«Les défis du développement industriel des thérapies cellulaires et géniques une perspective règlementaire Européenne et Américaine»

Transcription

1 «Les défis du développement industriel des thérapies cellulaires et géniques une perspective règlementaire Européenne et Américaine» Anne-Virginie Eggimann, M.Sc. Vice President Regulatory Science, bluebird bio, Inc 19 March 2015

2 ABSTRACT Challenges and opportunities in the development of cell and gene therapy products an EU/ US regulatory perspective illustrated with case studies. In the European Union, cell and gene therapy medicinal products must seek centralized marketing authorization under the framework of the Advanced Therapy Medicinal Product (ATMP) Regulation(Regulation (EC) 1394/2007 amending Directive 2001/83/EC and Regulation (EC) No 726/2004) unless they are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient ( hospital exemption ); or if they are being developed in a clinical trial under Clinical Trial Directive 2001/20/EC. In the latter two cases, the national authorities of each Member State are responsible for their regulation. In the US, cell and gene therapy products, also referred to as Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P's) are regulated solely by the FDA and fall under different framework depending on whether they are considered to be minimally manipulated (Section 361 of the Public Health Service Act) or not (Section 351 of the PHS Act), and whether they are marketed products or products in clinical development. This presentation will provide details on these regulatory frameworks with illustration from specific examples, including feedback received from regulatory agencies during the development of bluebird bio gene therapy products. The presentation will also provide a brief overview of the anticipated improvements in the EU Clinical Trial Directive and the ATMP Regulation, as well the current regulatory trends applicable to the development of advanced therapy products. 2

3 bluebird bio Strategic Intent Severe Genetic Diseases Hematopoietic Stem Cells (HSCs) Immunotherapy T Cells Lentiviral Gene Delivery High Quality and Large Scale Cellular Transduction Capabilities Global Gene Editing MegaTALs/Homing Endonucleases Deliver transformative data in the clinic on a global scale Advance SGD and immunotherapy products through late stage clinical trials Leverage, integrate and grow core technologies to build a pipeline and collaborations for the long-term Engage with regulatory authorities and payers to chart the course for one-time transformative therapies 3

4 Gene Therapy Platform Capabilities Drive Pipeline Slides from Nick Leschly s presentation at JP Morgan in January

5 How Our Gene Therapy Approach Works Produce Virus With Therapeutic Payload Isolate Target Cells From Patient Transduce Target Cells ex vivo Test & Re-infuse Gene Modified Cells <1 Week 4-6 Weeks (when ready) 2 Weeks Investments in Product Enhancements Improved process Selective vector changes Results ü fold reduction in non-infectious viral particles ü 3x vector copy number increase (in vitro) 5

6 bluebird Pipeline Products Program Area Preclinical Phase 1/2 Phase 2/3 Rights CNS Diseases Target Milestones Lenti-D Childhood Cerebral ALD Starbeam Study* Worldwide Complete enrollment Hematologic Diseases β-thalassemia/scd (France) HGB-205 Study** Complete enrollment & present data LentiGlobin β-thalassemia (U.S./Thailand/Australia) Northstar Study** (HGB-204) Worldwide Complete enrollment, present data & define regulatory path Sickle Cell Disease (U.S.) HGB-206 Study Enroll patients & present data Oncology CAR T Cells Hematologic/Solid Tumors Global Celgene Collaboration Initiate clinical study in early 2016 Research Early Pipeline Undisclosed + Gene Editing Worldwide Advance preclinical pipeline * The Phase 2/3 Starbeam Study is our first clinical study of our current Lenti-D viral vector and product candidate ** The Phase 1/2 HGB-205 and Northstar Studies are our first clinical studies of our current LentiGlobin viral vector and product candidate 6

