Approved

Alex Kesin and Matthew Pech
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Life sciences, under the hood. Deep dives into the patent filings, regulatory gauntlets, and capital-risks that shape the business of biology.

Episodes

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

    4 DAYS AGO

    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." Forbes, Jul 26, 2017. The definitive Organon-era origin story.Loftus, Peter. "Why Merck Is Betting Big on One Cancer Drug." WSJ, Apr 15, 2018. Source for Perlmutter's "whatever other projects you're working on, you can stop now."Lowe, Derek. "The Keytruda Story." In the Pipeline.Graeber, Charles. The Breakthrough. 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." Science (1974). The flawed experiment that killed tumor immunology for two decades.Shankaran et al. "IFNγ and lymphocytes prevent primary tumour development." Nature (2001). Schreiber's cancer immunoediting paper.Leach, Krummel & Allison. "Antitumor immunity by CTLA-4 blockade." Science (1996). Allison's '100-to-zero' experiment.Ishida, Agata, Shibahara & Honjo. "Induced expression of PD-1." EMBO J (1992). Honjo discovers PD-1.Dong, Strome et al. "B7-H1 promotes T-cell apoptosis." Nat Med (2002). Lieping Chen's PD-L1 immune-evasion paper.Pivotal trials Topalian et al. "Anti-PD-1 ...

    2h 8m
  2. Episode #2: Geron

    13 MAR

    Episode #2: Geron

    Listen on Spotify Listen on Apple Podcasts Listen on YouTube 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” by nerowski * Special thanks to the team at NFX 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. Williams, Tory. Inevitable Collision: The Inspiring Story That Brought Stem Cell Research to Conservative America.Mary Ann Liebert, Inc., 2014. II. KEY SCIENTIFIC PUBLICATIONS Hayflick, L. & Moorhead, P.S. “The serial cultivation of human diploid cell strains.” Experimental Cell Research 25 (1961): 585–621. Kim, N.W. et al. “Specific association of human telomerase activity with immortal cells and cancer.” Science 266, no. 5193 (1994): 2011–2015. Feng, J. et al. “The RNA component of human telomerase.” Science 269, no. 5228 (1995): 1236–1241. Nakamura, T.M. et al. “Telomerase catalytic subunit homologs from fission yeast and human.” Science 277, no. 5328 (1997): 955–959. 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. Bodnar, A.G. et al. “Extension of life-span by introduction of telomerase into normal human cells.” Science 279, no. 5349 (1998): 349–352. Thomson, J.A. et al. “Embryonic stem cell lines derived from human blastocysts.” Science 282, no. 5391 (1998): 1145–1147. Asai, A. et al. “A novel telomerase template antagonist (GRN163) as a potential anticancer agent.” Cancer Research 63, no. 14 (2003): 3931–3939.  Herbert, B-S et al. “Effect of the lipid modification of GRN163.” Nature: Oncogene 24 (2005): 5765–5772.  Baerlochr, G. et al. “A pilot study of the telomerase inhibitor imetelstat for myelofibrosis.” New England Journal of Medicine 373 (2015): 908–919.  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). 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). Scott, C. & Magnus, D. “Wrongful Termination: Lessons From the Geron Clinical Trial” Stem Cell Reports 3, no. 5 (2014): 721–723.  III. REGULATORY & CLINICAL Prescribing Information (Label) U.S. Food and Drug Administration. “RYTELO (imetelstat) for injection: Highlights of Prescribing Information.” NDA 217779. June 2024.  NDA Approval Letter U.S. Food and Drug Administration. “NDA Approval Letter: RYTELO (imetelstat) for injection.” NDA 217779. June 6, 2024.  Multi-Discipline Review & Evaluation U.S. Food and Drug Administration. “NDA Multi-Disciplinary Review and Evaluation: RYTELO (imetelstat).” NDA 217779Orig1s000. 2024.  ODAC Briefing Document U.S. Food and Drug Administration. “FDA Briefing Document: Oncologic Drugs Advisory Committee Meeting, NDA 217779, Imetelstat.” March 14, 2024.  REMS/Risk Assessment Review U.S. Food and Drug Administration. “Risk Assessment and Risk Mitigation Review: RYTELO (imetelstat).” NDA 217779Orig1s000. 2024.  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. FDA. “FDA Approves Imetelstat for Low- to Intermediate-1-Risk Myelodysplastic Syndromes with Transfusion-Dependent Anemia.” June 2024. ICER. “Evidence Report: Treatment for Anemia in Myelodysplastic Syndrome.” August 2024.  ICER. Press Release on Imetelstat Evidence Assessment.  ClinicalTrials.gov. GRNOPC1 Phase I Trial. NCT01217008.  Myelodysplastic Syndrome Epidemiology. PMC4553145. MDS Risk and AML Progression. Blood (2023).  IV. CORPORATE FILINGS & PRESENTATIONS

