Incivek? Sounds like an alien from “Dr. Who.”

I will never fathom how marketing comes up with brand names for Rx drugs. Anyway, the FDA officially approved telaprevir (see post below) on Monday, May 23.

From Zennie62’s blog on SFGates (San Francisco Chronicle), here’s an interview with Steve Goodwin, a chief engineer who was diagnosed with hepatitis C, who was treated with telaprevir/Incivek. In the video, Goodwin tells “how he came to find out about Incivek via the use of the website Clinical Trials, at clinicaltrials.gov, and how it’s helped him to a more normal path of life.”

“My baby” is about to graduate! FDA panel recommends Vertex Pharma’s telaprevir for approval to treat hepatitis C

This week, panels of non-FDA experts reviewed the clinical data for Merck’s* boceprevir and Vertex’s telaprevir for potential market approval as first-in-class** treatments for patients infected with hepatitis C.

Panel to FDA: Give OK to Vertex hepatitis C drug

Are telaprevir and boceprevir perfect drugs? No. Each has side effects. There are the proven side effects of Xarelto even. I’ll note, however, that the “nasty rash,” the most common adverse effect (AE) of telaprevir, was generally mild to moderate and treatable with antihistamines or corticosteroid creams. Only 2% of subjects discontinued treatment because of the rash. So it’s an AE that is tolerable.

The drugs will also be quite expensive: $35-40K per course of treatment. Yikes almighty! Yet these are complex molecules that are not facile to synthesize. Also, consider that a liver transplant costs in the order of $250K to $310K (and higher).

VX-950 a.k.a. Telaprevir

That’s the structure of “my baby” above. Of course, it’s not strictly mine. Not by a long shot, but with all the work I did on that molecule, I feel like one of its many parents. We had a hell of a team at Vertex, and there’s a critical piece of the molecule that was added by Mark T., a wicked smart medicinal chemist, who was then at Lilly (former collaborators; Lilly and Vertex had, uh, differences in approach and thus had a fairly amicable divorce). My contribution was to study the detailed inhibition kinetics of VX-950, using isolated HCV protease for in vitro assays. I demonstrated that VX-950 was a slow binding inhibitor with a slow off-rate. It’s sticky in other words, and hangs onto the the protease for a good while before being hydrolyzed off the enzyme by water in the cell.

The close teamwork of biochemists/enzymologists and virologists at Vertex proved to be a very powerful combination. The virology team was able to demonstrate the efficacy of the protease inhibition in their viral RNA replication assay, and that the slow off-rate appears to play a role. These experiments were performed in 2003/2004, and became pivotal elements of the package, which included major contributions from medicinal chemistry, protein chemistry, process chemistry, toxicology, and pharmacokinetics, which brought VX-950 (telaprevir) forward as a clinical candidate. And now…well, I wonder what its brand name will be?

The odds of a compound at the bench becoming a drug are incredibly small, e.g., for every 10,000 compounds that enter the drug discovery pipeline, only 250 will progress to pre-clinical development (2.5-5%); 5 move forward into human testing, Phase I studies (0.1-0.5%); and only a single compound will survive through Phase II and Phase III studies to be an approved drug (0.01%).

So this is a rare thing, and telaprevir is not just any drug. It will meet a significant unmet medical need. Anyway, forgive me for so much gratuitous backslapping, but I’m proud to have been part of the team — a great group of scientists, many of whom (including myself) no longer work at Vertex — who discovered the compound and brought it to clinical candidate status.

*Boceprevir is actually from the former Schering-Plough, which Merck acquired.
** Strictly speaking, boceprevir is the first approved HCV protease inhibitor and thus truly “first-in-class,” but I use the phrase collectively here, as the approvals were almost back-to-back.

Congratulations, JoAnne Stubbe!

An e-mail this morning from one of my former Univ. of Wisconsin-Madison classmates informed me that JoAnne Stubbe, Novartis Professor of Chemistry, Professor of Biology at the Massachusetts Institute of Technology, and who was the first woman to achieve tenure in the biochemistry department at the UW-Madison, received the National Medal of Science from Barack Obama yesterday.

