A decade later, Sanofi paid roughly $9 billion for the company... just not for a cancer drug. Blueprint’s blockbuster asset, avapritinib (AYVAKIT), found its real market almost by accident: indolent systemic mastocytosis, a debilitating, often-undiagnosed mast-cell disease that took patients years to get diagnosed and had no approved treatment.

In this episode, we trace two threads at once: the science of designing truly selective kinase inhibitors, and the venture capital philosophy -- company creation, not just company funding -- that built Blueprint from a whiteboard sketch into a platform biotech. We cover the near-death Series B, the accidental discovery that opened up mastocytosis, the GAVRETO partnership that fell apart against a faster competitor, the Sanofi negotiation (CVRs and all), and the wide gap between what the venture firm and hired executives made versus what the founding scientists -- like Gleevec’s co-inventor Nick Lydon -- walked away with. We end covering the efforts of Blueprint diaspora to create a new model of seed investing: Curie Bio.

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.

* This episode is presented by JLL. Featuring Grant Dettmer on biotech real estate strategy.

Featuring interviews with:

• Alexis Borisy: Former Blueprint CEO/Chairman; founding chairman, Curie.Bio

• Christoph Lengauer: Founding CSO, Blueprint Medicines; Chief Drug Hunter, Curie.Bio

• Erica Evans: Former VP Biology, Blueprint Medicines; SVP, Curie.Bio

• Tim Guzi: Former Head of Medicinal Chemistry, Blueprint Medicines

• Dr. Charles Sawyers, M.D. — Academic co-founder, Blueprint Medicines

• Dr. Mariana Castells, M.D., Ph.D — Director, Mastocytosis Center, Brigham and Women’s Hospital

Chapters

00:00:00 Introduction & Hook

00:03:21 Third Rock Ventures: The Venture Creation Model

00:16:07 Blueprint’s Science: Kinase Selectivity & Gleevec

00:23:45 Blueprint Is Born: Founding & Early Challenges

00:27:06 The Platform: Building the Kinase Library

00:34:33 Near-Death & Series B: Running on Fumes

00:42:49 IPO & Clinical Programs: The Platform Pays Off

00:50:19 The Pivot: From Cancer to Mastocytosis

01:00:20 Clinical Wins, Commercial Struggles & Kate Haviland

01:24:31 FDA Approval & Diagnosis Ecosystem

01:35:35 The Sanofi Deal: A $9B Acquisition

01:53:25 Competition: Cogent Biosciences & Bezuclastinib

01:57:45 Post-Acquisition & Curie Bio: The Next Generation

02:15:31 Blueprint vs. Bluebird: A Tale of Two Platforms

02:21:12 Scorecard: Patient, Financial & Academic Impact

Sources

1. Books and case studies

• Vasella, Daniel, with Robert Slater. Magic Cancer Bullet: How a Tiny Orange Pill Is Rewriting Medical History. HarperBusiness, New York, 2003. ISBN 9780060010300 · OCLC 50859163.

• Hamermesh, Richard G., Kathy Giusti, and Susie L. Ma. “Breakthroughs at Blueprint Medicines.” Harvard Business School Case 820-001, June 29, 2020.

• Levin, Mark. “Mastering the Value Chain: An Interview with Mark Levin of Millennium Pharmaceuticals.” Harvard Business Review, June 2001.

2. SEC filings

Blueprint Medicines (CIK 1597264)

• Form S-1, March 23, 2015.

• Stockholders Agreement (Ex. 4.5), November 7, 2014.

• Investors’ Rights Agreement (Ex. 4.4), November 7, 2014.

• Schedule 14D-9, June 17, 2025.

• Schedule 14D-9 Amendment No. 1, July 10, 2025.

• Schedule 14D-9 Amendment No. 3, July 18, 2025.

• Form 8-K — Roche immunokinase collaboration press release, March 18, 2016.

• Form 8-K — VOYAGER Phase 3 topline, April 28, 2020.

• Form 8-K — Roche pralsetinib collaboration press release, July 14, 2020.

• Roche Collaboration Agreement (Ex. 10.1 to Q2 2020 10-Q).

• Form 8-K — Royalty Pharma + Sixth Street financing, June 30, 2022.

