November 2011 Major Amendment • FDA asks for updated analyses to – Determine impact of additional exposure on liver safety signal – Determine impact of additional exposure on malignancy signal – Assess the estimate of CV-risk with additional data • Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes’, issued December 2008, “FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.” 73 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 74 No Signal for Drug Induced Liver Injury No preclinical liver signal No increases in liver test abnormalities All cases of combined elevations of aminotransferase (>3X ULN) and bilirubin (>2X ULN) have alternative diagnoses 75 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 76 Bladder cancer concerns 2011 : No bladder cancer in vitro (animal data) 2011 : 10 (+1 with placebo) cases of bladder cancers in vivo (humain data) 2013 : No bladder cancer in vitro (animal data) 2013 : FDA asked for updated information – Results : Dapagliflozin Comparator 9/1626 (0,15%) 1/1150 (0,03%) Populations : IRR = 5,428 (IC 95% - 0,712 ; 245,10) • Risk factors : 60% used tabacoo and history of using tabacoo, some of them were taking pioglitazon • 5/9 patients on dapagliflozin had bladder cancer within 1-2 years compared to none in placebo group • 4/9 patients on dapagliflozin had bladder cancer within 6 months compated to one in placebo group 77 Bladder cancer explanations FDA concluded no link between bladder cancer and dapagliflozine due to : No statistically significant data over 9 cases (4 30 months) Patients may had cancer previously and were not diagnosed + long-time evolution More frequent monitoring due to higher rates of urogenital AEs among dapagliflozin patients Event rates for males observed in the active treatment arms significantly exceeded the rates expected in an age-matched reference diabetic population. “Dr. Hampp points out that the limitations of these analyses preclude a conclusion of an association between dapagliflozin treatment and bladder cancer risk, but states the rate ratios unfavorable to dapagliflozin cannot be ignored, must be taken into account for a thorough assessment of the risks and benefits regarding a regulatory action and, if approved, must continue to be evaluated postmarketing.” 78 Overview of Safety ● ● General Safety - Hypoglycemia - Weight - Renal function / Urinary tract infections Safety topic of interests - Hepatic safety - Malignancy assessment - CV safety 79 Study CV: original NDA Submission → conducted to compare the effect of standard treatment (target LDL-C level: <120 mg/dL (JASGL 2007 target level)) and intensive treatment (target LDL-C level: <70 mg/dL) in the prevention of major adverse cardiac events (MACE) in hypercholesterolemia patients with concomitant type 2 diabetes and hypertension. - Interventionnal study Randomized Efficacy study Open label Single Group Assignment 80 *in 2011 81 CV Endpoint: original NDA Submission NON SIGNIFICANT 82 Study Meta-analysis CV for New application New application : 2 updated meta-analysis of a pool of fourteen Phase 2b and Phase 3 clinical trials to support CV safety of dapagliflozin Primary endpoint : composite of time-to-first event of CV death myocardial infarction (MI), stroke, and hospitalization for unstable angina (MACE-plus), with all events adjudicated by an independent endpoints committee, blinded to treatment assignments → HR point estimate of this analysis was 0.67 (98%CI: 0.38-1.18) in favor of dapagliflozin over comparators 83 Study Meta-analysis CV for New application No unacceptable increase in CV risk No risk of over mortality proven demonstrated 84 Dapagliflozin Safety Conclusion FDA concluded : AEs with significant meaning : Hepatic failure, tumors (especially bladder cancers), CV failure Post-Marketing requirements 85 Post-marketing requirements 86 RMP (1/4) Risk Management Plan December 2010 : RMP submitted by the sponsors on Two main categories of risks : 1/ Identified risks : genital infections and urinary tract infections 2/ Potential risks : hypoglycemia, volume depletion, clinical consequences of increased hematocrit, renal impairment/failure, bone fracture and liver injury + limited informations in populations as ederly, pregnancy, … NO REMS (Risk Evaluation and Mitigation Strategy) 87 RMP (2/4) Risk Management Plan • Revised version of the RMP included breast and bladder cancers August 2011 September 2011 October 2011 • Revised version of the label including a Medication Guide and a redline version of the revised RMP • FDA meeting is scheduled (discussion of data from ongoing clinical trials, a revised PV plan) • Risks of breast and bladder cancer • Medication guide to replace the proposed patient package insert • Update to the cardiovascular outcome trial synopsis 88 RMP (3/4) Risk Management Plan July 2013 : resubmission but without REMS or RMP Use of the previous RMP 89 RMP (4/4) Risk Management Plan Routine pharmacovigilance activities include the following to address all the identified and potential risks Targeted questionnaires : events of genital infections (serious), UTI (serious), renal impairment/failure and liver impairment Supplemental CRF (Case Report Form) : more detailed information and assessment in clinical studies Evalution/communication of potential risk in product labeling Cumulative review of events of interest Describe results of cumulative safety reviews in aggregate reports Pharmacoepidemiology studies ++ 90 DECLARE – TIMI58 (Study D1693C00001) (1/2) Dapagliflozin Effect on Cardiovascular Events CV outcome trial (CVOT) asked by FDA (first review cycle) = morbidity/mortality study Designed in accordance with the recommendations of the 2008 FDA Guidance […] Evaluating Cardiovascular Risk in New Antidiabetic Therapies […] Randomized, controlled, double blind, Phase III 17 150 patients with T2DM : CV disease or at least two CV risk factors 91 DECLARE – TIMI58 (Study D1693C00001) (2/2) Dapagliflozin Effect on Cardiovascular Events Superior study dapa 10mg oral dose versus placebo The primary outcome measure: reduction of Major Adverse CV Event (MACE) = CV death,myocardial infarction (MI), or ischemic stroke 6 years Study start date : April 2013 92 http://www.timi.org/index.php?page=declare-timi-58 93 Conclusion 94 Conclusion • Dapagliflozin FARXIGA® • Indications • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus • Approval • Many challenges for approbation: 2 submissions • No animal data which show signs of carcinogenesis BUT clinical cases of bladder cancer in clinical trials • RMP BUT no REMS • Study DECLARE The weight of evidence does not support a causal link between Dapagliflozin and bladder cancer 95 Sources Center for Drug Evaluation and Research – Administrative and correspondence documents Center for Drug Evaluation and Research – Chemistry review(s) Center for Drug Evaluation and Research – Clinical pharmacology and biopharmaceutics review(s) Center for Drug Evaluation and Research – Cross discipline team leader review Center for Drug Evaluation and Research – Medical review(s) Center for Drug Evaluation and Research – Microbiology/virology review(s) Center for Drug Evaluation and Research – Proprietary name review(s) Center for Drug Evaluation and Research – Pharmacology review(s) Center for Drug Evaluation and Research – Risk assessment and risk mitigation review(s) Guidance for Industry – Diabetes Mellitus – Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes 96 97