JoAnne is a fiercely brilliant woman who intimidated the bejeebus out of me when I was a fledgling grad student and later as a callow post-doc. She was one of five professors (including my advisor) who raked us over the coals during student research seminars. I also faced her wrath when I overtightened the valve to her lab’s French press. But later, when out and about in the real world, my encounters with Professor Stubbe were nothing but good. She’s funny, intense, and passionate about science. She’s a superb intellectual role model, and even though she was not my advisor, she nonetheless influenced me along with many of us in the biochem. department at the UW-Madison. Her award is a such fantastic and well-deserved achievement!

She was at the vanguard of women entering academia and industry in disciplines like chemistry and physics which were long dominated (and still dominated) by men, but these awards as well as the Nobels with 3 women winners in the sciences this year, including Elizabeth Blackburn and Carol Greider for telomeres/telomerase, indicate that “an old girls” network is forming at last.

Here’s a link to the article in the Boston Globe about JoAnne.

Her picture receiving the medal is here in the White House blog (scroll down) and below the cut is the press release (see bolded type a ways down for JoAnne’s award).

Continue reading “Congratulations, JoAnne Stubbe!”

Last trip into downtown Doltsville for the day

And I won’t even write anything here. But it’s difficult to imagine packing any more ignorance about climate change into a single comment thread than has been done here, and I suspect the cranks coming in from all sides have only begun warming up.
On this day of my birth, I, for all of my foibles and frailties, am grateful to have been born evidently lacking the capacity to be as bereft of cognitive function as these clowns. I credit my parents for not being missing, psychotic, or more reminiscent of Magilla Gorilla than of the Cleavers. Enjoy.

So. The new gig.

After coping with an immediate family member’s severe illness (thankfully resolved; better living through chemistry pays off) and discovering that my talents do not lie in management within a very large company, I stepped back from my almost 20 year career in discovery research several months ago. I gleefully wallowed around the home front, decompressing from an especially stressful time in my life and just generally vegetating. But I kept my foot in the door of the Dark Tower of Pharma-dur by taking a class in drug development in a regulatory affairs program at a (sort of) local university. As it turned out, I really liked it.
When I was ready to re-enter the workforce after about 6 months, jobs for principal investigators (veteran research biochemists at any rate) in discovery pharma were very scarce. Couple that with “reductions in force” from various companies, and the job market wasn’t (and isn’t) so hot.
So, in my less-than-introspective process of thinking about “what do I want to be when I grow up,” or more accurately, “how do I wish to reinvent myself so that I can be employable,” I continued to take classes in regulatory affairs and kept an eye out for entry level jobs in the area. Wikipedia has this boilerplate description of regulatory affairs. It’s not referenced, but I can attest to its succinct accuracy. Regulatory within the pharma industry provides documentation and guidance for the highly complex process of channeling clinical findings to the Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Well, I found such a position as a medical writer in a full-service contract research organization. And I finished a not-horrible first draft of a Phase II clinical protocol today, second week into the job!
The clinical/regulatory side is a very different aspect of the Pharma-dur than discovery, but still engages my interest, even though I still get twinges for wanting to get back to the bench and design an assay or de-convolute a complex biochemical mechanism. It’s less abstract. It’s one thing to work on various defined targets for cancer: one kinase after another, maybe a methyltransferase as a novelty gag, or a metabolic enzyme that a tumor favors. It’s another to read and write a Phase I document in which patients with advanced stage carcinoma are described, knowing that they are husbands, wives, mothers, fathers, sisters, brothers and friends who are likely dying and grasping for that last gold ring of life by letting sophisticated poisons course through their blood and organs.
Thankfully, Jim has been holding down the Refuge. Not that I’m essential to this joint (and I well know there’s the pie-eyed and ever hopeful “Bring back Beck” faction), but hopefully, I can pipe up a bit more now and then now that my brain is more scientifically engaged.