7 Clinical Programs 7

8 β-thalassemia Major: Disease Overview Disease β-thalassemia major (e.g. transfusion-dependent) Monogenic, severe anemia Loss of or reduced β-globin production Poor quality of life and shortened lifespan Current Treatments Frequent, chronic transfusions leading to iron overload and organ failure Ongoing iron chelation, frequently suboptimal Allogeneic transplant can be curative (rarely used) - Finding a suitable match - Morbidity/mortality with graft rejection, graft versus host disease and immunosuppression Epidemiology Global prevalence ~288K; incidence ~60K US/EU prevalence (treated) ~15K; incidence ~1.5K % severe/major Affects people of Mediterranean, Middle Eastern, South Asian and SE Asian descent 8

9 β-thalassemia: Innovative Vector Design Philippe Leboulch IN-VIVO BIOMARKER ANTI-SICKLING PROPERTIES βs βs βs β-87 V F T L V F Q L polymerization destabilization 9

10 β-thalassemia: Clinical Trial Summary Second Generation BB305 Vector HGB-205 (HGB-204) Phase 1/2, multi-center, global study Phase 1/2, single-center study in France N=15 subjects Centralized transduction for drug product manufacturing Positive data presented at ASH 2014 annual meeting Enrollment completion expected in 2015 N=7 subjects Positive data presented at ASH 2014 annual meeting First subject with SCD ever treated with gene therapy in 2014 Enrollment completion expected in

11 Demographics and Baseline Characteristics for Treated Subjects with β-thalassemia Major TRIAL Northstar* HGB-205 Subject Age/Sex 18/F 21/F 20/F 26/F 18/F 18/F 16/M Country of birth USA Thailand Pakistan Australia USA Syria France Genotype β0/βe β0/βe β0/β0 β0/β0 β0/β+ β0/βe β0/βe Transfusion requirement (mls/kg/year) CD34+ VCN (preinfusion) CD34+ cell count (x10 6 /kg) Follow-up (months)*** /1.1** 0.7/0.7** **** 3 1 < * Drug products for untreated Subjects 1109 and 1110 have been produced resulting in VCNs of 0.6/0.6 and 0.7 respectively ** If more than one drug product was manufactured the VCN of each product lot is quantified *** Data as of December 1, 2014 from an open database and is subject to change **** Efficacy data only available for 1 month follow-up post-transplant 11

12 Clinical Safety for Treated Subjects with β-thalassemia Major ` Neutrophil engraftment ANC > 500/µL Platelet engraftment Unsupported platelet count > 20,000/µL Subject 1102 Subject 1104 Subject 1106 Subject 1107 Subject 1201 Subject 1202 Day +17 Day +18 Day +29 Day +14 Day +13 Day +15 Day +28 Day +31 Day +30 Day +27 Day +17 Day +24 Non-laboratory Grade 3 AEs postinfusion Mucositis Bacteremia Febrile neutropenia Mucositis Mucositis Epistaxis Febrile neutropenia Mucositis Infection Headache Premature menopause Mucositis Mucositis* SAEs post-infusion None Catheter Thrombosis Data from Northstar as of November 21, 2014; Data from HGB 205 as of October 27, 2014 Subject 1108 was infused in November 2014 and no data is available Subject 1201 had an asymptomatic Grade 3 AST and ALT elevation from Day 23 to Day 90 * Mucositis on Subject #1202 started 1 day before infusion None None None None All AEs consistent with myeloablative conditioning No Grade 3 AEs related to drug product, no RCL at 3 and 6 months Integration site analysis on 3 subjects to-date, reveals highly polyclonal (>1000 clones) reconstitution at 3 and 6 months, without clonal dominance Data as Presented at ASH

13 Consistently Robust βa-t87q-globin Levels Subject HbA T87Q Hb A 2 Hb F Hb E Hb A Hb g/dl Months post-drug product infusion 13

