Vincent Rajkumar: Incredible Story of How Ibrutinib Came About in CLL by Jeff Sharman

Vincent Rajkumar, Professor of Medicine at the Mayo Clinic in Rochester, shared a post on X by Jeff Sharman, Medical Director of Hematology Research at Sarah Cannon Research Institute, adding:

“Incredible story of how ibrutinib came about in CLL! How Jeff Sharman came about with the initial idea and the trials. Read on below.”

Quoting Jeff Sharman’s post:

“BTK inhibitors have transformed the lives of many patients with Chronic Lymphocytic Leukemia and other lymphomas. These drugs ‘exploded’ onto the scene in 2013-2014 and have fundamentally changed the way we treat the disease. What many people don’t know is how it all happened…

In 2004, I became convinced that turning off B-cell receptor signalling would cause cancerous B-cells to stop growing. This theory came into focus based upon an understanding of Epstein-Barr virus protein LMP2A, EBV relationship to Hodgkin lymphoma, and other breadcrumbs. I decided the best way to turn off the receptor would be to use drugs which shut off the signalling pathways emanating from the B cell receptor – notably SYK.

Fortunately, Ron Levy, M.D. of Stanford, was willing to let me test the hypothesis in the laboratory. I acquired fostamatinib from Rigel Therapeutics and set to work – quickly learning that I didn’t belong in the lab at all (not my skill set). Fortunately, others came to a similar idea, and shortly thereafter, we began testing the compound in patients with lymphoma. Our results were presented in the plenary session at ASH in 2010 by Dr. Friedberg.

‘Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia‘

At the time, Pharmacyclics was a zombie company, almost left for dead, but Richard Miller, M,D was at the helm and saw my patients with me at Stanford receiving fostamatinib. I explained to him the hypothesis of BCR signalling inhibitio,n which turned into a critical moment. He had PCI-32765, a molecule that inhibited the next enzyme in the BCR signalling pathway – BTK.

Based upon our experience with fostamatinib, we set up a consulting agreement, and I helped design a study to test ibrutinib in patients with NHL/CLL. Graduating from Stanford, I had to find a job and I settled on a community practice job in Oregon at the Willamette Valley Cancer Institute and turned the research project over to Daniel Pollyea – in the class behind me.

It took a year for the first cohort to enrol, which is a disaster for a small biotec,h so Pharmacyclics reached out to my new group to see if we could assist in enrolling patients into the study. Shortly thereafter, I treated the first CLL patients in the world with ibrutinib. What happened next was beyond anything I could ever imagine and has been turned into a novel that was published this week.

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

It is a dynamic story told by Nathan Vardi which details the clash of powerful personalities resulting in enormous fortunes for investors along the way. Like many in the book – I never made a penny off of the original idea, but I am very proud that an idea I brought forward has resulted in so much good for so many patients.

I love being a doctor, and I would never trade that experience for the fortune I may have made had I followed the idea into industry… a choice that would have fundamentally re-routed the course of my life. I am also very grateful for the incredible hard work put forward by so many others, without which the drug would have never made it so far.

Putting this string back up as a new book has been published that is definitely worth the read. One of the most wonderful parts of being part of a discovery is watching all the places it goes. Congrats to the Lilly team for bringing this important drug to the clinic. Thanks for letting me join for the ride!”

‘Race for a Remedy: The Science and Scientists behind the Next Life-Saving Cancer Medicine‘

‘Lilly’s Jaypirca (pirtobrutinib) recommended by CHMP for approval in the European Union for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) previously treated with a BTK inhibitor‘

More posts featuring Vincent Rajkumar and Jeff Sharman.