• Form 10-K, FY2022.

• Form 8-K — Roche termination of Gavreto collaboration, February 23, 2023.

• Form 8-K — EGFR program discontinuation, January 8, 2024.

• Form 8-K — Gavreto handoff to Rigel, February 22, 2024.

• Form 8-K — BLU-222 deprioritization, January 13, 2025.

• CORRESP — response to SEC accounting comments, 2021.

• DEF 14A, 2018.

• DEF 14A, 2019.

• DEF 14A, 2021.

• DEF 14A, June 18, 2025.

Sanofi

• Schedule TO-T (Offer to Purchase), June 17, 2025.

• Schedule TO-C — Hudson deal-call transcript, June 3, 2025.

• Schedule TO-T/A, July 17, 2025.

• Form 6-K, June 2, 2025.

• Form 20-F, FY2024.

• Q4 / FY2025 press release.

• Q1 2026 press release.

Third Rock Ventures and insider filings

• SC 13G, February 2016.

• SC 13G/A Amendment No. 1, February 2017.

• SC 13G/A Amendment No. 2, February 2018.

• SC 13G/A Amendment No. 3 (exit), February 2019.

• Kevin Starr, Form 4, December 2016.

• Mark Levin, Form 4, March 2017.

Comparator and adjacent companies

• Loxo Oncology, Schedule 14D-9, January 17, 2019.

• Loxo Oncology, Form S-1, 2014.

• Array BioPharma, Schedule 14D-9, June 2019.

• Mirati Therapeutics, DEFM14A, 2023.

• bluebird bio, Form 424B4 (IPO prospectus), June 2013.

• Genzyme, Form 8-K, February 2011.

• Unum Therapeutics / Kiq LLC, Form 8-K (Ex. 2.1), July 6, 2020.

• Invitae, Chapter 11 filing, February 13, 2024.

• Sage Therapeutics, Form 424B4 (IPO prospectus), July 2014.

• Editas Medicine, Form 424B1 (IPO prospectus), 2016.

• Day One Biopharmaceuticals, Form 424B4 (IPO prospectus), 2021.

• Neon Therapeutics, Form 8-K, 2018.

3. FDA

• NDA 212608 (Ayvakit) — Drugs@FDA supplement index.

• NDA 212608/S-000 — Multi-Discipline Review, GIST approval, January 9, 2020.

• NDA 212608/S-007 — Advanced SM / MCL approval letter, June 16, 2021.

• NDA 212608/S-013 — Multi-Discipline Review, indolent SM, May 22, 2023.

• NDA 212608/S-013 — approval letter.

• NDA 212608/S-013 — approved label.

• NDA 213721/S-014 — Gavreto thyroid indication withdrawal letter, July 20, 2023.

• FDA, “FDA approves pralsetinib for lung cancer with RET gene fusions,” September 4, 2020.

• FDA, “FDA approves pralsetinib for RET-altered thyroid cancers,” December 1, 2020.

4. Clinical trials

• NCT02508532 — NAVIGATOR (avapritinib, GIST).

• NCT02561988 — EXPLORER (avapritinib, advanced SM).

• NCT03465722 — VOYAGER (avapritinib vs. regorafenib, GIST).

• NCT03580655 — PATHFINDER (avapritinib, advanced SM).

• NCT03731260 — PIONEER (avapritinib, indolent SM).

• NCT04910685 — HARBOR (elenestinib, ISM).

• NCT05609942 — elenestinib + azacitidine, advanced SM (terminated March 2025).

• NCT06931405 — BLU-808, Phase 2 CSU/CIndU.

5. Patents

• US 9,944,651 B2 — avapritinib (BLU-285) composition of matter.

• US 10,030,005 B2 — pralsetinib (BLU-667) composition of matter.

• Justia — Brian L. Hodous inventor index.

• Justia — Joseph L. Kim inventor index.

6. Scientific literature

• Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A. “Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand.” EMBO J 1987;6(11):3341–51.

• Furitsu T, et al. “Identification of mutations in the coding sequence of the proto-oncogene c-kit.” J Clin Invest 1993;92:1736–1744.