14 All Subjects with at Least 3 Months of Follow-up are Transfusion-Free, Regardless of Genotype Days Transfusion-Free Days Transfusion-Free as of December 1, 2014 β0/βe 359 days days Subject β0/βe β0/βe 260 days 154 days β0/β0 94 days Months post-drug product infusion 14

15 Sickle Cell Disease (SCD): Overview Disease Current Treatments Monogenic, severe anemia Polymerization of β-globin chains deforms / sickles red blood cells Poor quality of life Pain crises, stroke, splenomegaly Shortened lifespan Non curative treatments - Hydroxyurea - Blood transfusions - Pain management Allogeneic Transplant - Match uncommon - High morbidity / mortality Epidemiology US/EU prevalence ~150K US/EU incidence ~3K Global prevalence ~25M Global incidence ~300K 15

16 Anti-sickling Activity of β A-T87Q- globin: Evidence for Why LentiGlobin May Work for SCD LentiGlobin incorporates an antisickling amino acid that is found in fetal hemoglobin (glutamine at position 87) Anti-sickling activity of β A-T87Q globin has been demonstrated in a mouse model of SCD (Science, 2001) Elevated fetal hemoglobin from hereditary persistence of fetal hemoglobin (HPFH) has shown clinical benefit βs βs V F T L βs β-87 F V Q L polymerization destabilization 16

17 Sickle Cell Disease Clinical Program Underway HGB-205 First SCD subject treated Subject Trial Age/Sex Country of birth Genotype Transfusion requirement (mls/kg/year) CD34+ VCN CD34+ cell count (x10 6 /kg) Follow-up (months) 1204 HGB /M France β S /β S /1.0* HGB-206 N=8 Subjects with severe sickle cell disease Open label, multi-center, U.S.-based study Primary & Secondary Endpoints Safety and efficacy among subjects with severe SCD, as measured by changes in red cell function tests and hemolysis markers Clinical events secondary to SCD, including vaso-occlusive crises or acute chest syndrome events Status Open for enrollment Initial data expected in

18 Childhood Cerebral Adrenoleukodystrophy (CCALD): Disease Overview Disease Ultra-orphan, X-linked, monogenic, neurological disorder Mutated ABCD1 peroxisomal transporter results in toxic buildup of very long chain fatty acids (VLCFA) Leads to cerebral inflammation & demyelination Current Treatments Untreated cerebral ALD leads to dismal outcomes (vegetative state and death) Allogeneic stem cell transplant standard for CCALD (if possible) Epidemiology CCALD most severe form of ALD ALD incidence: 1 in 20,000 (live births) Cerebral disease - CCALD accounts for 30-40% of ALD - AMN accounts for 40-45% of ALD with 40% cerebral - ACALD accounts for 5% of ALD 18

19 Promising Clinical Data CCALD (TG ) Study PI: Patrick Aubourg Natural Course of Disease 12 months 18 months 24 months Disease progression stabilized in 3 out of 4 subjects Efficacy results comparable to allogeneic transplant No gene therapy-related adverse events 19

20 Starbeam Study Phase 2/3 Design Open label, multi-center, single arm, global study Design Primary Endpoints Secondary Endpoints 15 subjects Age 17 Gad Positive Loes Score NFS 1 % of Boys With Major Functional Disabilities at 24 Months After Transplant Neurological Functional Score (NFS) Gad +/- Loes Score Safety ü First subject enrolled (October 2013) ü Multiple clinical sites open Anticipate completion of enrollment in

21 Regulatory Lessons Learned

22 Regulatory Context In the US, gene therapy products are regulated under section 351 of the Public Health Service Act (PHS Act) and 21 CFR Part 1271 as human cells, tissues, and cellular and tissue-based products (HCT/Ps) as defined in 21 CFR (d) In the European Union, gene therapy medicinal products are regulated as advanced therapy medicinal products (ATMPs) by Regulation (EC) No 1394/2007 In both jurisdictions, products are considered as particular drugs : Section 351 PHS biologics in the US and ATMPs in the EU In the US, our interactions are primarily with the Office of Cellular Tissue and Gene Therapies (OCTGT) In the EU, gene therapy products are approved by European Commission based on opinion from CHMP, after expert advice is received from the Committee for Advanced Therapy (CAT) Cell and Gene therapy regulations/guidelines are relevant

