OSWG’s Role in Shaping the Regulatory Development of Oligos

- A Potential Model for Moving Forward -

David H. SchubertVP, Regulatory and Quality

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Outline

• What?

• Background and History

• Who?

• How?

• OSWG Committees and Publications

• Is the OSWG Valuable?

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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 -

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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

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0

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1990 1995 2000 2005 2010

Year

Nu

mb

er o

f IN

Ds

and

P

reIN

Ds

Oligonucleotide-based therapy IND and Pre-IND submissions (n=105) were on the increase…….

Background (cont.)

S. Leigh Verbois, DIA Oligo Mtg, OSWG, 14June2010

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Background (cont.)

0

10

20

30

1991-1999 2000-2009

PS-ASO

2'-MOE

CpG

Aptamer

siRNA

Miscellaneous

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

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Background (cont.)

Genetic Toxicology

Exaggerated Pharmacology

Immunomodulatory

Off-Target Effects

Repro & Developmental Tox

?Diverse Mechanisms of Action

Nonclinical Safety Regulatory Assessments

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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

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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

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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

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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

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Subcommittees

Genotox

Exaggerated Pharmacology - retired

Immunomodulatory

Inhalation- retired

Repro & Carci

Safety Pharmacology

Formulated Oligos - new

Publications

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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”

• 2008 - Successfully justified exclusion of synthetic oligonucleotides from definition of Advanced Medicinal Products (e.g. gene therapy) as proposed by the European Commission

• 2009/2010 - Actively involved in responses to NIH proposal requiring RAC review of clinical protocols for synthetic oligonucleotides

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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

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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

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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

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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: 10.1089/nat.2012.0399. Epub 2013 Jan 4.

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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

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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

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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

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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) :246-254 doi: 10.1089/nat.2012.0345

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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

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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]

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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

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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

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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

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OT Publication

Lindow M, et al. (2012) Assessing unintended hybridization induced biological effects of oligonucleotides. Nature Biotechnology; 30: 920-923 doi: 10.1083/nbt.2376

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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

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Repro Publication

Cavagnaro J, et al. (2014) Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-based Therapeutics. Nucleic Acid Ther. DOI: 10.1089/nat.2014.0490

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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

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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

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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?

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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. 

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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

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OSWG Experience

Commitment with meaningful

discussions and common

understanding helps move the

conversations forward…..

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THANK YOU !

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OSWG Publications ListBerman C, et al. (2014) Recommendations for Safety Pharmacology Evaluations of Oligonucleotide-Based Therapeutics. Nucleic Acid Ther. Jun 19. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/24946015

 

Kornbrust D, et al. (2013) Oligo safety working group exaggerated pharmacology subcommittee consensus document. Nucleic Acid Ther. Feb;23(1):21-8. doi: 10.1089/nat.2012.0399. Epub 2013 Jan 4.

http://www.ncbi.nlm.nih.gov/pubmed/23289535

 

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) :246-254 doi: 10.1089/nat.2012.0345

http://online.liebertpub.com/doi/pdfplus/10.1089/nat.2012.0345

 

Schubert D, et al. (2012) The Oligonucleotide Safety Working Group (OSWG). Nucleic Acid Ther. 22(4): 211-212 doi: 10.1089/nat.2012.0345

http://online.liebertpub.com/doi/pdfplus/10.1089/nat.2012.0383

 

Capaldi D, et al. (2012) Quality Aspects of Oligonucleotide Drug Development: Specifications for Active Pharmaceutical Ingredients (API), Therapeutic Innovation & Regulatory Science; doi: 10.1177/0092861512445311

http://dij.sagepub.com/content/early/2012/05/11/0092861512445311

 

Lindow M, et al. (2012) Assessing unintended hybridization induced biological effects of oligonucleotides. Nature Biotechnology; 30: 920-923 doi: 10.1083/nbt.2376

http://usrexp-sandbox.nature.com/nbt/journal/v30/n10/full/nbt.2376.html

Cavagnaro J, et al. (2014) Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-based Therapeutics. Nucleic Acid Ther. DOI: 10.1089/nat.2014.0490

http://online.liebertpub.com/doi/pdfplus/10.1089/nat.2014.0490