• Kim JL, et al. “Crystal structure of the hepatitis C virus NS3 protease domain.” Cell 1996;87:343–355.

• Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. “The protein kinase complement of the human genome.” Science 2002;298(5600):1912–34.

• Kantarjian H, et al. (incl. Druker B). “The price of drugs for chronic myeloid leukemia (CML): a reflection of the unsustainable cancer drug prices.” Blood 2013;121(22):4439–4442.

• “First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway.” Cancer Discovery 2015;5(4):424.

• Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, et al. “A precision therapy against cancers driven by KIT/PDGFRA mutations.” Sci Transl Med 2017;9(414):eaao1690.

• “Precision targeted therapy with BLU-667 for RET-driven cancers.” Cancer Discovery 2018;8(7):836.

• “First-in-human Phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma.” Cancer Discovery 2019;9(12):1696.

• Heinrich, et al. “Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR).” Lancet Oncology 2020.

• “Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.” Nature Medicine 2021.

• Mesa, et al. “TouchStone SM patient survey.” Cancer 2022.

• Slaff, et al. “TouchStone SM healthcare-provider survey.” Cancer 2022.

• Castells M, et al. “Avapritinib versus placebo in indolent systemic mastocytosis (PIONEER).” NEJM Evidence, May 23, 2023.

• Duncan CN, et al. “Hematologic malignancies after elivaldogene autotemcel for cerebral adrenoleukodystrophy.” NEJM, October 9, 2024. DOI 10.1056/NEJMoa2400442 (companion: 10.1056/NEJMoa2405541)

• “[MASTering SM](https://www.jaci-global.org/article/S2772-8293(24).” JACI Global 2024.

• “Avapritinib for Systemic Mastocytosis“ (review), PMC.

• Cogent Biosciences, SUMMIT primary analysis abstract. Blood 2025;146(Suppl 1):80.

• Blueprint Medicines, elenestinib HARBOR Part 1 abstract. Blood 2023;142(Suppl 1):76.

• STK17B / kinase-selectivity context. Frontiers in Immunology 2024.

7. Journalism

Blueprint Medicines

• C&EN — “Blueprint Medicines Is Oncology Start-Up,” October 26, 2011.

• Boston Globe — “Fidelity Biosciences invests in Blueprint Medicines,” May 24, 2012.

• Fierce Biotech — “Third Rock’s Blueprint Medicines scores $147M windfall in another hot IPO,” April 2015.

• Boston Globe — “Blueprint shares up after raising $147 million in IPO,” April 30, 2015.

• Fierce Biotech — “Blueprint Medicines Announces Worldwide Cancer-Immunotherapy Collaboration,” March 2016.

• BioPharma Dive — “Blueprint posts ‘impressive’ data for lead candidate, but investor response tepid,” 2018.

• STAT — “Blueprint gains approval for its first drug, a treatment for a rare GI cancer,” January 9, 2020.

• OncLive — “Avapritinib Falls Short in VOYAGER Phase 3 GIST Trial,” 2020.

• Fierce Biotech — “Roche to pay Blueprint $775M for pralsetinib rights, setting up showdown with Lilly,” July 2020.

• BioPharma Dive — “Blueprint’s Gavreto wins FDA approval,” September 2020.

• Boston Globe — “Blueprint Medicines wins FDA approval for drug to treat rare blood disorder,” June 16, 2021.

• STAT — “Blueprint Medicines seeks ‘continuity, not change’ in CEO transition,” January 6, 2022.

• Fierce Pharma — “Blueprint’s Albers hands CEO baton to deal mastermind Haviland,” January 2022.

• BioPharma Dive — “Blueprint secures access to more than $1B in funding through two new deals,” June/July 2022.

• STAT — “Blueprint drug reduces mastocytosis symptoms in a new study,” August 17, 2022.

• BioPharma Dive — “Roche takes $2.8B in impairments, writing down Spark and Gavreto,” February 3, 2023.

• Fierce Pharma — “After splashing $1B, Roche returns lagging cancer drug Gavreto to Blueprint,” February 2023.

• Fierce Pharma — “Blueprint CEO touts Ayvakit’s rare disease win, but analysts flag looming ‘commercial debate’,” 2023.

