1. David H. Schubert VP, Regulatory and Quality
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?

3. - Open forum where scientific & regulatory principles are discussed -
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 -

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

5. Background (cont.)
Oligonucleotide-based therapy IND and Pre-IND submissions (n=105) were on the increase…….
S. Leigh Verbois, DIA Oligo Mtg, OSWG, 14June2010

6. Rise in new ON classes of drugs being developed…
Background (cont.)
Rise in new ON classes of drugs being developed…
Oligonucleotide IND and Pre-INDs submissions by decade and class
S. Leigh Verbois, DIA Oligo Mtg, OSWG, 14June2010

7. Nonclinical Safety Regulatory Assessments
Background (cont.)
Nonclinical Safety Regulatory Assessments
Genetic Toxicology
Exaggerated Pharmacology
Immunomodulatory
Off-Target Effects
Repro & Developmental Tox ?
Oligonucleotides have a wide array of mechanisms of actions. With this burgeoning field it is necessary to understand the pharmacology and toxicology associated with each subset of oligonucleotides. The OSWG and the subunits of the OSWG have enhanced understanding of the nuances of each of the components.
Diverse Mechanisms of Action

8. History
In 2007…
1st 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

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

10. Membership Includes representatives from Started as Yahoo group
>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

11. Structure Hold monthly teleconference meetings Subcommittees
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

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

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

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

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

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

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.

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

19. Immunomodulatory Complement activation Immunomodulatory effects
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

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

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

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

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]

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

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 up-regulation 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

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

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

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

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

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

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 PD- and PK-related effects

32. Emerging Topics Formulated Oligos Carcinogenicity
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?

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. 

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

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

36. THANK YOU !

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 Oligonucleotide-based Therapeutics. Nucleic Acid Ther. DOI: /nat