OSWG s Role in Shaping the Regulatory Development of Oligos - A Potential Model for Moving Forward -

Transcription

1 OSWG s Role in Shaping the Regulatory Development of Oligos - A Potential Model for Moving Forward - David H. Schubert VP, Regulatory and Quality

2 Outline What? Background and History Who? How? OSWG Committees and Publications Is the OSWG Valuable? Slide 2

3 The OSWG Oligo Safety Working Group A group of industry and regulatory professionals who choose to engage in addressing the nonclinical safety issues and challenges associated with the development of oligonucleotide-based therapeutics - Open forum where scientific & regulatory principles are discussed - Slide 3

4 Background Mid 2000s. Shift from the development of oligonucleotides as a academic interest to an active industry New class of pharmaceutical compound faced regulatory challenges that perhaps might not be best served by the current rules for small molecules or biological products Slide 4

5 Background (cont.) Oligonucleotide-based therapy IND and Pre-IND submissions (n=105) were on the increase. 16 Number of INDs and PreINDs Year S. Leigh Verbois, DIA Oligo Mtg, OSWG, 14June2010 Slide 5

6 Background (cont.) Rise in new ON classes of drugs being developed Oligonucleotide IND and Pre-INDs submissions by decade and class PS-ASO 2'-MOE CpG Aptamer sirna Miscellaneous S. Leigh Verbois, DIA Oligo Mtg, OSWG, 14June2010 Slide 6

7 Background (cont.) Nonclinical Safety Regulatory Assessments Genetic Toxicology? Exaggerated Pharmacology Immunomodulatory Off-Target Effects Diverse Mechanisms of Action Repro & Developmental Tox Slide 7

8 History In st DIA (Drug Information Association) Oligonucleotide-based Therapeutics Conference Douglas Throckmorton s closing remarks challenged Sponsors and Regulators to work together OSWG formally established January 2008 Slide 8

9 Objectives To share information, facilitate dialog and enable discussion on issues (observed and anticipated) in the development of synthetic oligonucleotides as drugs Reflect current thinking of members, companies and regulatory authorities on issues Goal Provide recommendations on the best practice for nonclinical development of oligonucleotides-based therapeutics Slide 9

10 Membership Includes representatives from >30 pharmaceutical companies (US, EU and Japan) >10 independent consultants Regulatory agencies (FDA, Health Canada, EU) Started as Yahoo group Joined DIA, a neutral community, March 2013 Group in Biotechnology & Innovative Preclinical Sciences Community Access group need to be DIA member Participation open to all interested parties Slide 10

11 Structure Hold monthly teleconference meetings Last Tuesday at 12 noon, EST (1 hour) Subcommittee updates Forum for open communication Way for new members to connect with Subcommittees Subcommittees Meet routinely Define issues within the area Develop goals/charter for the subgroup Develop/affect change in those areas Strive to share info and/or data to support the issues Slide 11

12 Subcommittees Genotox Exaggerated Pharmacology - retired Immunomodulatory Inhalation- retired Repro & Carci Safety Pharmacology Formulated Oligos - new Publications Slide 12

13 Accomplishments Organized and participated in 6 DIA specific Oligonucleotide-based Therapeutics Conferences to date Next September 2015 Generated 7 peer reviewed publications In process of generating additional white papers Successfully justified exclusion of synthetic oligonucleotides from definition of Advanced Medicinal Products (e.g. gene therapy) as proposed by the European Commission 2009/ Actively involved in responses to NIH proposal requiring RAC review of clinical protocols for synthetic oligonucleotides Slide 13

14 Genotox Objective: Provide guidance on evaluation of genotoxic potential for an oligo-drugs that considers the platform issues A primary question is the appropriateness of standard genotoxicity tests established primarily for small molecules Ames Assay (bacterial gene mutation) Mouse Lymphoma Assay (Mammalian Cell Mutation test) Chromosome Aberration Test Micronucleus Test (i.e., mouse) What tests are appropriate and when they are appropriate have been proposed to regulatory agencies FDA has not established a formal position 2005 reflection paper by EMEA White Paper is written and out for external review Slide 14

15 Exaggerated Pharmacology (EP) Adverse effects resulting from the intended pharmacology Excludes off-target effects and non-specific (class) effects Relevance to clinical development is dependent on multiple factors Know or perceived clinical impact Primary and secondary effects Magnitude and duration of the effect Slide 15

16 EP (cont.) Evaluation has varied over time and among regulatory agencies Reflection of the progression from viral targets, to cancer targets, to targets involved in normal cell processes Knowledge base throughout the industry has increased and thus consistency among companies and regulatory agencies This topic has received considerable debate among OSWG participants and in the ON community EP Subcommittee published consensus document in 2013 Slide 16

