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 ...

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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

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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...