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: April 2026

I. Primary Interviews

Original interviews conducted for this episode. Quotes attributed to these speakers throughout the script come from these conversations unless otherwise noted.

• Greg Carven — Approved podcast interview (2026). Named inventor on the pembrolizumab patent; ran the antibody campaign at Organon Cambridge that produced MK-3475.

• Michel Streuli — Approved podcast interview (2026). Head of research at Organon Cambridge after 15 years in tumor immunology at Dana-Farber; the scientist who insisted on running the screening assay in solution.

• Roy Baynes — Approved podcast interview (2026). Senior Vice President & Head of Global Clinical Development at Merck Research Laboratories; led Keytruda’s clinical program from 2013 onward.

II. Books

• Graeber, Charles. The Breakthrough: Immunotherapy and the Race to Cure Cancer. Twelve, 2018.

III. Key Scientific Publications

Foundational immune-surveillance & checkpoint biology

• Stutman, O. “Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice.” Science 183 (1974): 534–536. The flawed nude-mouse experiment that effectively killed the tumor immunology field for two decades.

• Shankaran, V. et al. “IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity.” Nature 410 (2001): 1107–1111. Bob Schreiber’s RAG2-knockout experiment — the cancer immunoediting paper that re-opened the field.

• Leach, D.R., Krummel, M.F., & Allison, J.P. “Enhancement of antitumor immunity by CTLA-4 blockade.” Science 271 (1996): 1734–1736. Jim Allison’s ‘100-to-zero’ mouse experiment that founded the modern checkpoint-inhibitor era.

• Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. “Induced expression of PD-1 upon programmed cell death.” EMBO Journal 11 (1992): 3887–3895. Tasuku Honjo’s lab discovers PD-1.

• Dong, H., Strome, S.E., et al. “Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.” Nature Medicine 8 (2002): 793–800. Lieping Chen’s lab establishes that PD-L1 is upregulated on tumors and shuts down T-cells.

Pivotal pembrolizumab & nivolumab trials

• Topalian, S.L., Hodi, F.S., Brahmer, J.R., et al. “Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.” NEJM 366 (2012): 2443–2454. BMS’s landmark Phase 1 readout for nivolumab — the data print that woke Merck up to PD-1.

• Brahmer, J.R., Tykodi, S.S., Chow, L.Q., et al. “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.” NEJM 366 (2012): 2455–2465.

• Hamid, O., Robert, C., Daud, A., et al. “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.” NEJM 369 (2013): 134–144. First major pembrolizumab clinical readout (KEYNOTE-001 expansion).

• Le, D.T., Uram, J.N., Wang, H., et al. “PD-1 blockade in tumors with mismatch-repair deficiency.” NEJM 372 (2015): 2509–2520. The Diaz/Le 41-patient MSI-H trial that produced the first tissue-agnostic FDA approval.

• Reck, M., Rodríguez-Abreu, D., Robinson, A.G., et al. “Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.” NEJM 375 (2016): 1823–1833. KEYNOTE-024. The biomarker-enriched first-line lung trial that decided the BMS/Merck war.

• Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., et al. “Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.” NEJM 378 (2018): 2078–2092. KEYNOTE-189 — the chemo-combination trial that captured the all-comers first-line market.

• Reck, M. et al. “Five-year outcomes with pembrolizumab versus chemotherapy for metastatic NSCLC with PD-L1 TPS ≥50%.” JCO (2021). Long-term KEYNOTE-024 follow-up: 31.9% vs 16.3% five-year OS.

Mechanism of action & checkpoint biology reviews

• Chen, L. & Han, X. “Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future.” (review). Lieping Chen’s history-of-the-target review.

• Chen, L. “PD-L1 and the dawn of modern cancer immunotherapy.” Nature Medicine (2025). Chen’s retrospective on the discovery and translation of PD-L1.

• Chen, L. “Why has immune checkpoint therapy failed in most clinical trials?” (2025). Chen’s argument for why TIGIT, TIM-3, CD47 and the rest of the post-PD-1 graveyard didn’t work.

• Sharma, P. & Allison, J.P. “Dissecting the mechanisms of immune checkpoint therapy.” Annual Review of Cancer Biology.