• Fierce Pharma — “Roche pulls Gavreto’s accelerated approval as Blueprint severance and confirmatory trial turns,” July 2023.

• pharmaphorum — “After Roche’s exit, Blueprint passes Gavreto on to Rigel,” 2024.

• Fierce Pharma — “Blueprint boosts Ayvakit peak sales estimate to $2B,” 2024.

• Fierce Biotech — “Blueprint ends work on clinical-stage CDK2 inhibitor,” January 2025.

• ApexOnco — “Blueprint clears house: EGFR.”

• pharmaphorum — “Ipsen adds Blueprint’s FOP rare disease drug to pipeline for $535M,” September 2019.

• Drug Hunter — avapritinib molecule case study.
  

The Sanofi acquisition

• BioPharma Dive — “Sanofi to acquire Blueprint for up to $9.5B,” June 2, 2025.

• STAT — “Sanofi to buy Blueprint Medicines in deal worth more than $9 billion,” June 2, 2025.

• Nature Biotechnology — “Mast cells drive Blueprint mega-deal,” July 2025.

• Endpoints News — “Sanofi’s new CEO faces a reckoning on immunology-focused R&D strategy.”

• BioSpace — “Biopharma’s continued staff cuts in 2025,” November 2025.
  

Cogent Biosciences and the competitive landscape

• STAT — “Cogent Biosciences–Blueprint Medicines tiff turns spicy on eve of immune drug study readout“ (Adam Feuerstein), June 19, 2025.

• BioSpace — “Cogent Jumps on Positive Mid-Stage Mastocytosis Data and NDA Plans,” July 7, 2025.

• Drug Hunter — bezuclastinib (CGT9486) molecule page.
  

Third Rock Ventures and the company-creation model

• VentureBeat — “Life sciences briefing: Friday, Sept. 14, 2007.”

• Xconomy Boston — “Third Rock Ventures Heads ‘Back to the Basics’,” September 23, 2008.

• Xconomy Boston — “Agios Lands Genentech Cancer Drug Leader as New CEO,” May 27, 2009.

• MIT Technology Review — “Co-opting a Cancer Treatment to Spur Fat Loss,” July 15, 2009.

• Global Venturing — “Third Rock incubates new venture capital model,” October 4, 2010.

• Boston Globe — “Boston’s Third Rock Ventures closes $516m fund,” March 25, 2013.

• Boston Globe — “Foundation Medicine files to go public,” July 30, 2013.

• VentureBeat — “Foundation Medicine shares pop 89 percent after $106M IPO,” September 2013.

• MIT Technology Review — “Biotech’s Top VCs“ (Antonio Regalado), February 18, 2014.

• Nature — “Biotechnology: The start-up engine,” 2014.

• Boston Globe — “Third Rock Ventures has emerged as a key Boston-area engine for forming biotech startups“ (Robert Weisman), June 14, 2014.

• Boston Globe — “Third Rock’s IPO class of 2013 remain stock market favorites,” February 3, 2015.

• Fortune — “Third Rock Ventures: Giving birth to a new generation of biotechs“ (Erika Fry), February 19, 2015.

• BioSpace — Mark Levin, MassBio Innovative Leadership (Termeer) Award, March 2015.

• Boston Globe — “Third Rock hunting for Cambridge lab space,” May 14, 2015.

• Boston Globe — “Pharma gives drug development the Hollywood treatment“ (Robert Weisman), September 27, 2015.

• Boston Globe — “Third Rock launches cancer-fighting startup“ (Neon), October 1, 2015.

• GeekWire — “Editas Medicine raises $94M in first gene-editing IPO,” February 2016.

• Fierce Biotech — “Third Rock raises $616m for fourth biotech venture fund,” October 31, 2016.

• Boston Globe — “Five things you should know about Abbie Celniker,” February 17, 2017.

• Boston Globe — “With $55 million, Third Rock launches cancer drug startup Tango Therapeutics,” March 31, 2017.

• Endpoints News — “Protein degradation 2.0? Third Rock sinks $56M into Cedilla’s unusual approach,” April 2018.

• Fierce Biotech — “Celsius bags $65M to develop precision meds for cancer, autoimmune disease,” 2018.

