Episode #2: Geron

Keytruda: How Merck's Pembrolizumab Became the Best-Selling Cancer Drug of All Time

Keytruda is Merck's $31 billion a year PD-1 inhibitor and the best-selling cancer drug of all time. In Episode 3 of Approved, Alex Kesin and Matthew Pech trace the development of pembrolizumab , featuring interviews the scientists who drove the program forward : co-inventors Gregory Carven and Michel Streuli, and former Merck oncology CMO Roy Baynes. Topics include preclinical PD1 / CTLA-4 checkpoint biology that brought industry attention to the target (Jim Allison's CTLA-4 work and Tasuku Honjo's PD-1 discovery); how pembro started as a failed rheumatoid arthritis antibody program at a Dutch subsidiary of a paint company; the two mega-mergers that nearly killed the program;  the biomarker enrichment trial design behind KEYNOTE-024 that let Merck break BMS's lead in lung cancer;  the 41-patient Johns Hopkins MSI-H trial behind the first tissue-agnostic FDA approval, and the Jimmy Carter melanoma case that brought pembrolizumab to the public conscious. The episode closes on what comes next for Merck: the 2028 patent cliff, the Keytruda QLEX subcutaneous launch, and efforts to find the next blockbuster checkpoint inhibitor, including Summit/Akeso's PD-1 / VEGF bispecific ivonescimab. This episode is presented by JLL. Featuring Grant Dettmer on biotech real estate strategy. CHAPTERS   00:00:00  —  Introduction: The Best-Selling Cancer Drug of All Time   00:02:15  —  Part One — A Century of Failed Cancer Immunotherapy   00:04:17  —  T Cells, CD28, and the Two-Signal Model of Immune Activation   00:06:25  —  Jim Allison's CTLA-4 Discovery and the Path to Yervoy   00:12:03  —  Tasuku Honjo Discovers PD-1: A Better Brake on T Cells   00:14:26  —  Lieping Chen and the PD-L1 Tumor Evasion Hypothesis   00:16:26  —  Part Two — Organon: The Dutch Paint-Company Subsidiary Behind Keytruda   00:19:48  —  How Michel Streuli Caught the Solid-Phase Screening Artifact   00:22:09  —  The Accidental Antagonist: From Rheumatoid Arthritis Drug to Cancer Drug   00:26:34  —  Sponsor: Grant Detmer (JLL) on Biotech Real Estate Strategy   00:30:01  —  Russian Nesting-Doll M&A: Schering-Plough Acquires Organon (2007)   00:31:43  —  The $41 Billion Merck–Schering-Plough Mega-Merger of 2009   00:34:58  —  Corporate Guerrilla Warfare: Four Scrappy Stunts That Saved Pembrolizumab   00:39:32  —  BioNovion's Spite-Company Bid to Buy Pembro Back   00:42:10  —  BMS at ASCO 2010: The Data Print That Revived Merck's PD-1 Program   00:45:55  —  Part Three — Roger Perlmutter Joins a Bleeding Merck (April 2013)   00:50:48  —  "Let Me Manage the Tigers": Ken Frazier Backs the All-In Bet on Pembrolizumab   00:55:22  —  Breakthrough Therapy Designation and Eric Rubin's Adaptive Trial Design   00:58:25  —  Keytruda's 2014 FDA Approval Erases BMS's Four-Year Lead   01:00:24  —  The Lung Cancer Battlefield and the PD-L1 Biomarker Bet   01:02:19  —  BMS vs. Merck: All-Comers vs. Biomarker-Enriched Trial Strategy   01:08:18  —  KEYNOTE-024 vs. CheckMate-026: The Trial That Decided the Category   01:12:03  —  Luis Diaz, MSI-H, and the Failed BMS Trial That Made Keytruda Tissue-Agnostic   01:17:18  —  KEYNOTE-189: Perlmutter's Bet on Combining Keytruda with Chemotherapy   01:19:21  —  Merck's Clinical Development Playbook: Basket Trials, Backwards March, External Collabs   01:25:29  —  Part Four — The IO Graveyard: TIGIT, CD47, IDO1, LAG-3 and Tens of Billions Incinerated   01:30:23  —  Why PD-1 Was the Only Checkpoint That Worked (Lieping Chen Revisited)   01:33:32  —  Part Five — Inside the Best-Selling Drug of All Time   01:37:03  —  "Build a Wall, High and Wide": Merck’s Commercial Strategy for Keytruda   01:43:44  —  Part Six — The Patent Cliff and Loss of Exclusivity in Pharma   01:45:35  —  Keytruda QLEX (Subcutaneous) and the Lifecycle Management Playbook   01:50:23  —  PD-1/VEGF Bispecifics: Ivonescimab, Summit Therapeutics, and the Next Threat   01:55:31  —  The Scorecard: Patient, Academic, and Financial Impact   02:01:19  —  Who Actually Profited: Merck vs. Organon vs. the Scientists Who Built the Drug   02:05:54  —  Epilogue: The Jimmy Carter Drug Sources Last updated: May 2026 Essential reading * Shaywitz, David. "The Startling History Behind Merck's New Cancer Blockbuster." [https://www.forbes.com/sites/davidshaywitz/2017/07/26/the-startling-history-behind-mercks-new-cancer-blockbuster/] Forbes, Jul 26, 2017. The definitive Organon-era origin story. * Loftus, Peter. "Why Merck Is Betting Big on One Cancer Drug." [https://www.wsj.com/articles/why-merck-is-betting-big-on-one-cancer-drug-1523790000] WSJ, Apr 15, 2018. Source for Perlmutter's "whatever other projects you're working on, you can stop now." * Lowe, Derek. "The Keytruda Story." [https://www.science.org/content/blog-post/keytruda-story] In the Pipeline. * Graeber, Charles. The Breakthrough [https://www.amazon.com/Breakthrough-Immunotherapy-Race-Cure-Cancer/dp/1455568503]. Twelve, 2018. Primary interviews Greg Carven, Michel Streuli, Roy Baynes — Approved podcast interviews (2026). Quotes attributed to these speakers come from these conversations unless otherwise noted. Foundational science * Stutman. "Tumor development in athymic-nude mice." [https://www.science.org/doi/10.1126/science.183.4124.534] Science (1974). The flawed experiment that killed tumor immunology for two decades. * Shankaran et al. "IFNγ and lymphocytes prevent primary tumour development." [https://www.nature.com/articles/35074122] Nature (2001). Schreiber's cancer immunoediting paper. * Leach, Krummel & Allison. "Antitumor immunity by CTLA-4 blockade." [https://www.science.org/doi/10.1126/science.271.5256.1734] Science (1996). Allison's '100-to-zero' experiment. * Ishida, Agata, Shibahara & Honjo. "Induced expression of PD-1." [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556898/] EMBO J (1992). Honjo discovers PD-1. * Dong, Strome et al. "B7-H1 promotes T-cell apoptosis." [https://www.nature.com/articles/nm730] Nat Med (2002). Lieping Chen's PD-L1 immune-evasion paper. Pivotal trials * Topalian et al. "Anti-PD-1 ... [https://www.nejm.org/doi/full/10.1056/NEJMoa1200690]

Episode #2: Geron

Listen on Spotify [https://open.spotify.com/episode/4COpXyTfI7jifq6da7wM52?si=EHI93INORPWlX8CabI6wcg] Listen on Apple Podcasts [https://podcasts.apple.com/us/podcast/episode-2-geron/id1873356046?i=1000755117965] Listen on YouTube [https://www.youtube.com/watch?v=ryeqeon5y4s] TABLE OF CONTENTS (00:00:00) - Introduction  (00:01:19) - Hayflick Limit  (00:08:30) - Michael West & Founding of Geron  (00:15:16) - Early Science & IP Strategy  (00:27:25) - Cloning the Telomerase Gene  (00:29:30) - Embryonic Stem Cells & Political Context  (00:44:21) - Okarma, West’s Departure & Corporate Turmoil  (01:05:08) - Spinal Cord Injury Trial  (01:30:45) - Pivot to Blood Cancer  (01:43:08) - Clinical & Commercial Drama (02:01:45) - Legacy & Lessons CREDITS Co-hosted by Alex Kesin and Matthew Pech Written, edited, and produced by Alex Kesin Music: “Food” [https://www.youtube.com/watch?v=4PoCA4taNyg] by nerowski * Special thanks to the team at NFX [https://www.nfx.com/] for the use of their recording studio. SOURCES Last updated: March 2026 I. BOOKS Hall, Stephen S. Merchants of Immortality: Chasing the Dream of Human Life Extension. Houghton Mifflin, 2003. [https://www.amazon.com/Merchants-Immortality-Pa-Stephen-Hall/dp/0618492216] Williams, Tory. Inevitable Collision: The Inspiring Story That Brought Stem Cell Research to Conservative America.Mary Ann Liebert, Inc., 2014. [https://www.amazon.com/Inevitable-Collision-Inspiring-Research-Conservative-ebook/dp/B00NGRMSHC] II. KEY SCIENTIFIC PUBLICATIONS Hayflick, L. & Moorhead, P.S. “The serial cultivation of human diploid cell strains.” Experimental Cell Research 25 (1961): 585–621. [https://pubmed.ncbi.nlm.nih.gov/13905658/] Kim, N.W. et al. “Specific association of human telomerase activity with immortal cells and cancer.” Science 266, no. 5193 (1994): 2011–2015. [https://pubmed.ncbi.nlm.nih.gov/7605428/] Feng, J. et al. “The RNA component of human telomerase.” Science 269, no. 5228 (1995): 1236–1241. [https://pubmed.ncbi.nlm.nih.gov/7544491/] Nakamura, T.M. et al. “Telomerase catalytic subunit homologs from fission yeast and human.” Science 277, no. 5328 (1997): 955–959. [https://www.science.org/doi/10.1126/science.277.5328.955] Meyerson, M. et al. “hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization.” Cell 90, no. 4 (1997): 785–795. [https://www.cell.com/cell/pdf/S0092-8674(00)80538-3.pdf] Bodnar, A.G. et al. “Extension of life-span by introduction of telomerase into normal human cells.” Science 279, no. 5349 (1998): 349–352. [https://www.science.org/doi/10.1126/science.279.5349.349] Thomson, J.A. et al. “Embryonic stem cell lines derived from human blastocysts.” Science 282, no. 5391 (1998): 1145–1147. [https://www.science.org/doi/abs/10.1126/science.282.5391.1145] Asai, A. et al. “A novel telomerase template antagonist (GRN163) as a potential anticancer agent.” Cancer Research 63, no. 14 (2003): 3931–3939.  [https://pubmed.ncbi.nlm.nih.gov/12873987/] Herbert, B-S et al. “Effect of the lipid modification of GRN163.” Nature: Oncogene 24 (2005): 5765–5772.  [https://pubmed.ncbi.nlm.nih.gov/15940257/] Baerlochr, G. et al. “A pilot study of the telomerase inhibitor imetelstat for myelofibrosis.” New England Journal of Medicine 373 (2015): 908–919.  [https://www.nejm.org/doi/full/10.1056/NEJMoa1503479] Platzbecker, U. et al. “Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge).” The Lancet (2024). [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01724-5/abstract] Lennox, A.L et al. “Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.” Clinical and Translational Science 17, no. 11 (2024). [https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.70076] Scott, C. & Magnus, D. “Wrongful Termination: Lessons From the Geron Clinical Trial” Stem Cell Reports 3, no. 5 (2014): 721–723.  [https://pmc.ncbi.nlm.nih.gov/articles/PMC4250218/] III. REGULATORY & CLINICAL Prescribing Information (Label) U.S. Food and Drug Administration. “RYTELO (imetelstat) for injection: Highlights of Prescribing Information.” NDA 217779. June 2024.  [https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217779s000lbl.pdf] NDA Approval Letter U.S. Food and Drug Administration. “NDA Approval Letter: RYTELO (imetelstat) for injection.” NDA 217779. June 6, 2024.  [https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/217779Orig1s000ltr.pdf] Multi-Discipline Review & Evaluation U.S. Food and Drug Administration. “NDA Multi-Disciplinary Review and Evaluation: RYTELO (imetelstat).” NDA 217779Orig1s000. 2024.  [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217779Orig1s000OtherR.pdf] ODAC Briefing Document U.S. Food and Drug Administration. “FDA Briefing Document: Oncologic Drugs Advisory Committee Meeting, NDA 217779, Imetelstat.” March 14, 2024.  [https://www.fda.gov/media/176966/download] REMS/Risk Assessment Review U.S. Food and Drug Administration. “Risk Assessment and Risk Mitigation Review: RYTELO (imetelstat).” NDA 217779Orig1s000. 2024.  [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217779Orig1s000RiskR.pdf] Kim, N. et al. “US Food and Drug Administration Approval Summary: Imetelstat for Selected Patients With Low- to Intermediate-1 Risk Myelodysplastic Syndromes With Transfusion-Dependent Anemia.” The Oncologist (2025). PMID: 41135032. [https://ascopubs.org/doi/abs/10.1200/JCO-25-01369] FDA. “FDA Approves Imetelstat for Low- to Intermediate-1-Risk Myelodysplastic Syndromes with Transfusion-Dependent Anemia.” June 2024. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent] ICER. “Evidence Report: Treatment for Anemia in Myelodysplastic Syndrome.” August 2024.  [https://icer.org/wp-content/uploads/2024/08/MDS_Final-Report_For-Publication_08222024.pdf] ICER. Press Release on Imetelstat Evidence Assessment.  [https://icer.org/news-insights/press-releases/institute-for-clinical-and-economic-review-publishes-evidence-report-on-treatment-for-anemia-in-myelodysplastic-syndrome/] ClinicalTrials.gov. GRNOPC1 Phase I Trial. NCT01217008.  [https://clinicaltrials.gov/study/NCT01217008] Myelodysplastic Syndrome Epidemiology. PMC4553145. [https://pmc.ncbi.nlm.nih.gov/articles/PMC4553145/] MDS Risk and AML Progression. Blood (2023).  [https://ashpublications.org/blood/article/142/26/2247/498176/Diagnosis-and-classification-of-myelodysplastic] IV. CORPORATE FILINGS & PRESENTATIONS https://d18rn0p25nwr6d.cloudfront...

Episode #1: Amylin Pharmaceuticals

Listen on Spotify [https://open.spotify.com/show/66IeBvvuoDma0ysf8c4I8Z] Listen on Apple Podcasts [https://podcasts.apple.com/us/podcast/episode-1-amylin-pharmaceuticals/id1873356046?i=1000747377804] Listen on YouTube [https://www.youtube.com/watch?v=cddzPaXBzqg] TABLE OF CONTENTS (00:00:00) - Introduction (00:04:40) - $50 of Dried Lizard Venom (00:29:17) - Fax of Death (00:43:04) - Sleeping Beauty Awakens (00:52:07) - Carl Icahn Sends a Letter (01:09:19) - Endgame (01:13:40) - Postmortem & Playbook CREDITS Co-hosted by Alex Kesin and Matthew Pech  Written, edited, and produced by Alex Kesin Music: “Food” [https://www.youtube.com/watch?v=4PoCA4taNyg] by nerowski * Special thanks to the team at NFX [https://www.nfx.com/] for the use of their recording studio. SOURCES Last updated: January 2026 I. PRIMARY DOCUMENTS FDA Regulatory Documents Symlin (pramlintide acetate) - NDA 21-332 * Approval Letter & Package (March 16, 2005) [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%2520Injection_approv.PDF] * Medical Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%2520Injection_medr.PDF] * Statistical Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%2520Injection_statr.PDF] * Clinical Pharmacology & Biopharmaceutics Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%2520Injection_biopharmr.PDF] * Administrative Documents & Correspondence [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%2520Injection_admincorres.PDF] Byetta (exenatide) - NDA 21-773 * Approval Letter & Package (April 28, 2005) [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_approv.PDF] * Medical Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_medr.PDF] * Statistical Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_statr.PDF] * Clinical Pharmacology & Biopharmaceutics Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_biopharmr.PDF] * Administrative Documents & Correspondence [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_admincorres.PDF] Bydureon (exenatide ER) - NDA 22-200 * Approval Letter (January 27, 2012) [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000Approv.pdf] * Other Action Letters (Complete Response) [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000OtherActionLtrs.pdf] * Summary Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000SumRedt.pdf] * REMS [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000Rems.pdf] * Administrative Correspondence [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000Admincorresedt.pdf] SEC Filings & Financial Documents * Amylin 2005 Results Press Release (Ex-99.1, 8-K) [https://www.sec.gov/Archives/edgar/data/881464/000110465906007417/a06-4671_1ex99d1.htm] * Amylin 2007 Results Press Release (Ex-99.1) [https://www.sec.gov/Archives/edgar/data/881464/000110465908005085/a08-3824_1ex99d1.htm] * Amylin 2011 Form 10-K (Net Product Sales) [https://www.sec.gov/Archives/edgar/data/881464/000119312512072788/d260205d10k.htm] * Carl Icahn SEC Filing (Schedule 13D) [https://www.sec.gov/divisions/corpfin/cf-noaction/2009/icahnassociates032709-sec14-incoming.pdf] Proxy Fight & Legal Documents * Carl Icahn Letter to Amylin (April 15, 2009) [https://www.fiercebiotech.com/biotech/letter-from-carl-icahn-to-amylin-pharmaceutical] * Amylin Response to Icahn (April 20, 2009) [https://www.fiercebiotech.com/biotech/amylin-letter-to-carl-icahn] * Police Fund v. Bradbury (Amylin) Trial (May 4, 2009) [https://cvn.com/proceedings/police-fund-v-bradbury-amylin-trial-2009-05-04] * Lilly Litigation Ruling (May 25, 2011) [https://investor.lilly.com/static-files/51a2a9a3-6b73-4e44-9f48-c22133624708] II. ORAL HISTORY & INTERVIEWS * Howard Greene Oral History (UCSD Library, October 8, 2008) [https://library.ucsd.edu/dc/object/bb2187116q/_1_1.pdf] - Primary source for Hybritech founding, Ted Greene’s background, and early Amylin history III. NEWS & TRADE PRESS 2000 * “The Rumsfeld Resume” - CBS News (December 28, 2000) [https://www.cbsnews.com/news/the-rumsfeld-resume/] - Donald Rumsfeld’s board tenure at Amylin (1991-1996) * “Roller Coasting” - Forbes (July 24, 2000) [https://www.forbes.com/forbes/2000/0724/6603205a.html] - Joe Cook narrative, J&J partnership collapse 2005 * “Investing for a Profit and a Daughter’s Health” - NYT (March 19, 2005) [https://www.nytimes.com/2005/03/19/business/investing-for-a-profit-and-a-daughters-health.html] - Allen Andersson investment story, “tablecloth deal” 2006 * “Diabetics see hope (and weight loss) in new drug” - NYT (March 2, 2006) [https://www.nytimes.com/2006/03/02/business/worldbusiness/02iht-drug.html] - “Lizzie” nickname, patient testimonials * “4 Diabetes Drugs Are Seen Raising Hope and Profit” - NYT (June 22, 2006) [https://www.nytimes.com/2006/06/22/business/22diabetes.html] - Manufacturing shortage, 400,000+ patients * “Don’t kill off life-saving drugs” - Heritage Foundation (August 15, 2006) [https://www.heritage.org/public-health/commentary/dont-kill-life-saving-drugs] - Policy perspective on Byetta’s potential impact * “Byetta Craze Is First Salvo in Promising New Line of Drugs” - diaTribe [https://diatribe.org/diabetes-medications/byetta-craze-first-salvo-promising-new-line-drugs] - ADA conference chaos, “one man cried” 2007 * Dr. John Eng Profile - Diabetes In Control (September 18, 2007) [https://www.diabetesincontrol.com/dr-john-engs-research-found-that-the-saliva-of-the-gila-monster-contains-a-hormone-that-treats-diabetes-better-than-any-other-medicine/] - Eng’s discovery story, patent struggles, Amylin vs. Lilly negotiations 2008 * Xenome/Amylin Partnership - BioSpace (February 5, 2008) [https://www.biospace.com/xenome-ltd-names-b-ian-t-nisbet-phd-b-as-ceo] - Venom peptide library partnership 2009 * Eastbourne Capital Sells Stake - San Diego Union-Tribune (October 10, 2009) [https://www.sandiegouniontribune.com/2009/10/10/eastbourne-capital-sells-entire-stake-in-amylin/] - End of Eastbourne activist campaign * Survey: Additional Diabetes Dru... [https://cardiovascularbusiness.com/topics/clinical/structural-heart-disease/survey-additional-diabetes-drugs-dpp-iv-inhibitors-needed]