17 EP Publication Kornbrust D, et al. (2013) Oligo safety working group exaggerated pharmacology subcommittee consensus document. Nucleic Acid Ther. Feb;23(1):21-8. doi: /nat Epub 2013 Jan 4. Slide 17

18 EP (cont.) Subcommittee recommendations: Case-by-case considerations about MOA, structure, nature of target, duration of effect, tissue persistence, route/exposure, duration of treatment, clinical indication, etc. Class differences for oligonucleotides can influence if and how the evaluation can be conducted mirna - Aptamers -Immunostimulatory Identification of relevant species for toxicology evaluation is desirable, but in the absence of activity in multiple species, assessment in one species may be sufficient If no cross-species activity, the use of animal active analogues should be considered The use of analogues posses challenges to the development program, resource-intensive and increases risk for misleading results Slide 18

19 Immunomodulatory Complement activation Summary of experience in non-human primates following exposure to phosphorothioate containing oligonucleotides Status: Summary document completed. White Paper in progress Immunomodulatory effects Comparison between those designed for Toll like receptor mediation from those designed to function through non-immune MOA Status: Summary document ongoing via dialogue on monthly TCons Risk assessment of immunomodulation: Induction of autoimmune responses? Activation of local immune system versus systemic: proliferation and redistribution of immune cells Selection of biomarkers for risk assessment Status: some discussion included in above TCons Slide 19

20 Inhalation To date, the number of non-clinical and clinical studies for inhalation of ON are limited and additional data is needed Subcommittee identified key questions/issues for consideration Response of the lung to ON Type (single strand, duplex, length) and chemical modifications (conjugates) Response of the lung to formulations Species differences; rodent vs. NHP, NHP vs. human Exposure differences Models/biomarkers to monitor lung toxicity and relevance to humans (species, assays, endpoints) Subcommittee published consensus points and recommendations in 2012 Slide 20

21 Inhalation Publication Alton EW, et al. (2012) Clinical Expert Panel on Monitoring Potential Lung Toxicity of Inhaled Oligonucleotides: Consensus Points and Recommendations Nucleic Acid Ther.; 22(4) : doi: /nat Slide 21

22 Safety Pharmacology ICH S7A does not specifically call out oligonucleotides; similar to other guidelines this should be applied as appropriate. investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. Appropriateness of dedicated safety pharmacology studies should be determined by the data and indication If the toxicology studies do not provide a clear answer this may need a specific study focused on a organ system Clinical indication/route of administration may require dedicated safety pharmacology studies Safety Pharm Subcommittee published consensus document in 2014 Slide 22

23 Safety Pharm Publication Berman C, et al. (2014) Recommendations for Safety Pharmacology Evaluations of Oligonucleotide-Based Therapeutics. Nucleic Acid Ther. Jun 19. [Epub ahead of print] Slide 23

24 Safety Pharmacology Subcommittee recommendations: Safety pharm testing, as described ICH S7 guidance, is as applicable as it is to small molecule drugs and biotherapeutics Study design considerations Similar to those for other classes of drugs Studies should evaluate the drug product administered via the clinical route Species selection should ideally consider relevance of the model with regard to the endpoints of interest, pharmacological responsiveness, and continuity with the nonclinical development program. Evaluation of potential effects in the core battery (CV, CNS, and Resp) is recommended. In general: In vitro herg testing does not provide any specific value and is not warranted Emphasis on in-vivo evaluation of cardiovascular function, typically in nonhuman primates (NHPs) Due to the low level of concern, neurologic and respiratory function can be assessed concurrently with cardio-vascular safety pharmacology evaluation in NHPs, within repeat-dose toxicity studies, or as stand-alone studies (rodents are most commonly used). Other dedicated safety pharmacology studies, beyond the core battery, may have limited value Slide 24

25 Off-Target Effects The most debated issue among OSWG participants and in oligonucleotide community Always a hot-button for people coming into the field Definition Hybridization-dependent change in the expression of an unintended target; can be upregulation or down-regulation Can be a direct sequence-based effect Can be a secondary effect Change in expression results in a adverse effect Class effects, such as toxicities due to chemistry, or toxicity due to delivery systems are not off-target effects mirna agonists and antagonists are intended to modulate multiple pathways and not all pathways are recognized Off-target may actual be on-target Slide 25

26 Off-Target Effects Points to Consider Significance of an off-target effect is influenced by potential and consequence Confirmation/evaluation by in vitro or in vivo models can provide critical information for assessing off-target effects Pharmacology and toxicology studies conducted in preclinical development provide the most convincing evidence Assumes potential off-target effects can be monitored and appropriate monitoring will be included in studies Species differences should be considered when potential off-target effect is suspected Off-Target Subcommittee published consensus document in 2012 Slide 26

