Session 1: Considerations for Immunosuppressive Drugs
Chairs: Andrea Kiessling (Novartis) & Oliver Thomas (Amgen)
Immunosuppressive drugs make a substantial and clinically important contribution to the portfolio of biologics. This session highlights some key safety considerations for a diversity of modalities. Included are case studies of preclinical, translational and clinical safety findings and their impact on program design and execution. The specific and sometimes complex safety risks associated with such drugs can necessitate an integrative approach to first-in-human dose selection, which will be discussed in this session. Various methods for evaluating immunosuppressive drugs will be presented and the session will illustrate how development strategies can be adapted based on specific mechanistic requirements.
Session 2: Decoding in vitro approaches to off-target safety assessment
Chairs: Smita Salian-Mehta (Gilead) & Katy Fraser (Merck) & Leslie Bosseler (Johnson & Johnson)
Off-target safety assessment is a vital part of the safety evaluation of large molecules. Traditionally, Tissue Cross-Reactivity (TCR) assays have taken a central role in this, although developing and interpreting a TCR faces many challenges. More recently, other techniques complemented or even replaced TCR as the go-to in vitro off-target assay. The use, advantages and limitations of different Cell-based Protein Arrays (CBPA) in preclinical safety development and the evolution of the field in the near future will be discussed. Additionally, retrospective case analyses based on clinical findings and nonclinical strategies in presence or absence of a pharmacologically relevant species or non-host target off-target assessment of biologics will be presented. The session will be concluded by an interactive survey and panel discussion.
Session 3: Safety Strategies and Considerations for Gene Therapies
Chairs: Amanda Lucchini (Labcorp) & Sarah Benjamin (Johnson & Johnson)
Gene therapy is a rapidly expanding field, with increasingly diversifying modes of actions. Safety assessment and nonclinical strategies continue to be a regulatory requirement, however there are challenges to adapting a more standardized study approach for safety or efficacy assessments. This session will focus on case studies and strategies taken to address the program needs and regulatory requirements for gene therapies in a variety of actions. Topics will include strategies for emerging gene therapies (in vivo CAR Ts) and for specialty routes of administration (ocular programs). This session will also address risks associated with gene therapies, specifically focusing on vertical transmission. Overall, the discussion will aim to cover both practical strategies for study conduct and considerations for mitigating risk while moving this novel field forward.
Session 4: Oligonucleotides drugs – A New Era
Chairs: Michaël Maes (J&J) & Helen Lightfoot (Roche)
Speaker 1: Recommendations for the assessment of hybridization-dependent off-targets of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)
Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) can bind to unintended RNA transcripts, triggering the same downstream processes, despite some mismatches, as they do with their perfectly complementary (intended) RNA targets. This occurs because nucleic acid strand hybridization and subsequent pharmacological activities of ASOs or siRNAs tolerate some mismatches. This phenomenon is a major contributor to the potential toxicity of these modalities. Uniquely, this off-target activity can be partially predicted through sequence complementarity analyses. However, these predictions are imperfect and require additional precautions and validations, which themselves have limitations. Moreover, ongoing methodological debates, unaccounted-for variables, and continuous advancements in the field further complicate off-target assessments. As a result, comprehensive regulatory guidelines have yet to be established, although a Final Concept Paper1 from the International Council for Harmonization and a draft guidance2 from the U.S. Food and Drug Administration were recently issued. This talk will present updated industry recommendations for assessing ASO and siRNA off-target effects, as recently published3 by the Oligonucleotide Safety Working Group4 of the Oligonucleotide Therapeutic Society, as well as relevant case studies. These recommendations aim to enhance the safety of ASOs and siRNAs in clinical trials and mitigate unavoidable off-target effects. They may serve as a valuable resource for pharmaceutical development and inform future regulatory frameworks in this field.
