Using Existing Drugs in New Ways to Treat & Cure Diseases of Brain & Body _ Dr. David Fajgenbaum
Dr. David Fajgenbaum, a physician-scientist at the University of Pennsylvania, shares how his near-fatal battle with Castleman's disease led him to discover that existing FDA-approved drugs can treat diseases beyond their original purpose. He founded EveryCure, a nonprofit using AI to systematically match all 4,000 FDA-approved drugs to the 18,000 known human diseases. His work challenges the medical system's structural blind spots around drug repurposing and advocates for greater patient agency in navigating treatment options.
Summary
Dr. David Fajgenbaum opens by describing the moment his physician told him there were no remaining treatment options for his Castleman's disease — a rare, life-threatening immune disorder. Rather than accepting this verdict, he pivoted to searching for existing, approved drugs that might work for his condition through different mechanisms. This personal crisis became the foundation for a broader scientific and humanitarian mission.
Fajgenbaum explains a fundamental but underappreciated truth about pharmacology: the average FDA-approved small molecule drug binds to between 20 and 30 different proteins in the body, yet drugs are typically approved for just one or two conditions. This creates an enormous gap where potentially beneficial uses are never explored, particularly once a drug becomes generic and loses commercial incentive for further development. He cites examples including aspirin reducing colon cancer recurrence in patients with mTOR pathway mutations, Viagra being repurposed for a rare pediatric lung disease, lidocaine injections before breast cancer surgery potentially reducing five-year mortality by 29%, colchicine reducing heart attack risk in high-risk patients, and thalidomide treating both leprosy and multiple myeloma despite its history of causing birth defects.
Fajgenbaum traces his path through medicine, beginning with the death of his mother from glioblastoma when he was 18, which prompted him to dedicate his career to finding treatments for deadly diseases. Years later, as a third-year medical student at Penn, he rapidly developed multi-organ failure from undiagnosed Castleman's disease, nearly dying five separate times over roughly two years. He received last rites at age 25. Using his own blood samples, flow cytometry, and serum proteomics, he identified hyperactivation of the mTOR signaling pathway in his disease. He then proposed and received sirolimus (rapamycin), a drug approved for organ transplant rejection, which put him into remission. He has now been in remission for over 11 years on this drug.
His laboratory subsequently identified drug repurposing opportunities for other patients, including a PD-L1 inhibitor for a patient with metastatic angiosarcoma who has now been in remission for nine years and recently walked his daughter down the aisle, a TNF inhibitor for a Castleman's patient in Vancouver published in the New England Journal of Medicine, ruxolitinib for a pediatric Castleman's patient now in college, and a combination chemotherapy regimen for a patient with POEM syndrome who was near death.
Fajgenbaum co-founded EveryCure, a nonprofit that uses biomedical knowledge graphs and machine learning to score the likelihood of every FDA-approved drug treating every known disease. The organization currently has nine active programs and accepts submissions of potential drug-disease connections from the public, researchers, and clinicians. He emphasizes that EveryCure is structured to conduct rigorous laboratory and clinical validation before advocating any new drug use, distinguishing it from speculative or anecdotal approaches.
The conversation also covers structural problems in the medical system, including how physicians have limited time to track primary literature, how the independent investigator model in academic research creates information silos, how drug patents create financial disincentives for exploring generic drug repurposing, and how rare disease communities and disease-specific advocacy organizations serve as underutilized knowledge networks. Fajgenbaum advocates for centralized AI-driven databases that patients and physicians could access to identify promising treatment options based on individual disease profiles and family history.
Andrew Huberman raises the neuroscience of resilience and hope, connecting Fajgenbaum's described psychological circuit of hope, action, and impact to research on the anterior mid-cingulate cortex — a brain region associated with tenacity, positive anticipation of the future, and longevity, particularly in so-called super-agers. Fajgenbaum reflects on how his athletic background as a Division I college quarterback trained him in goal-setting, physical endurance, and resilience under failure, all of which he credits with helping him survive and pursue solutions during his illness.
Key Insights
- Fajgenbaum argues that the average FDA-approved small molecule drug binds 20 to 30 different proteins in the body, yet is approved and marketed for only one or two conditions, leaving dozens of potential therapeutic uses unexplored.
- Fajgenbaum contends that once a drug becomes generic, all research and development by pharmaceutical companies ceases entirely, eliminating any financial incentive to find new uses for that drug even if strong scientific evidence exists.
- Fajgenbaum claims that of the 4,000 FDA-approved drugs, 80% are already generic, meaning the vast majority of existing medicines have no commercial entity motivated to discover or promote additional therapeutic uses.
- Fajgenbaum argues that a single large Indian trial found a 29% reduction in five-year mortality for localized breast cancer patients who received lidocaine injections around the tumor before surgery — yet this finding has seen almost no clinical uptake despite being published in the Journal of Clinical Oncology.
- Fajgenbaum describes discovering through his own blood proteomics and lymph node staining that the mTOR pathway was hyperactivated in his Castleman's disease, leading him to propose sirolimus — a drug approved for organ transplant rejection — which has kept him in remission for over 11 years.
- Fajgenbaum argues that physicians are not systematically exposed to the full body of relevant literature, and that treatment decisions are often shaped by random exposure to papers, conference talks, or colleague recommendations rather than comprehensive evidence review.
- Fajgenbaum describes how a doctor accidentally discovered that TNF inhibitors stopped strokes in children with DADA2, a genetic condition causing repeated childhood strokes — but that word did not spread for approximately 10 years, during which hundreds of children died who could have been treated.
- Fajgenbaum argues that drug companies, as patents near expiration, typically seek new formulations or doses of the same drug to extend intellectual property rather than investigating entirely new diseases, meaning cross-disease repurposing is systematically neglected.
- Fajgenbaum claims that a patient with metastatic angiosarcoma was given a PD-L1 inhibitor based on a 2013 lab paper showing elevated PD-L1 expression in angiosarcoma tumors — a connection no one had translated into clinical use in the three years since publication — and the patient has now been in remission for nine years.
- Fajgenbaum describes EveryCure's approach as scoring every FDA-approved drug against every known disease using machine learning and biomedical knowledge graphs, then conducting rigorous laboratory and clinical validation on the highest-ranked matches before advocating their use.
- Fajgenbaum argues that rapamycin's immunosuppressive effects at transplant-level doses are likely to counteract any longevity benefit in humans who, unlike caged laboratory animals, are regularly exposed to pathogens and infectious disease.
- Fajgenbaum proposes that the medical system's core blind spot is not negligence or bad intent but structural: drugs are studied and approved for specific conditions by entities with financial stakes in those conditions, and once that financial stake expires with patent loss, the drug effectively disappears from active scientific investigation.
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