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Science, Greed, Ambition Led to Development of BTK Inhibitors

December 19, 2023

January 2024

Andrew Cowan, MD

Andrew J. Cowan, MD, is an associate professor in the Clinical Research Division of Fred Hutchinson Cancer Center in Seattle.

For Blood and Money: Billionaires, Biotech and the Quest for a Blockbuster Drug

Title: For Blood and Money: Billionaires, Biotech and the Quest for a Blockbuster Drug

Author: Nathan Vardi

Length: 288 pages

Published: January 2023, W. W. Norton & Company

About the Author

Nathan Vardi is a managing editor at MarketWatch and former senior editor at Forbes. He writes about big money investors, hedge funds, private equity firms, and the intersection of Wall Street and biopharma. He lives in Edgemont, New York.

About the Book

For Blood and Money tells the story of the development of the Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib for the treatment of chronic lymphocytic leukemia (CLL) and other hematologic malignancies. From the first page, the excitement, greed, eccentricities, and ruthlessness that are often present at the intersection of investment and biotech are abundantly clear.

However, For Blood and Money takes a unique approach: The story centers around a pivotal new class of drugs and the individuals who developed them. Ibrutinib and other BTK inhibitors have prolonged countless lives of those with CLL and other hematologic malignancies, which makes the avarice, ambition, and losses even more ironic and poignant as a backdrop.

Vardi leads us through the development of ibrutinib, and the detail with which he describes the science and background is impressive. Many readers are likely familiar with this story, but to recap briefly: Ibrutinib was first synthesized by scientists at Celera Genomics to study BTK function (originally developed for arthritis), and we learn that its irreversible binding to BTK was not considered ideal at first. Later, the drug was bought by Pharmacyclics, which was then run by Richard Miller, MD. Through a series of events, Robert Duggan assumed leadership of Pharmacyclics, and the principal clinical lead, Ahmed Hamdy, MD, and scientists who helped develop ibrutinib, including Raquel Izumi, PhD, were pushed out. Drs. Hamdy and Izumi both played an ongoing role in the development of BTK inhibitors, even after leaving Pharmacyclics.

The book demonstrates how drug development is littered with missed chances and losses for the individuals who are involved. Dr. Miller, a cofounder of the company, left Pharmacyclics before the drug (and the company’s stock) took off. Drs. Hamdy and Izumi were involved with the development of different BTK inhibitors, yet at different times, both had to step away from the development of treatments they helped bring to market.

Although many in academia like to believe in the bench-to-bedside fantasy world where drugs are discovered in labs, tested rigorously in animal models, and then delivered to humans, For Blood and Money highlights the roles that luck and circumstance often play in the discovery of pivotal findings in biomedical science. One does not need to look far to recall the accidental discovery of penicillin by Alexander Fleming or the fortuitous discovery of cyclosporine while researching soil fungi in order to develop new antibiotics. Serendipity and luck play often-underappreciated roles in the development of important findings in medicine, and in describing the central characters of the saga, the drama surrounding it, and the near misses and catches that result in the drugs’ efficacy and widespread use in CLL, this book is a reminder of that. Had circumstances been slightly different, ibrutinib could still be sitting in a drug company’s closet.

In academia and clinical practice, we sometimes forget about the vast forces that underpin drug development in finance and biotech. This book reminds the reader that decisions about a drug are often made that don’t reflect the benefits for patients but are driven by the bottom line. Likewise, readers who don’t have a health care background will better understand the perspective of a clinician investigator such as John Byrd, MD, whose life and work are detailed in the book.

One of the most enjoyable aspects of this book was that while the science and medicine are described in detail, the real story is about the players involved in developing BTK inhibitors. Through Vardi’s writing style, readers understand the motivations and driving forces of these individuals — Dr. Hamdy, Dr. Izumi, Mr. Duggan, Wayne Rothbaum, Dave Johnson, and Dr. Byrd — but Vardi never demonizes them when others might, given their actions. Too often stories of successful individuals are one-sided, focusing only on the wins, but this book sheds important light on the lowest of lows. The passage about Dr. Izumi crying during her former company’s presentation on ibrutinib at an American Society of Hematology (ASH) annual meeting after having lost her job at Pharmacyclics is particularly poignant.

The ASH annual meeting played a role in the careers of the clinicians, scientists, and businesspeople who helped develop BTK inhibitors. In a nice nod to the importance of the ASH poster hall sessions, Vardi notes that the first results from the phase I trial of ibrutinib were presented in poster format, and discussions about the poster led to rapid increases in Pharmacyclics’ stock price when money-​hungry investors quickly bought up shares. These anecdotes remind us that the action is not always in the oral abstracts; posters can provide early insight into up-and-coming drugs that may not be so obvious otherwise.

For Blood and Money is a compelling, engrossing tale of the thrills and woes of drug development, predominantly written from the viewpoint of the individuals on the biotech side, though the clinical investigator perspective is included. For clinical investigators and clinicians, the book serves as a good reminder of the many pitfalls and challenges of drug development and the miracle that takes place when a pivotal drug makes it through early-phase trials and benefits our patients.

Disclosures

Dr. Cowan receives consultancy from BMS and Adaptive Biotechnologies. Dr. Cowan receives research funding from Janssen, Sanofi, Adaptive Biotechnologies, Harpoon, Nektar, BMS, and AbbVie.

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