23 Our Regulatory Challenges: Terminology (1/3) When joining bluebird in 2011: GTP referred to the recombinant transfer vector GMO referred to transduced autologous bone marrow CD34 + cells No FDA guidance EU Directive 2009/120/EC helped: Drug Product: finished medicinal product consist of genetically modified cells formulated in the final immediate container for the intended medical use. Drug Substance: genetically modified cells (prior to formulation ) Starting materials: HEK293T Master and Work Cell Banks Plasmids, including transfer plasmid encoding for the gene/cdna of interest Lentiviral Vector (NOT DRUG SUBSTANCE) Human cells For the purpose of our INDs and our CTAs we stated our Drug Product = Drug Substance

24 Example from our LentiGlobin BB305 Drug Product (2/3) LentiGlobin BB305 Drug Product: autologous CD34+ cells transduced with LentiGlobin BB305 lentiviral vector encoding for the β A-T87Q -globin gene and suspended in cryopreservative solution Drug Substance: autologous CD34+ cells transduced with LentiGlobin BB305 lentiviral vector encoding for the β A-T87Q -globin gene Why is terminology important? because the active substance receives orphan designation to write clear and consistent regulatory documents to improve internal communication to know where to put the information in required format (CTD*) *Common Technical Document; would recommend customization for cell and gene therapy products

25 Our Regulatory Challenges: Terminology (3/3) FDA told us ok with the proposed approach for INDs; but this would need to be addressed again at time of BLA filing This is how FDA calls our product: "Autologous CD34+ Hematopoietic Stem Cells Transduced with Lentiviral Vector, LentiGlobin BB305, Encoding the Human β A-T87Q -Globin Gene, Selected the CliniMACS Plus Device; Cultured with XXX, YYY, and ZZZ ; Following Mobilization with G-CSF or G-CSF and Plerixafor; Administered Intravenously.

26 Our Regulatory Challenges: Defining our Dose Number of cells: Total number of CD34 + cells? Total number of viable CD34 + cells? Total number of transduced CD34 + cells? Total number of transduced viable CD34 + cells? Total number of transduced true stem cells (~1% of cells)? Inkling from Draft FDA Guidance dose may be defined as transduced CD34 + cells: For gene-modified cells, dosing should take transduction efficiency into account. [ ] Ideally, manufacturers should work to control variability in the transduction process. If variability in transduction is occurring, using the transduced cell number might provide more consistent dosing among subjects when that number can be identified prior to product administration.

27 Our Regulatory Challenges: Manufacturing and Control Number of minor issues raised by Agencies during review of CTAs or INDs : Control, characterization of cell banks SOPs Recommended to use terminal sterile filtration for LVV Viral Safety Residuals RCL testing - FDA asked to use attenuated virus as control Cross contamination questions (LVV manufacturing) Further characterization on all cell populations in final product Overall agreement that healthy donor cells are sufficient surrogates to validate drug product manufacturing process Traceability, shipping, storage/stability of LVV and DP

28 Our Regulatory Challenges: Manufacturing and Control Comparability: LVV produced using suspension process vs. ten tray cell factories Drug product produced by multiple manufacturers Characterization Complex national regulations for import/export Drug Product in the EU: Qualified Person ( QP ) EU GMO Documents are not adapted to ex-vivo integrating vector gene therapy products

29 Our Regulatory Challenges: Manufacturing and Control Issues specific to France: HGB-205 is conducted at Necker Hospital Principal Investigator: Pr. Marina Cavazzana Clinical Trial Application was approved by ANSM in 2012 Unclear how the future MTI-PP* framework will impact cell and gene therapy clinical trials in France Transitioning to full GMP can be challenging for academic centers MESR process and GMO documents burdensome *Médicaments de Thérapie Innovante Préparé Ponctuellement 29

