IQ Symposium

Thursday, October 13, 2022
National Press Club, Washington DC

Emerging Trends in Pharmaceutical Innovation: Novel Modalities and Development Strategies

The past decade has seen a dramatic expansion of research and investment in nontraditional pharmaceutical modalities, including genetic medicine, next-generation vaccines, cell-based therapy, protein degraders, antibody-drug conjugates, and advanced peptides.

This wave of innovation is built on years of foundational research and driven in part by advances in genetics, protein and cell engineering, and nanotechnology. With these advances, the pharmaceutical industry has a tremendous opportunity to address unmet medical needs for genetic diseases. At the same time, these advancements come with new challenges in translating cutting-edge science to positive outcomes for patients.

Event Goals



      Experiences in Guiding Compassionate Use INDs for Ultrarare, Severe/life-threatening Genetic Diseases
      Lauren Black, Charles River Laboratories
      Dr. Black will share observations and learnings from ~a dozen n-1 and ultrarare INDs, where she helped guide safety and regulatory strategy for novels CNS oligos, classed as small molecule agents. 

The projects to speed these newly invented drugs to the patient employed a new use of the compassionate use regulations written for AIDS patients in the early 90s which were open to NMEs but were employed in the main for off-label drugs. These current programs required multi-organizational team building focused around the rate of decline in the health of the patients - but most other recognized toxicology rules i.e. the ICH M3 guidelines and traditional reporting standards were gutted in an effort to treat the patient in time. This work has helped fuel the new n=1 guidelines at FDA; and while trying the patience of regulators, in every case the results were in reviewable format. The rodent-only INDs revealed dose-responsive toxic effects and a safe starting dose – therein, meeting the requirements of the Code of Federal Regulations 21CFR312.23 – the bedrock of risk assessment. Programs occurred during COVID staff limits, and monkey shipment limits, and were also sharply confined by family or non-profit funding sources.  N-Lorem (an offshoot of Ionis) followed suit, increasing the numbers of patients in the future who may be able to access such extreme personalized drugs. Some patients have quietly improved, and one drug is now in a commercial IND, in Phase 3 trials. The hope here reaches beyond extreme drugs - that sharing these experiences with critically ill patients, leads us all to rechallenge the status quo in toxicology, and refocus around the balance of risk between severe disease progression, certain morbidity/mortality, and the potential for drug intervening. 

      Gene-based Therapies: What Have We Learned to Date?
      IQ Novel Modalities Working Group

Cell and gene therapies are exciting new modalities that are emerging as new medicines with new promising results in patients. Given the fact that industry and regulators have limited knowledge in this area, it is very important to harmonize and decide on best practices for the translational and ADME characterization of these modalities. Within IQ, a working group was formed by the TALG and CPLG in order to:

a) Identification of risks associated with the next-generation therapies using cell, viral and non-viral platforms.
b) Developing a risk-based strategy that can drive the preclinical, translational, and bioanalytical strategies in discovery and development;
c) Provide recommendations on novel bioanalytical and immunogenicity assays, best practices, and standardization approaches for the development and validation of these assays and
d) Develop a roadmap for clinical pharmacology strategies; PK/PD analysis and dose translation from non-clinical models to patients

      The talk will cover the translational ADME and PKPD considerations of the novel modalities for Cell and Gene therapies and provide the IQ audience with an understanding of approaches employed for currently approved products as well as gaps and opportunities to contribute to draft regulatory guidance.
      Recent advances in RNAi therapeutics
      Vasant Jadhav, Alnylam
      Dr. Jadhav will cover the major milestones over the last two decades that led to harnessing the power of RNAi technology for molecular medicines. The presentation will include the highlights of current clinical programs and advances in extra-hepatic delivery for expanding the scope of RNAi therapeutics.
      Patient & Caregiver Perspective 
      Eric Camino Parent Project Muscular Dystrophy

Patients and Patient Advocacy Groups (PAGs) have been around for many years, investing in basic science, seeking out experts, and encouraging industry to become partners in development. Patients and their families gather information from every imaginable source from dr. Google to scientific articles, from social media to investor calls. Industry suggests they want patients ‘at the table’, when in fact the ‘table’ belongs to patients to those who live with the diagnosis and its impact every minute of the day. From this ‘table’, Patients and their families encouraged regulatory agencies to listen to their voices, to understand the implications of living with their disease; what that means to the patient, what compromises and accommodations are necessary, and how this impacts the quality of their lives and the people who love and care for them.   Thus, Patient-Focused Drug Development or PFDD has evolved as a systematic approach to ensure the patient voice is meaningfully incorporated into the drug development paradigm.   It means more than a focus group and attending a meeting, but rather an intense understanding of ‘living with’ the diagnosis and how that ‘living with’ impacts perspectives, needs, and priorities. 

This is a talk about including patients every step of the way from basic science to therapy development and access.

      Lessons Learned from the Pandemic: mRNA-LNP Vaccine Development
      Advait Badkar, Pfizer
      The speed and scale of industry response to the Covid pandemic were unprecedented, ultimately leading to the availability of several vaccines in under a year. The speaker will discuss the approach taken by Pfizer, with their partner BioNTech, in the development, manufacture, and distribution of the vaccine drug product while reflecting on lessons that may be applicable to future product development.
      TPD En Route to Bedside: The Evolution of PROTACs
      Jacques Saarbach, Yale University
      Over the past decade, Targeted Protein Degradation (TPD) has taken drug discovery by storm and has been reshuffling the cards of which protein is druggable or not. Proteolysis TArgeting Chimaeras (PROTACs) are heterobifunctional small molecules, where one end binds to the protein to degrade and the other end recruits an E3 ubiquitin ligase complex (E3 ligase). PROTACs induce a ternary complex between the protein of interest and the E3 ligase; which will lead to the polyubiquitination of the target protein and eventually its degradation. PROTACs have come a long way since the report of the first peptide-based PROTAC in 2001 by Crews and Dehsaies, to the first small molecule PROTAC in 2008 and finally, the first clinical trial started in 2019 by Arvinas. The technology has matured, and rules for developing these molecules start to emerge as well as their advantages over small molecules operating on the classical occupancy-driven mechanism. Throughout this presentation, I will focus on the main advantages and some limitations of PROTACs using contributions from the Crews lab as support.

A Cross-Pharma Benchmark of the Current Preclinical ADME & Safety Assessment Practices to Support Development of Targeted Protein Degraders: Results from an IQ Survey

IQ Protein Degrader Working Group

      The novel small molecule platform of targeted protein degraders reached a milestone in 2019 when the first Phase 1 clinical trial using the platform was initiated in advanced cancer patients. Since then, at least a dozen more targeted protein degraders have started clinical trials, some in indications other than oncology, with many more trials forecasted to start over the next decade. 
Although the idea of using the ubiquitin-proteasome system to degrade a target protein for potential therapeutic benefit was over a decade old at the time of the first clinical trial, some theoretical ADME and safety concerns were starting to be posed for the platform. The IQ Consortium Protein Degrader Working Group conducted two surveys to benchmark the current preclinical practices for targeted protein degraders. The aim of the surveys was to aid in more rigorous, effective, and swift nonclinical ADME & safety assessments of degraders. In general, responses provided insight into potential screening gaps and best practices for nonclinical safety and ADME assessments, preIND/IND regulatory feedback, and human starting dose calculations that can be applied by companies new to the field.