• STAT — “Third Rock raises $770 million in new funding round“ (Damian Garde), June 6, 2019.

• Fierce Biotech — “Third Rock raises $770M to build and grow more biotechs,” June 2019.

• Endpoints News — “Maze Therapeutics launches with $191M led by Arch, Third Rock,” February 2019.

• BioCentury — “Solving for the medical and business case in pediatric cancer: Day One,” 2020.

• Fierce Biotech — “Daphne Koller, A-list backers unite to create machine-learning drug R&D startup,” 2020.

• BioSpace — “Precision oncology startup Flare Therapeutics launches with $82M Series A,” May 2021.

• C&EN — “MOMA Therapeutics launches,” 2021.

• STAT — “Third Rock Ventures plots next chapter after raising $1.1 billion fund“ (Allison DeAngelis), June 15, 2022.

• STAT — “American Cancer Society’s BrightEdge and Third Rock to collaborate on oncology,” July 2022.

• STAT — “Faze Medicines is shutting down,” November 8, 2022.

• Fierce Biotech — “Third Rock, J&J spinout Rapport arrives with $100M,” March 7, 2023.

• Fierce Biotech — “Clasp Tx hooks $150M Series A for next-gen cancer treatments,” March 20, 2024.

• Fierce Biotech — “Third Rock’s Rapport reveals upsized $154M IPO,” June 2024.

• Fierce Biotech — “Third Rock-backed Trace uses $101M Series A to go after same ALS target as Lilly,” November 2024.

• STAT — “Third Rock Ventures tops STAT’s annual biotech VC rankings“ (Allison DeAngelis), August 27, 2025.

• Fierce Biotech — “Third Rock-backed Merida launches with $121M Series A,” 2025.

• STAT — “Servier to acquire Day One Biopharmaceuticals,” March 6, 2026.

• Axial Observations — “Eight lessons from Mark Levin, Third Rock.”

Curie.Bio and “freeing the founders”

• STAT — “A new biotech investment firm, headed by a pair of noteworthy VCs, seeks to ‘free the founders’,” May 11, 2022.

• STAT — “With $520 million in hand, two entrepreneurs try to upend the biotech funding model,” February 14, 2023.

• Fast Company — “Why Curie.Bio believes it can change how new drugs get discovered,” February 2023.

• STAT — “Biotech incubator Curie.Bio graduates its first startup,” November 8, 2023.

• STAT — “Biotech accelerator Curie.Bio extends its reach with new $380 million fund,” June 26, 2024.

• C&EN — “Cashing in on founder-led biotech,” November 2024 (102/i36).

• BioWorld — “Alkira Bio exits stealth via seed round to develop GPCR-targeting antibodies,” 2024.

• STAT — “Biotech accelerator Curie.Bio raises $340 million for a new seed fund,” January 29, 2025.

• Drug Hunter — “From AZ to VC: Tracing Our Industry’s Recent Evolution Through A Career“ (Chris De Savi), 2025.

• STAT — “For its first two medicines, EQRx abandons its bold strategy to lower drug prices,” November 10, 2022.

• STAT — “EQRx, failed developer of low-priced cancer drugs, is sold for cash,” August 1, 2023.
  

bluebird bio and the comparator TRV/2015 IPO cohort

• Xconomy Boston — “bluebird bio (Third Rock, Genzyme’s Gene-Therapy Bet) Shows Promise for Blood Disorder,” September 15, 2010.

• Boston Globe — “Bluebird shares soar after gene therapy shows promise treating inherited blood disease,” December 9, 2014.

• STAT — “Axovant’s intepirdine fails in Alzheimer’s trial,” September 26, 2017.

• GEN — “Top 20 Biopharma IPOs of January–June 2015.”

• PharmiWeb — “Merck to complete acquisition of Cidara Therapeutics in $9.2 billion deal.”

• DCAT Value Chain Insights — “Roche completes $4.3 billion acquisition of Spark Therapeutics.”

• BioPharma Dive — “Josh Bilenker, Loxo: Executive of the Year.”

• Fierce Pharma — “Array CEO Squarer, other execs to take home tens of millions in Pfizer sale.”