• Pardoll, D. “The blockade of immune checkpoints in cancer immunotherapy.” Nature Reviews Cancer. Foundational review of the checkpoint-blockade mechanism.

IV. First-Person Accounts & Executive Interviews

Roger Perlmutter

• Nature Reviews Drug Discovery. “An interview with Roger Perlmutter.” (2019). Source for Perlmutter’s “12 axes” comment and the γ-interferon/PD-L1 inflammation insight.

• Reed Magazine. “The Discovery: Roger Perlmutter & Eikon.” (2024). Long-form profile covering Merck tenure and post-Merck second act.

• Wall Street Journal. “Why Merck Is Betting Big on One Cancer Drug.” (April 15, 2018). Source for the “Whatever other projects you’re working on, you can stop now” quote.

• BioPharma Dive. “Merck’s Roger Perlmutter to retire; Dean Li to take over.” (2020).

Roy Baynes

• The Conference Forum. “Dr. Roy Baynes on Strategy Development for Keytruda.” (editorial). Background reading for Baynes’s clinical-development philosophy.

• Fierce Biotech. “After masterful development of Keytruda, Merck’s CMO follows Roger Perlmutter to Eikon.” (2022).

Lieping Chen

• Chen, L. “PD-L1 and the dawn of modern cancer immunotherapy.” Nature Medicine (2025).

• Chen, L. “Why has immune ‘checkpoint’ therapy failed in most clinical trials?” (2025).

Luis Diaz

• Ludwig Cancer Research. “The Tumor Targeter — interview with Luis Diaz.” (2019). Source for the Hopkins/Vogelstein hallway-conversation origin story.

Other inventor interviews

• Labiotech.eu. “Interview with Keytruda Cancer Inventors.” (2018).

• Medscape. Interview on the development of pembrolizumab.

V. Regulatory & Clinical

• FDA. KEYTRUDA (pembrolizumab) — full prescribing information.

• FDA. Approval of pembrolizumab for tissue-agnostic MSI-H/dMMR solid tumors. (May 23, 2017). The first tissue-agnostic FDA approval.

• KEYNOTE-024 ClinicalTrials.gov record (NCT02142738).

• FDA Oncologic Drugs Advisory Committee. PD-L1 cutoffs in upper-GI cancers (full meeting, YouTube). BMS’s argument against narrowing labels; the “0.55 inter-pathologist correlation” data point.

• FDA. “FDA Approves Pembrolizumab Subcutaneous Formulation (Keytruda Qlex).”

VI. Corporate Documents & Press Releases

• Merck. “Keytruda plus pemetrexed and platinum chemotherapy reduced the risk of death by half” — KEYNOTE-189 press release (2018).

• Fierce Pharma. “Keytruda taught Merck how to build a blockbuster — manufacturing the second lightning bolt is easier said than done.” (2024). Manufacturing scale-up and post-Keytruda strategy.

• PharmaVoice. “Inside Merck’s oncology cancer drug Keytruda + Daiichi ADC.”

• HARMONi-2 — Summit/Akeso ivonescimab data (WCLC 2024 presentation, PDF).

VII. News & Trade Press

[2014] First approval & launch

• [2014] Forbes (Matthew Herper). “Cancer Drug Approval Is a Triumph for Merck — What’s Next?” (September 5, 2014). Same-day coverage of the FDA accelerated approval.

• [2014] Fierce Pharma. “Merck’s melanoma game-changer Keytruda likely to bolster drug-pricing debate.” Source for the analyst projection that Keytruda would do $1.5B by 2017 (it actually did $5B).

[2015] First commercial year

• [2015] Managed Care Magazine. “Cancer immunotherapies and their cost take center stage at ASCO’s 2015 annual meeting.”

[2016] The lung cancer fork

• [2016] Fierce Pharma. “Opdivo in its sights, Merck’s Keytruda nabs breakthrough tag in 1L lung cancer.” Real-time coverage of the KEYNOTE-024 / CheckMate-026 inflection point.

• [2016] Johns Hopkins Medicine. “The Final Frontier: Immune Therapies Break Through Cancer’s Protective Barriers.”