Speaker 2: Opportunities for More Tailored Approaches to Genotoxicity Testing for Oligonucleotide Therapeutics: Outcome of an Industry Survey
As oligonucleotide therapeutics (ONTs) are synthetic drugs, their nonclinical safety evaluation currently follows ICH guidelines for small molecules and requires the full battery of in vitro and in vivo genotoxicity tests to support development. However, ONTs are not expected to interact chemically (e.g., by covalent binding) with DNA or other cellular targets, such as mitotic microtubules, that could result in genotoxicity. Nevertheless, ICH S2(R1) guidance does not identify specific considerations for ONTs. The European Federation of Pharmaceutical Industries and Associations (EFPIA) – Preclinical Development Expert Group (PDEG) established an Oligonucleotide Working Group (OWG) to review industry experience of developing ONTs. An industry survey was conducted to understand current practices and regulatory expectations for genotoxicity assessment of ONTs, along with historical genotoxicity testing results (Parry et al, Nuc Acid Ther 2025). The survey, involving 29 pharmaceutical and biotechnology companies, revealed a consistent absence of genotoxicity signals across a diverse range of oligonucleotide classes and chemistries, consistent with previous observations. Despite the lack of ONT genotoxicity, companies reported following standard testing guidelines, with only limited divergence. The survey data support the view that well-established ONT modifications can be considered “precedented,” in terms of negligible genotoxic risk. As such, further testing of new ONT candidates containing only precedented modifications is likely not warranted, when defined criteria are met. Further, the OWG proposes a pathway for novel ONT chemical modifications to achieve precedented status. Overall, the survey findings underscored the need for a more tailored approach to the nonclinical safety assessment of ONTs. The OWG hopes that the findings of this survey provide valuable input to the recent ICH S13 topic on ‘Nonclinical Safety Evaluation of Oligonucleotide-Based Therapeutics’, which commenced in the second half of 2024.
Session 5: Navigating Regulatory Pathways for Innovative Biologics
Chairs: Ulrike Hopfer (Roche) & Bindu Bennet (AstraZeneca)
Interactions with regulators are the spice in our daily work. Exchanging regulatory feedback on tricky programs, 3Rs, or fast and lean programs enriches and supports the development of new modalities. This session will cover interactions and discussions with regulatory authorities that shape the development of complex biologics. We will explore several case studies that highlight the strategic interactions with health authorities to advance novel therapeutic candidates. We will discuss several case examples in which NHP repeat-dose toxicity testing was not required despite target binding, NHP in vitro functionality or NHPs being a pharmacologically relevant species. We will also discuss regulatory considerations for global submissions for Advanced Therapy Medicinal Products and Genetically Modified Organism (ATMPs/GMOs) and the regulatory path of a first-in-class antibody-cytokine conjugate with a development path from first in vivo demonstration of efficacy until IND approval of only two years.
Session 6: 3R’s
Chairs: Sarah Gould (CRL) & Anna Bottomley (ToxStrategies)
The 3Rs: Replace, Reduce and Refine the use of animals was first described in 1959 by William Russell and Rex Burch. Since then, various activities and progress has been made, such as the removal of acute studies or enriching the cage environment. However, there is still more to be done and as we enter 2025, it’s hard not to say, much remains the same to what was laid out in the ICH guidelines written over 25 years ago and that may partly relate to concerns and risks of regulatory push back. Whilst, regulatory guidelines provide support, they cannot be all encompassing, and much has changed since they were first written. This session looks at 3R’s policies across the globe, considers the guidelines and asks what small but quicker steps can be made to advance and better support the 3R’s? We look at the implementation of virtual controls, the reuse of NHP’s for biologicals and species selection. We consider the key factors that drive species selection and how we could select alternative species to the NHP, in particular, for biologicals. We have pulled together a team who will debate and discuss ways we can move forward. We also aim to facilitate discussions on species selection, including case studies to encourage audience participation.
Breakout Sessions and Networking Opportunities
In person attendance is highly encouraged to allow for the fullest participation in Breakout Sessions and Networking opportunities. This year we are targeting having several options for breakout sessions. One topic will take deeper dive into the current use, challenges and hurdles for the use of cell-based expression profiling to understand off target binding for biologics and discuss the barriers and data that would be needed to encourage regulators to consistently accept cell-based expression profiling as an alternative to tissue cross reactivity assays. Input in this group will shape the direction of a proposed Biosafe Taskforce on this topic. Another Breakout session will also take a deeper dive into the case studies that were shared in the October 2024 FDA/DruSafe/BioSafe meeting to give our general membership a chance to weigh in on nonclinical strategy to reduce animal use during biologics development. Our moderators will also share the discussion that took place with our counterparts at the FDA. Additional break out session topics will be shared once they are available. While virtual attendees will not be able to participate in the breakout discussions, they will have the opportunity to hear the read outs for each of the sessions in which moderators will come back online to share the key discussion points from each session. Finally, based on feedback on recent BioSafe GMM meetings we will allow for more time for in-person networking opportunities with your Biosafe colleagues.