30 ANSM Clinical Trial Authorization for HGB

31 Principales différences réglementaires entre MTI, MTI-PP et préparation (1/2) MTI MTI- PP Prepara+on Médicaments thérapie génique, thérapie cellulaire soma6que, issus de l ingénierie cellulaire ou 6ssulaire; ou combinés MTI préparé de façon ponctuelle à l aaen6on d un malade déterminé et uniquement dans un Etat Membre Tissus / Cellules à effet thérapeu6que qui ne sont pas des MTI Direc6ves Tissus / Cellules 2004/23/CE, 2006/17/CE et 2006/86/CE Oui pour les aspects rela6fs aux dons à l obten6on et aux contrôles des cellules et 6ssus. Oui pour les aspects rela6fs aux dons à l obten6on et aux contrôles des cellules et 6ssus. Oui Mise sur le marché Européenne Procédure centralisée obligatoire EMA- CAT 2001/83/CE modifiée Na6onale Décret en a2ente Na6onale Décret du 16 décembre 2008 Arrêté du 27 octobre 2011 Bonnes pra6ques de fabrica6on BPF médicaments (L alinéa 1er) BPF médicaments pour les établissements pharmaceu6ques (L alinéa 1er) ou BPF spécifique MTI pour les établissements autorisés non Établissement pharmaceu6que (L alinéa 3) Bonnes pra6ques 6ssus cellules (L ) 31

32 Principales différences réglementaires entre MTI, MTI-PP et préparation (2/2) Etablissement de fabrica6on Direc6ve 2001/20/CE Essais clinique Loi du N du 9 août 2004 recherche Biomédicale MTI MTI- PP Prepara+on Etablissement pharmaceu6que (L ou L ) Etablissement pharmaceu6que (L ou L ) ou Etablissement autorisé par l ANSM pour fabrica6on de MTI- PP (L ) Oui Oui Non Oui Arrêtés médicaments Oui Arrêtés médicaments Unités de Thérapie Cellulaire autorisées par l'ansm (Ar6cle L ) Oui Arrêtés spécifiques Vigilance Pharmacovigilance Pharmacovigilance Biovigilance From: 32

33 Hospital Exemption in Regulation 1394/2007/EC Advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient, should be excluded from the scope of this Regulation whilst at the same time ensuring that relevant Community rules related to quality and safety are not undermined. Recommend to keep the hospital exemption currently (MTI-PP) only for early phase clinical studies 33

34 Our Regulatory Challenges: Nonclinical Development Lack of relevant models for toxicology No specific guidance for ex vivo lentiviral gene therapy In vitro work mostly based on normal donor cells (vs. patients cells) No consensus on duration of toxicology studies to support first in human trials : 3 mo. vs. 4 mo. vs. 6 mo.; primary vs. primary and secondary transplants Mice model seems accepted. No request for NHP. Limitations in 2 ndary transplant : spontaneous tumors ( by total body irradiation) FDA recommended nonclinical tox VCN bracket clinical VCN target range Long-term FDA recommended conducting tox study with a positive control Likely reproductive toxicology studies not needed because full myeloablation Challenges to conduct studies GLP Lack of clarity when in vivo studies needed to support changes in manufacturing process Integration site analysis data challenging to interpret

35 Our Regulatory Challenges: Clinical Minor challenges: Ensuring trial design and oversight addresses safety concerns, eg, DMC review, initial treatment stagger For conditions not immediately life threatening, recommendations to start with adults prior to treating adolescents and children More Challenging Issues related to targeting ultra-orphan diseases: Small sample size achievable, lack of validated endpoints, heterogeneous disease course, lack of robust natural history data, etc. precludes conventional trial design and statistics Document natural history of disease (retrospective vs. prospective) Control data when randomized trials are not feasible Anticipated safety database needed for registration (number of patients + duration of follow-up) Challenges in conducting global trials due to restrictions in Drug Product manufacturing capabilities