[2017] Tissue-agnostic approval

• [2017] Forbes (David Shaywitz). “The Startling History Behind Merck’s New Cancer Blockbuster.” (July 26, 2017). The single most important secondary source on the Organon-era origin story.

• [2017] New York Times. “How Cancer Drug Keytruda Shrinks Tumors.” (June 8, 2017). Coverage of the tissue-agnostic MSI-H approval.

• [2017] BioPharma Dive. “Merck Keytruda combo, Q4 earnings.”

[2018] All-in lung & the IDO graveyard

• [2018] Wall Street Journal. “Why Merck Is Betting Big on One Cancer Drug.” (April 15, 2018).

• [2018] STAT News (Adam Feuerstein). “Incyte trial failure deals serious blow to immuno-oncology hopes.” (April 6, 2018). Real-time coverage of the epacadostat/Keytruda IDO trial failure.

• [2018] Chemical & Engineering News. “Merck, Incyte IDO inhibitor fails in Phase 3.”

• [2018] Cancer Discovery (AACR). “Companies Scaling Back IDO1 Inhibitor.”

• [2018] BioPharma Dive. “Incyte IDO drug development scaled back.”

• [2018] GEN. “Incyte/Merck halt Phase III trial after epacadostat/Keytruda combination fails in melanoma.”

[2020–2022] TIGIT and the post-PD-1 graveyard

• [2022] BioPharma Dive. “Roche tiragolumab TIGIT lung cancer trial.”

• [2022] Fierce Biotech. “Roche’s TIGIT prospect fails another Phase 3 lung cancer test.”

[2023–2024] CD47 implosion & ten-year retrospectives

• [2023] Fierce Biotech. “Gilead gives 4.9B antibody solid-tumor plan unravels.”

• [2023] Fierce Biotech. “Gilead ends Phase 3 leukemia trial early after data disappoint, dealing another blow to 4.9B bet.”

• [2024] Fierce Biotech. “Gilead’s 4.9B CD47 bet faces latest setback as company cans MDS ambitions for magrolimab.”

• [2024] Fierce Biotech. “New EHA data reveal how Gilead’s 4.9B bet on CD47 imploded.”

• [2024] BioPharma Dive. “Gilead/Magrolimab discontinue ENHANCE study in MDS.”

• [2024] BioPharma Dive. “Cancer immunotherapy decade — Keytruda, Opdivo, PD-1 oncology.” Ten-year retrospective on the PD-1 era.

• [2024] Johns Hopkins Medicine. “Immunotherapy: A Game Changer.” (July 2024).

• [2024] Drug Hunter. “That Jimmy Carter Drug.” Origin of the public nickname.

• [2024] DrugWonder. “Keytruda: the journey of a blockbuster drug from discovery to market dominance.”

[2025] PD-1/VEGF bispecifics, TIGIT post-mortem, subQ launch

• [2025] Bloomberg. “Experimental, cheaper treatments — cancer capitalism.” Long-form investigation into Keytruda dosing, pricing, and the off-label landscape.

• [2025] Fierce Pharma. “Akeso/Summit PD-1 bispecific crushes Merck Keytruda — new standard in lung cancer?”

• [2025] Fierce Pharma. “Analysts impressed after Summit/Akeso PD-1/VEGF antibody triumphs over Keytruda in lung cancer.”

• [2025] BioSpace. “Summit’s bispecific misses survival endpoint in global Phase III trial, but analysts remain optimistic.”

• [2025] BioPharma Dive. “Summit ivonescimab + chemotherapy lung cancer (HARMONi WCLC).”

• [2025] BioPharma Dive. “PD-1/VEGF inhibitors — cancer immunotherapy bispecific startups.”

• [2025] Fierce Biotech. “Summit leading the charge — Pfizer lays out its own plan to replace Keytruda with a bispecific.”

• [2025] Oncology Pipeline (ApexOnco). “5,000 patients later, Roche scraps its TIGIT.”

• [2025] Oncology Pipeline (ApexOnco). “Roche reins in TIGIT expectations.”

• [2025] Med Path. “Roche presents complete TIGIT failure data at ESMO 2025, revealing costly misstep in cancer immunotherapy.”

