Shawn Ryan Show

#240 Dr. David Fajgenbaum - Can AI Find Cures to Rare Diseases Using Existing Medicine?

September 29, 2025

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  • Dr. David Fajgenbaum survived five near-death experiences with Idiopathic Multicentric Castleman Disease after his mother died of brain cancer, leading him to dedicate his life to finding treatments for rare diseases. 
  • The primary roadblock to drug repurposing is that most existing drugs are generic, making further research into new uses unprofitable for pharmaceutical companies. 
  • Dr. Fajgenbaum discovered his life-saving treatment, sirolimus (Rapamycin), by identifying an overactive immune communication line and repurposing an existing drug used for organ transplantation. 
  • The primary barrier to drug repurposing for generic drugs is the lack of financial incentive for pharmaceutical companies once patent exclusivity expires, leading to a research gap for 80% of existing medicines. 
  • Dr. Fajgenbaum's organization, Every Cure, utilizes a biomedical knowledge graph and AI to calculate potential drug-disease matches across 75 million possibilities, significantly speeding up the identification of viable treatments. 
  • Disseminating successful drug repurposing findings is currently sporadic, relying on publications and conferences, highlighting the critical need for better, systematic methods to inform the global medical community. 

Segments

Roadblocks to Drug Repurposing
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(00:04:33)
  • Key Takeaway: The primary roadblock to repurposing existing drugs is lack of profitability, as most are generic.
  • Summary: The host asks about roadblocks in the medical establishment to breakthroughs like Dr. Fajgenbaum’s. The main obstacle cited is that generic drugs offer no profit incentive for advancement, requiring external efforts like Every Cure to pursue these opportunities.
Finding a Good Doctor
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(00:07:23)
  • Key Takeaway: When facing rare or difficult diseases, patients must often travel to find the specific expert, starting with Google searches and disease organizations.
  • Summary: The discussion covers how an uneducated person can find a good doctor, suggesting starting with Google searches for disease organizations, who can then recommend specialists. It also contrasts the time spent by concierge doctors versus traditional in-network physicians.
Mother’s Battle and Promise
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(00:09:30)
  • Key Takeaway: Witnessing his mother’s struggle with brain cancer inspired Dr. Fajgenbaum to promise her he would dedicate his life to finding medical treatments.
  • Summary: Dr. Fajgenbaum recounts growing up focused on football, followed by the devastating news of his mother’s brain cancer. He shares an emotional story about her strength post-surgery and the promise he made on her deathbed to become a doctor and find cures.
Diagnosis of Castleman Disease
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(00:18:16)
  • Key Takeaway: While in medical school, Dr. Fajgenbaum became critically ill with a rare, life-threatening autoimmune disorder called Castleman Disease.
  • Summary: Dr. Fajgenbaum describes the rapid onset of severe fatigue and organ failure at age 25. He was hospitalized, temporarily blinded, and received last rites before doctors identified his condition as Castleman Disease, leading to initial chemotherapy.
Survival Mindset and Support
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(00:22:36)
  • Key Takeaway: Survival through critical illness required visualizing the future, relying on a strong support system, and focusing only on the immediate next breath.
  • Summary: Dr. Fajgenbaum details the three factors that helped him survive six months in critical condition: visualizing his future with his fiancée, the strength derived from his family’s support, and taking life one breath at a time.
Relapse and Drug Repurposing Focus
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(00:33:34)
  • Key Takeaway: After relapsing through the only known experimental drug for Castleman’s, Dr. Fajgenbaum realized he needed to find an existing drug to repurpose.
  • Summary: He describes relapsing through an experimental drug, being told by the world expert there were no more options, and subsequently deciding to dedicate his life to finding existing drugs that could treat Castleman Disease.
The Cure: Sirolimus Discovery
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(00:38:01)
  • Key Takeaway: By analyzing his stored blood samples, Dr. Fajgenbaum identified an overactive immune pathway and successfully convinced doctors to try Sirolimus (Rapamycin), an existing transplant drug, which put him into remission.