27 OT Publication Lindow M, et al. (2012) Assessing unintended hybridization induced biological effects of oligonucleotides. Nature Biotechnology; 30: doi: /nbt.2376 Slide 27

28 Off-Target Effects Subcommittee recommendations: Off-target effects can occur with all drug classes Oligonucleotides probably do not posses any greater potential for off-target effects maybe less Compared to small molecules it is easier to predict off-target effects for oligos Best Practice approach to the evaluation of off-target effects In silico screening - find sequences with minimized potential for off-target hybridization-dependent effects Characterization should be on a case by case basis Exploration of off-target effects should be data driven and given careful consideration Toxicity studies in two species remain best way to detect unintended effects Slide 28

29 Repro Publication Cavagnaro J, et al. (2014) Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-based Therapeutics. Nucleic Acid Ther. DOI: /nat Slide 29

30 Repro & Developmental Tox Subcommittee recommendations: ONs have attributes that are similar to NCEs and NBEs Both sets of guidelines can be useful when planning reproductive toxicity studies; (ICH) S5 (R2)/ ICH S6(R1) Approach to DART should take into account both potential effects of chemical structure & intended pharmacology of the ON Standard reproductive toxicity species (rodent/rabbit) can often be used because most ON toxicity is related to chemical structure Animal-active surrogates can be useful to assess potential reproductive effects related to pharmacology in addition to effects related to the chemical back-bone Slide 30

31 Repro & Developmental Tox Subcommittee recommendations (cont.): Choice of the relevant animal model, the dosing regimen, and whether to use the clinical candidate or an animal surrogate will all need to be considered carefully based on the specific product attributes of the ON Information from general toxicity studies and previous experience with similar ONs can also help to inform these decisions NHP studies should be used only as needed to answer specific questions or when surrogates are not practical Dosing regimens should be tailored to ensure adequate exposure throughout the period of organogenesis without compromising the ability to assess PDand PK-related effects Slide 31

32 Emerging Topics Formulated Oligos Charter being developed Carcinogenicity Designated as an area for OSWG subcommittee focus Appropriateness of carci studies for ONs Clinical dosing schedule and patient population Pharmacology/toxicology profile in target organs Extent and duration of exposure to target organs If carcinogenicity studies are required can this can be accomplished in rodents? Slide 32

33 Is the OSWG Valuable? Industry perspective Allows for establishment of uniform views of important topics across the industry Presenting OSWG work at various scientific meetings provides a collective voice for its members and their work in OSWG. Educates scientists who are new to this field, so that we can move projects forward with a relatively good degree of consistency across programs, at least with regard to some of the key scientific and regulatory strategies. Provides a conduit for passing on our legacy of oligo safety assessment expertise to the next generation of oligo toxicologists White papers and publications represent consensus opinions of the knowledgeable pharmaceutical scientists working in this area and serve as a guide for newcomers and others who may have uncertainties about specific aspects of oligo safety. Slide 33

34 Is the OSWG Valuable? Regulatory Perspective Those of us interested in oligonucleotide therapeutics in the agency recognize that the OSWG provides a useful forum in which companies and others can share information. The agency appreciates the opportunity to hear these discussions and is interested in reading the published accounts of these discussions. OSWG allows regulators to listen to OSWG discussions, affording them an opportunity to hear about the challenges and current thinking from an industry perspective Slide 34

35 OSWG Experience Commitment with meaningful discussions and common understanding helps move the conversations forward.. Slide 35

36 THANK YOU! Slide 36

37 OSWG Publications List Berman C, et al. (2014) Recommendations for Safety Pharmacology Evaluations of Oligonucleotide-Based Therapeutics. Nucleic Acid Ther. Jun 19. [Epub ahead of print] Kornbrust D, et al. (2013) Oligo safety working group exaggerated pharmacology subcommittee consensus document. Nucleic Acid Ther. Feb;23(1):21-8. doi: /nat Epub 2013 Jan 4. Alton EW, et al. (2012) Clinical Expert Panel on Monitoring Potential Lung Toxicity of Inhaled Oligonucleotides: Consensus Points and Recommendations Nucleic Acid Ther.; 22(4) : doi: /nat Schubert D, et al. (2012) The Oligonucleotide Safety Working Group (OSWG). Nucleic Acid Ther. 22(4): doi: /nat Capaldi D, et al. (2012) Quality Aspects of Oligonucleotide Drug Development: Specifications for Active Pharmaceutical Ingredients (API), Therapeutic Innovation & Regulatory Science; doi: / Lindow M, et al. (2012) Assessing unintended hybridization induced biological effects of oligonucleotides. Nature Biotechnology; 30: doi: /nbt Cavagnaro J, et al. (2014) Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotidebased Therapeutics. Nucleic Acid Ther. DOI: /nat Slide 37