VIII. PD-L1 Biomarker Heterogeneity

Sources supporting Part Three’s discussion of PD-L1 assay messiness, sampling error, and pathologist concordance.

• Munari, E. et al. “PD-L1 expression heterogeneity in non-small-cell lung cancer: defining criteria for harmonization with surgical specimens.” Journal of Thoracic Oncology (2021). 52% discordance between biopsies and surgical resection; sample-size dependent.

• Spatial heterogeneity of PD-L1 expression in breast cancer (PubMed 28195880).

• Park, Y. et al. “Spatial and temporal heterogeneity of PD-L1 expression in gastric cancer.” Clinical Cancer Research (2020).

• PD-L1 heterogeneity in lung cancer (PubMed 29049375).

• PD-L1 false negatives in small biopsies (PMC 5648155).

• BMJ Oncology. PD-L1 testing review.

IX. Analysis & Commentary

• Liang Chang. “Can AI Make Better Decisions Than Humans?” Substack. The “send today’s AI back in time to June 2012” experiment on the BMS vs Merck biomarker fork.

• Derek Lowe. “The Keytruda Story.” In the Pipeline (Science).

• Matt Pech. “Precision oncology, AI, and commercial viability.” LinkedIn (2025). MFP’s analysis of why imperfect biomarkers are commercially load-bearing.

• Matt Pech. “Adoption hurdles for Keytruda Qlex, the subcutaneous formulation.” LinkedIn (2025).

• Wikipedia. “Pembrolizumab — History.”

X. Audio & Video

• FDA Oncologic Drugs Advisory Committee (ODAC) — PD-L1 cutoffs in upper-GI cancers (full meeting, YouTube). Source for the 0.55 inter-pathologist correlation, BMS’s argument against narrowing labels.

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

Geron Corporation. S-1 Registration Statement (1996 IPO).

Geron Corporation. Corporate presentations archive (2012–present).

Geron Corporation. 2012 R&D Strategy Presentation.

Geron Corporation. 2013 NSCLC Study Results.

Geron Corporation. 2015 Janssen/MF Collaboration Presentation. (p.41-)

Geron Corporation. 2016 Mechanism of Action Analysis (thrombocytopenia/TLR9).

Royalty Pharma. “Royalty Pharma to Acquire Royalty Interest in Geron’s Rytelo for $125 Million.” November 2024.

V. NEWS & MEDIA COVERAGE

[1994] New York Times. “Immortality Enzyme Is Discovered in Many Types of Cancer.” December 27, 1994.

[1995] New York Times. “New Light Shed on How Enzyme May Play Crucial Role in Cancer.” September 5, 1995.

[1996] New Yorker. “The New Age of Man.” September 30, 1996.

[1996] Bio.net Ageing Forum. Geron financing announcements.

[1996] Bio.net Ageing Forum. Geron NCI/SBIR grants.

[1996] Bio.net Ageing Forum. Kyowa Hakko deal.

[1996] Bio.net Ageing Forum. Kyowa Hakko deal details.

[1996] BioWorld. Geron IPO news.

[1998] ScienceDaily. “Human Embryonic Stem Cells Successfully Derived.” November 9, 1998.

[1998] New York Times. “Scientists Cultivate Cells at Root of Human Life.” November 6, 1998.

[1998] New York Times. “Essay: Immortality, of a Sort, Beckons to Biologists.” November 17, 1998.

[1999] Dooling, Richard. “Diary of an Immortal Man.” Published on KurzweilAI.net, May 1999.

[2000] Wired. “Embryonic Cell Debate Is On.” August 2000.

[2001] New York Times. “Public Lives: Cell Biologist Traded Religious Fervor for Scientific Zeal.” August 13, 2001

[2001] WARF. “WARF Amends Stem Cell Suit.”

[2001] USCCB. “Human Embryo Research Is Illegal, Immoral, and Unnecessary.”

[2002] Forbes. Stem cell coverage, January 31, 2002.

[2004] Nature Reviews - Telomere biology and cancer.