36 Our Regulatory Challenges: Clinical Long-Term follow-up Study: 15 year follow-up recommended by EMA and FDA guidance Disagreement with having multiple indications in same trial FDA recommends in current draft guidance on Early Phase Trials to conduct long-term follow-up in same protocol From industry perspective better to do in separate trial Which assays to be conducted? Which potential additional risks will be evaluated?

37 Concluding Remarks

38 Conclusions/Next Steps We look forward to further regulatory interactions to resolve pivotal/ registration issues, and for opportunities to increase industry collaboration FDA Breakthrough Designation welcome; wish parallel EMA designation Next steps: Continue to gather clinical data Agreeing on registration path with FDA and EMA end of phase 2 meetings / Sci. Advice (joint FDA/EMA) EU Certification procedures for CMC and Nonclinical Pre-MAA/BLA and Rapporteur meetings Anticipated legal framework for approval: Conditional Approval vs. under Exceptional Circumstances in the EU Potentially Accelerated Approval in the US

39 Recommendations Leverage existing regulatory programs to expedite* development: Orphan Drug Designation for rare conditions EMA Scientific Advice and FDA Type B and C Meetings (pre-ind, end of phase 2 can also go for pre-pre-ind for toxicology etc.) FDA Fast Track Designation Frequent interactions Priority Review Rolling submissions FDA Breakthrough Designation Serious or life-threatening disease or condition Preliminary clinical evidence indicates substantial improvement over existing therapies on 1 or more clinical significant endpoints FDA Accelerated / EMA Conditional Approval Using surrogate or intermediate endpoints Qualify biomarkers Japanese new framework for Regenerative Medicines File PIP (Pediatric Investigational Plan) with EMA after Phase 1 Anticipate compassionate use requests and plan program as appropriate *FDA Guidance for Industry - Expedited Programs for Serious Conditions Drugs and Biologics May 2014

40 Leverage current and potential future trends Current: Patient centric development Benefit risk algorithms Early multi-stakeholders development discussions New EU clinical trial Regulation No 536/2014 (repealing current Directive 2001/20/EC) Entered into force on 16 June 2014 but will apply no earlier than 28 May 2016 Part I 45 days (50 for ATMPs) centralized process with reporting Member State (Art.6) Part II local (Art.7) Notification through EU Portal Revision of ATMP Regulation (potential impact on hospital exemption) In the US: 21 st century cures Potential Future Trends: Emphasis on post-approval real life data Diminished importance or disappearance of randomized clinical trials Big data; continuous monitoring Accelerated pathways for curative treatment addressing underlying cause of serious and life-threatening genetic diseases 40

41 New EU Clinical Trial Regulation No 536/2014 Implemented no earlier than 28 May 2016 Regulatory Assessment led by 1 Mber State PART I Introduction and general principles Cover letter EU application form Protocol Investigator s Brochure GMP compliance documents IMPD/AMPD Content of IMP labeling Scientific Advice and PIP National process (Ethics Committee) PART II Recruitment arrangements Subject information and informed consent Suitability of investigators and sites Proof of insurance cover or indemnification Financial arrangements Proof of payment of fee 41

42 Key Takeaways There is now an EU wide regulatory framework for cell and gene therapy products However, at the Member State level its implementation is fragmented and somewhat unclear; leaving opportunities for unleveled playing field / unfair competition in some Member States Would recommend hospital exemption focuses solely on early phase clinical trials and NOT commercialization phase which should be restricted to centralized marketing authorization for cell and gene therapy products Implementation of the new clinical trial Regulation should streamline the process to obtain authorization to initiate clinical trials in Europe 42