    2h 22m
  3. Episode #1: Amylin Pharmaceuticals

    30 JAN

    Episode #1: Amylin Pharmaceuticals

    Listen on Spotify Listen on Apple Podcasts Listen on YouTube 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” by nerowski * Special thanks to the team at NFX 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) * Medical Review * Statistical Review * Clinical Pharmacology & Biopharmaceutics Review * Administrative Documents & Correspondence Byetta (exenatide) - NDA 21-773 * Approval Letter & Package (April 28, 2005) * Medical Review * Statistical Review * Clinical Pharmacology & Biopharmaceutics Review * Administrative Documents & Correspondence Bydureon (exenatide ER) - NDA 22-200 * Approval Letter (January 27, 2012) * Other Action Letters (Complete Response) * Summary Review * REMS * Administrative Correspondence SEC Filings & Financial Documents * Amylin 2005 Results Press Release (Ex-99.1, 8-K) * Amylin 2007 Results Press Release (Ex-99.1) * Amylin 2011 Form 10-K (Net Product Sales) * Carl Icahn SEC Filing (Schedule 13D) Proxy Fight & Legal Documents * Carl Icahn Letter to Amylin (April 15, 2009) * Amylin Response to Icahn (April 20, 2009) * Police Fund v. Bradbury (Amylin) Trial (May 4, 2009) * Lilly Litigation Ruling (May 25, 2011) II. ORAL HISTORY & INTERVIEWS * Howard Greene Oral History (UCSD Library, October 8, 2008) - 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) - Donald Rumsfeld’s board tenure at Amylin (1991-1996) * “Roller Coasting” - Forbes (July 24, 2000) - Joe Cook narrative, J&J partnership collapse 2005 * “Investing for a Profit and a Daughter’s Health” - NYT (March 19, 2005) - Allen Andersson investment story, “tablecloth deal” 2006 * “Diabetics see hope (and weight loss) in new drug” - NYT (March 2, 2006) - “Lizzie” nickname, patient testimonials * “4 Diabetes Drugs Are Seen Raising Hope and Profit” - NYT (June 22, 2006) - Manufacturing shortage, 400,000+ patients * “Don’t kill off life-saving drugs” - Heritage Foundation (August 15, 2006) - Policy perspective on Byetta’s potential impact * “Byetta Craze Is First Salvo in Promising New Line of Drugs” - diaTribe - ADA conference chaos, “one man cried” 2007 * Dr. John Eng Profile - Diabetes In Control (September 18, 2007) - Eng’s discovery story, patent struggles, Amylin vs. Lilly negotiations 2008 * Xenome/Amylin Partnership - BioSpace (February 5, 2008) - Venom peptide library partnership 2009 * Eastbourne Capital Sells Stake - San Diego Union-Tribune (October 10, 2009) - End of Eastbourne activist campaign * Survey: Additional Diabetes Dru...

    1hr 46min
  • 3 Episodes

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Life sciences, under the hood. Deep dives into the patent filings, regulatory gauntlets, and capital-risks that shape the business of biology.

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  • Creator
    Alex Kesin and Matthew Pech
  • Years Active
    2k
  • Episodes
    3
  • Rating
    Clean
  • Copyright
    © Alex Kesin
  • Show Website
    Approved

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