[2004] New York Times. “Cloning, Stem Cells: Medical and Ethical Issues Cloud Cloning for Therapy.” February 13, 2004.

[2004] Seattle University School of Law. “Geron and stem cell ethics.”

[2005] PharmaTimes. “Geron Leaps on Merck Deal.”

[2008] Gitschier, J. “Interview with James Thomson.” PLoS Genetics (2008).

[2010] New York Times. A First For Stem Cell Use In Therapy. October 11, 2010.

[2011] Forbes (Matthew Herper). “Stem Cell Innovator James Thomson Says Geron Blazed Trail.” November 15, 2011.

[2011] Washington Post. “First Patient to Get Stem Cell Therapy Is Identified.” April 2, 2011.

[2011] Washington Post. “Stem Cells Were God’s Will, Says First Recipient of Treatment.” April 14, 2011.

[2011] New York Times. Michael West / BioTime profile. May 19, 2011.

[2011] New York Times. “Geron Is Shutting Down Its Stem Cell Clinical Trial.” November 15, 2011.

[2011] The Guardian. “Geron Abandons Stem Cell Therapy.” November 15, 2011.

[2011] Science. “Geron Bails Out of Stem Cells.”

[2011] The Hastings Center. “Geron’s Discontinued Stem Cell Trial: What About the Research Participants?”

[2011] CIRM. “Geron Discontinues Stem Cell Program.” November 14, 2011.

[2013] The Scientist. “Geron’s Stem Cell Program Sold.” (Asterias/BioTime acquisition).

[2013] The Niche (Paul Knoepfler). Interview with BioTime CEO Michael West, Part 1.

[2013] The Niche. Interview with Mike West, Part 2: Geron hESC.

[2013] The Niche. Interview with Mike West, Part 3: Key Flaw in Stem Cell Field.

[2013] The Niche. “BioTime Subsidiary Asterias Acquires Geron Embryonic Stem Cell Program.”

[2013] Nature Medicine. “No End in Sight for Telomerase-Targeted Cancer Drugs.” January 2013.

[2016] USC Health Sciences. Kris Boesen stem cell recovery.

[2016] The Niche. “Asterias Interview: Stem Cell Spinal Cord Injury Trials Advance.” December 2016.

[2018] FierceBiotech. “Geron Craters as Janssen Bows Out of Imetelstat Pact Once Worth Up to $935M.” September 2018.

[2018] STAT News (Adam Feuerstein). “Geron Warning Signs.” September 27, 2018.

[2018] GlobeNewsWire. “Asterias Provides Update for AST-OPC1 Phase 1/2a Clinical Trial.” February 28, 2018.

[2023] Pharmaphorum. “Geron Finally Gets Close to a Product Approval with Imetelstat.”

[2023] STAT News. “Geron Success in Myelodysplastic Syndromes.” January 4, 2023.

[2024] Reuters. “US FDA Staff Flags Concerns About Geron’s Anemia Treatment.” March 12, 2024.

[2024] BioPharma Dive. “Geron Approval, Blood Disorder, Nobel Prize, Imetelstat.”

[2024] STAT News. “I Was Wrong About Geron’s Blood Cancer Drug. Now, Is It a Takeover Target?” March 18, 2024.

[2024] CIRM Blog. “Where Are They Now: Jake Javier.” August 19, 2024.

[2024] Christopher Reeve Foundation. “Pioneering Cell Transplants for the Treatment of SCI.”

[2024] Oncology Pipeline / ApexOnco. “Seven Problems Geron.”

[2024] AInvest. “Geron Navigating Legal Headwinds, Rytelo Commercial Crossroads.”

[2025] BiotechNation. “No More Transfusions: Dr. John Scarlett, CEO of Geron Corporation.”

[2025] PharmaVoice. “Geron’s Harout Semerjian on Drug Approval and Pharma.”

[2025] Investing.com. “Geron at Stifel 2025 Healthcare Conference: Strategic Adjustments for Rytelo.”

[2025] SFGate. “Geron Lays Off Third of Staff.”

[2025] Fierce Pharma. “Geron to Lay Off 13% of Workforce to Slash Operating Costs.”