  • Summary: After his fifth near-death flare, he analyzed his blood samples, discovered the mechanism of his disease, and found that Sirolimus, used for organ transplants, could turn off the faulty immune signaling. He has been in remission since starting the drug in 2014.
Founding Every Cure with AI
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(00:52:54)
  • Key Takeaway: To scale drug repurposing beyond his lab’s capacity, Dr. Fajgenbaum co-founded Every Cure to use AI to systematically match all existing drugs to all diseases.
  • Summary: Motivated by the success of repurposing, Dr. Fajgenbaum partnered with Grant Mitchell to launch Every Cure. The nonprofit uses AI to scan the world’s knowledge to find the most promising matches between the 4,000 approved drugs and 18,000 diseases.
Pharmaceutical Profit Motives
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(00:55:27)
  • Key Takeaway: Drug companies prioritize profitability within patent life, leading to neglect of off-patent drug repurposing.
  • Summary: Discussion on conspiracies about pharmaceutical companies hiding cures, leading to the explanation of the 8-12 year patent clock and how generic status stops company investment in new research.
The Unmet Need for Repurposing
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(00:57:43)
  • Key Takeaway: 80% of drugs are generic, meaning no company is incentivized to find new uses for them, creating a gap EveryCure aims to fill.
  • Summary: Quantifying the problem: 4,000 drugs are generic, and finding new uses for them is unprofitable, requiring external funding from government or philanthropists.
Incentivizing Drug Repurposing
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(00:59:03)
  • Key Takeaway: Incentivizing drug companies (e.g., via patent extension) would increase cures but also increase healthcare costs.
  • Summary: Exploring solutions like government incentives (patent extension) versus direct funding for research on cheap, generic drugs, noting the cost trade-offs.
EveryCure’s Model and Scale
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(01:00:55)
  • Key Takeaway: EveryCure uses federal funding (ARPA-H) to research new uses for existing drugs, aiming to save the healthcare system money.
  • Summary: Details on EveryCure’s federal contract and the vast gap between approved drugs (4,000) and diseases needing treatment (14,000 more).
Case Studies: Life-Saving Repurposing
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(01:03:16)
  • Key Takeaway: Existing drugs, when correctly matched, can dramatically alter outcomes for rare and aggressive diseases, as shown by patient examples.
  • Summary: Sharing success stories, including Michael’s angiosarcoma treatment with Pemberlizumab and Kyla’s Castleman treatment with a JAK inhibitor.
Disseminating Repurposing Knowledge
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(01:07:59)
  • Key Takeaway: Disseminating successful off-label treatments is sporadic and relies on luck, publications, or dedicated patient advocacy.
  • Summary: Discussing the difficulty of getting word out about successful repurposing, contrasting the Data II syndrome success (driven by a foundation) with the need for systemic solutions.
AI and Biomedical Knowledge Graphs
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(01:13:06)
  • Key Takeaway: AI uses a biomedical knowledge graph to calculate 75 million drug-disease match scores to prioritize research targets.
  • Summary: Explanation of how EveryCure uses machine learning trained on known treatments to score every drug against every disease, drastically reducing search time.
AI as a Starting Point
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(01:16:09)
  • Key Takeaway: AI predictions are powerful but must be validated by human experts and clinical trials; they should not replace existing data.
  • Summary: How the AI scores are ranked alongside existing FDA approvals and early data, emphasizing that AI is a guide, not the final authority.
Cancer Prevention and Inflammation
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(01:21:57)
  • Key Takeaway: Lidocaine injection around breast tumors shows promise in preventing recurrence, illustrating the potential of cheap, existing substances.
  • Summary: Discussion on cancer causes (somatic mutations, inflammation, sugar) and EveryCure’s program investigating lidocaine for breast cancer recurrence prevention.
Holistic vs. Pharmaceutical Medicine
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(01:26:46)
  • Key Takeaway: Medicine is gray; one should follow the data rather than rigidly adhering to ’natural’ versus ‘pharmaceutical’ sources.
  • Summary: Dr. Fajgenbaum discusses the source of his own life-saving drug (discovered in soil) and urges patients to follow data rather than source bias.