New Horizons for Accelerating Drug Repurposing

Webinar Housekeeping & Strategy

• Presenters shared slides with Q&A reserved for the end; questions can be entered into the chat during the session.
• The session is recorded and will be posted on the Faster Cures website post-completion.
• Participants were instructed to remain on camera throughout the Zoom meeting.
• Ray introduced TRiN (Translational Research Institute for Neurological Innovation), noting it engages over 160 foundations to support capacity building.
• TRiN Communities of Practice launched last year, organizing members into four domains: expertise, internal staff, one-on-one money (fundraising), and relationships.
• TRiN will turn 20 in 2025, celebrating with an "Impact Series" to highlight patient organization stories.
• 2025 programming plans include resources for CMS access determination and engagement in the med-tech space (devices, diagnostics, digital health).
• Faster Cures will host a mini-workshop at the World Orphan Drug Congress focusing on the Research Partnership Maturity Model.

Repurposing Landscape & Challenges

• Repurposing (or "resurrecting shelved assets") offers a lower-cost, faster pathway to approval but faces hurdles in financial liability, intellectual property, and data access.
• New AI technologies and platforms are improving the speed and accuracy of matching existing drugs to new therapeutic indications.
• 4,000 FDA-approved drugs currently treat roughly 4,000 human diseases, yet over 14,000 diseases still lack approved therapies.
• 30% of all US prescriptions are currently off-label, though many inexpensive generic drugs lack a formal path for label changes.
• Patient organizations are increasingly partnering to navigate challenges and accelerate the adoption of repurposed therapies.

EveryCure & AI-Driven Discovery (David Fagenbaum)

• David Fagenbaum, co-founder of EveryCure and founder of the Castleman Disease Collaborative Network (CDCN), shared a personal story of surviving Castleman's disease using repurposed drugs.
• CDCN discovered that Sirolimus (an mTOR inhibitor approved for LAM) could treat Castleman's disease due to overactive mTOR signaling.
• Fagenbaum has helped uncover 14 repurposed drugs for various conditions, helping thousands of patients globally.
• Case Study: Angiosarcoma: A simple literature search identified PD-L1 expression, leading to the use of PD-1 inhibitors (e.g., pembrolizumab), now recommended as first-line therapy.
• Case Study: DADA2: Despite existing lab and clinical data for TNF inhibitors, utilization was low until CHIP established treatment guidelines; the drug remains underutilized despite efficacy.
• EveryCure utilizes biomedical knowledge graphs and AI to perform ~75 million calculations (4,000 drugs vs. 18,500 diseases) to predict potential matches.
• Repurposing Archetypes Identified:
  • Frontier Explorers: Lab data exists, but no clinical evidence or adoption (e.g., Sirolimus for Castleman's initially).
  • Clinical Gems: Strong mechanism and some clinical data, but requires more clinical trials or registries (e.g., Pembrolizumab for Angiosarcoma).
  • Unsung Heroes: Strong mechanism and clinical data, but low utilization due to lack of patent protection (e.g., TNF inhibitors for DADA2).
• EveryCure's algorithm predicted TNF inhibitors for Castleman's disease prior to a successful case report saving a patient named "Al."
• EveryCure is shifting from "lowest hanging fruit" in single diseases to global optimization across the "entire forest" of diseases.
• Top predicted matches included Propranolol for ovarian cancer, Leflunomide for a rare autism subtype, Arginine for sickle cell disease, Bosutinib for ALS, Lidocaine for breast cancer, and Metformin for long COVID.
• EveryCure is not currently accepting specific disease requests but prioritizes based on high-scoring algorithmic matches and collaborates with patient groups for validation.

CURE HHT & Therapeutic Advocacy (Marianne Clancy)

• CURE HHT is a small advocacy organization that successfully led the repurposing of multiple drugs for Hereditary Hemorrhagic Telangiectasia (HHT), a genetic vascular disorder affecting 1 in 3,500 people.
• HHT currently has zero FDA-approved therapies; diagnosis is often delayed (average age 27–45) despite the presence of a 50% inheritance rate.
• Avastin (Bevacizumab): A 15-year journey where the group gathered off-label data, funded pilot trials, and secured CMS approval in 2020 for treating HHT-related anemia and bleeding.
• Pomalidomide (PATH Trial): CURE HHT collaborated on a multi-site trial (177 patients, 11 sites) which showed statistically significant improvements in hemoglobin and reduced nosebleeds; published in the NEJM in 2024.
• Pazopanib (Votrient):
  • Originally failed to proceed due to a pharmaceutical portfolio sale after a 2015 GSK-funded trial.
  • CURE HHT self-funded the program, raising $6.2 million in grants and investing $100,000 of their own funds over six years.
  • Secured FDA Breakthrough Designation, wrote the IND, and outsourced CRO/clinical operations.
  • Aims to enroll 80 patients by month-end and submit for FDA approval in 2025 for a repurposed dose (50mg-75mg) distinct from the kidney cancer dose.
• Lessons learned emphasize the need for relentless advocacy, patient voice power, and collaboration to drive treatment to market.
• Future repurposing pipeline for HHT includes Sirolimus and Tacrolimus.

NCATS Resources & Support (Christine Colvis)

• NCATS focuses on disease-agnostic technology and method development to bridge the gap between preclinical research and clinical translation.
• CureID: A mobile app/registry for sharing real-world evidence of off-label drug use, particularly useful for rare diseases and vulnerable populations; launched prior to the pandemic and gaining traction.
• Translators Program: A knowledge aggregator pulling data from ~200 sources to help researchers identify drug-gene-disease connections.
• Success Story: Used Translators to identify Guanfacine (an ADHD/HTN drug) for Schein syndrome, resulting in significant motor and behavioral improvements for a patient after 5 months.
• NCATS Pharmaceutical Collection: A library of 3,000 approved and experimental drugs available for high-throughput screening to find "lowest hanging fruit" for new indications.
• Preclinical Funding: A specific funding opportunity available (next receipt June) to support proof-of-concept studies in animal models for rare diseases (excluding rare cancers) to bridge the gap to IND.
• Therapeutics for Rare/Neglected Diseases (TREAT-NMD): A collaboration model (not direct funding) providing expertise, assays, and animal models for late-stage development.
• AstraZeneca Open Innovation: Offers access to preclinical and clinical-stage compounds for researchers to explore new indications via a proposal process.

Intellectual Property (IP) Strategy Discussion

• Consensus: IP is generally not necessary for repurposing existing generic drugs unless a new formulation, dose, or specific patentable claim is required.
• David Fagenbaum: Emphasized that for generic drugs with unchanged formulas, insurance coverage often depends on clinical evidence rather than IP; off-label prescribing is already common (30% of prescriptions).
• Marianne Clancy: Agreed that IP is only critical when a new dosage or formulation is needed (e.g., Pazopanib for HHT required a specific dose adjustment not covered by the original patent).
• Christine Colvis: Noted that unless a new formulation is needed to improve patient compliance (e.g., tablet size for a specific population), the cost of securing a use patent is often not worth the investment for generic drugs.
• Key Takeaway: The primary hurdle is generating clinical evidence and navigating payment pathways (CMS/Insurance), not IP protection, for most repurposing opportunities.