[2025] PharmaTimes. PCSK9 inhibitor launch comparison. https://pharmatimes.com/web_exclusives/are_pcsk9_inhibitors_about_to_take_off_1289184/

VI. BROADCAST & VIDEO COVERAGE

CBS News, 60 Minutes. Ed Bradley segment on Geron stem cell rat study (~2006).

YouTube. Geron documentary (2003).

CNBC Mad Money. Geron coverage: July 2009.

CNBC Squawk on the Street. Geron stock down: August 2009.

KCSM Newsline. Embryonic stem cells: October 2010.

C-SPAN Weekend. Okarma interview: October 2010.

KPIX CBS 5. “First Time Ever Stem Cell Injection Spinal Cord.” October 2010.

KGO ABC World News. Stem cell coverage: October 2010.

KPIX CBS 5. Geron layoffs, pivot to cancer: November 2011.

KTVU Fox 2. Geron cancels spinal cord study, patient interview: December 2011.

CNBC Squawk on the Street. Breast cancer study halted: September 2012.

KCSM Newsline. ACT vision stem cells: January 2012.

CNBC Street Signs. Geron stock up on cancer study: November 2013.

CNBC Squawk on the Street. Hold lifted after hepatotoxicity: June 2014.

CNBC Street Signs. Geron up 60% on J&J deal: December 2014.

CNBC Mad Money. Geron coverage: May 2018.

CNBC Power Lunch. J&J leaves deal: September 2018.

YouTube. Michael D. West, Longevity Summit Dublin (2022).

CNBC Mad Money. Geron coverage: March 2023.

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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 Drugs Needed - Cardiovascular Business (December 21, 2009) - Market research on GLP-1 adoption

2012

• “FDA review accuses Amylin of withholding data” - FierceBiotech (June 26, 2012) - Bydureon approval controversy

IV. ACADEMIC & SCIENTIFIC SOURCES

• “Structural insights into multiplexed pharmacological actions of tirzepatide...” - Nature Communications (February 25, 2022) - Tirzepatide structure, exenatide C-terminus connection

• “Structural and dynamic features of cagrilintide binding...” - Nature Communications (April 10, 2025) - Cagrilintide/pramlintide structural relationship

• “If You Poison Us Do We Not Die?” - BYU Law Review (May 1, 2010) - Legal analysis of poison put provisions

• “How GLP-1 Receptor Agonists Evolved from Diabetes to Weight Loss Treatments” - Historical overview of GLP-1 development

V. HARVARD BUSINESS SCHOOL CASES

• “Amylin Pharmaceuticals: Diabetes and Beyond” (December 9, 2008) - Authors: Richard G. Hamermesh, Rachel Gordon

• “Amylin Pharmaceuticals: Diabetes and Beyond” (November 2, 2012 revision) - Authors: Richard G. Hamermesh, Carin-Isabel Knoop

VI. CORPORATE DOCUMENTS & PRESENTATIONS

Amylin investor presentations from corporate IR archives. Specific slides referenced in the script are noted below.

Investor Presentations (Full Decks)

• 2006 R&D Day Presentation (PDF) - Phybrids platform, GIP mimetic program (slides 43, 46, 58-59)

• 2007 R&D Day Presentation (PDF) - Market sizing, obesity portfolio positioning (slides 14, 28, 29, 78)

• 2007 J.P. Morgan Healthcare Conference (PDF) - Symlin Pen timeline (slide 25)

• 2007 Lehman Brothers Healthcare Conference (PDF) - Investor overview and pipeline update

Individual Slide Presentations (HTML Archives)

• Early Corporate Presentation (WFVK) - Early-era company overview

• 2003 Headquarters Presentation - January 2003 corporate update

• ADA IR Presentation - American Diabetes Association investor materials

VII. ADDITIONAL REFERENCES

• Encyclopedia.com: Amylin Pharmaceuticals, Inc.

• Miami Serpentarium Laboratories (Gila monster venom source)

• Dan Bradbury (former Amylin CEO) - Vivani Board Profile - Now developing exenatide implant for weight loss

• Full-year 2008 results - FierceBiotech

VIII. PRIMARY SOURCE FIGURES

IX. ANALYSIS FIGURES