• Fierce Biotech — “Bayer bags Algeta’s cancer drug portfolio for $2.9B.”

• Fierce Biotech fundraising tracker, 2025.

Genzyme, Henri Termeer, and the Sanofi cultural lineage

• Boston Globe — “Genzyme family tree: how Henri Termeer spawned a network of Genzyme alums leading dozens of biotechs,” July 11, 2015.

• Boston Globe — Henri Termeer obituary, May 13, 2017.

• Boston Globe — “Family, friends recall contributions of former Genzyme executive Henri Termeer,” May 20, 2017.

• BioCentury — “Henri: N of 1.”

• Boston Globe — “Eleven years after buying Genzyme, Sanofi officially ditches subsidiary’s storied name,” February 3, 2022.

• Termeer Institute.

• BioPharma Dive — “Sanofi to pay $315 million to settle Lemtrada ‘go-slow’ claims.”

• Glenn Chan — “Genzyme contingent value rights (GCVRZ) post-mortem,” November 9, 2013.

• Fast Company — “The Trials of ImClone,” September 2004.

• CFO.com — “Onetime CFO Resigns as ImClone CEO,” November 14, 2005.

• STAT — “The Survivors“ (Gleevec patients, 25 years on), April 25, 2017.
  

8. Venture-model analysis (Bruce Booth / LifeSciVC)

• “The Biotech Venture Capital Math Problem,” March 2012.

• “Two Really Big Fish That Got Away,” March 2018.

• “2018’s Biotech IPO Bonanza: View From the After Market,” October 2018.

• “Generations: Talent Dispersion in Biotechnology“ (Tariq Kassum, guest), November 2018.

• “The Creation of Biotech Startups: Evolution Not Revolution,” August 2019.

• “Biotech Risk Cycles: Assets and Platforms,” October 2024.

• “Atlas XIV And Reflections On The VC Math Problem,” December 2024.

• “Twenty Years In Early Stage Biotech VC — Part 1: Science,” October 14, 2025.

• “Twenty Years In Early Stage Biotech VC — Part 2: People,” October 15, 2025.

• “Twenty Years In Early Stage Biotech VC — Part 3: Business,” October 16, 2025.

9. Patient accounts

• Suki Tipp, first-person essay, Business Insider / Yahoo News, August 2023.

• Suki Tipp follow-up, People, 2024.

• Valerie Slee, Rare Disease Advisor.

• Valerie Slee, Dermatology Times.

• Kathi Jo Chappell, Patient Power.

10. Web archives

• Blueprint Medicines pre-IPO homepage, March 19, 2015.

• Scientific Advisory Board page (Druker and Sawyers listed), February 15, 2015.

• Leadership page, June 2011 (Varma as CEO).

• Leadership page, May 2014 (Borisy interim).

• Leadership page, February 2015 (Albers as CEO).

• Pipeline page, April 2020 (pre-VOYAGER).

• Pipeline page, May 12, 2020 (post-VOYAGER).

• Pipeline page, February 7, 2023 (post-Roche return).

• Pipeline page, April 2024 (narrowed).

• Homepage, June 2024 (mast-cell franchise framing).

Beyond the science, Blueprint is a clear example of how biotech venture creation actually works. There was no founder pitching a VC. Instead, Third Rock generated the idea internally — building this company from scratch, deploying its own operators to support and run the company all along the way.

This vertically integrated studio model is historically one of the best-performing strategies in biotech, because it can providethe massive capital and early infrastructure of a big pharma — from lab space to legal templates — to a small biotech; so founders can focus strictly on the science.

But that support dictates an extreme equity split. Because Third Rock fundamentally believes clinical execution matters far more than the initial academic idea, they take the lion’s share of the cap table. That math worked out great for them! They managed to flip a $42 million early investment in the company into several hundred million dollars. On the other hand, the academic advisors and bench scientists who made this precision medicine paradigm at all possible walked away with only a fraction of that exit.

We have a great roster of interviews lined up for this episode: Alexis Borisy, Christoph Lengauer, Erica Evans, Tim Guzi, Charles Sawyers, and Mariana Castells.

Subscribe and it lands straight in your inbox next Tuesday.

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.

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 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