Archive for category The View from Pharma-dur

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.”

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“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.

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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).

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Paracetamoxyfrusebendroneomycin: The Movie!

I am so pleased to see that Adam Kay’s masterwork has made it to the big time: YouTube.
Happy holidays, bonobos!
(Pharma-phunnies, some medically graphic, contained therein.)

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Paracetamoxyfrusebendroneomycin: The Movie!

I am so pleased to see that Adam Kay’s masterwork has made it to the big time: YouTube.
Happy holidays, bonobos!
(Pharma-phunnies, some medically graphic, contained therein.)

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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.

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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.

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Personalized Pharmaceuticals

Finally! A prescription medication tailor-made for me!
From the makers of Damitol and Fukitol, here is…

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Judah Folkman: 1933-2008

Judah Folkman, a most extraordinary scientist, died Monday at age 74. Orac (Respectful Insolence) posted a fitting tribute which I highly recommend. See also Alex’s (Daily Transcript) entry and this New York Times article.
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Thanks to the intricate academic vascular network between Harvard and Boston biotech, Folkman visited the company in Cambridge MA for which I previously worked. His seminar enthralled us and exemplified his ability to communicate so effectively. Folkman’s persistent championship of the anti-angiogenic drugs born of his research illustrates his belief in his work and also the challenges of bringing novel chemical entities into the clinic. Development of orally administered small molecule antagonists of angiogenesis followed the entry of Avastin, Genentech’s monoclonal antibody therapeutic, into the clinical sphere. Astra-Zeneca’s Iressa and Pfizer’s Sutent, which interfere with angiogenesis through inhibition of key receptor tyrosine kinases (epidermal growth factor receptor for Iressa; multiple tyr kinases for Sutent), were discovered by building upon Folkman’s pivotal discoveries. See this diagram from Nature Reviews Drug Discovery for the simplified sites of interaction for these drugs. Thanks to Dr. Folkman, angiogenesis remains a continued source of interest for the discovery of new chemotherapeutics.
Folkman was interviewed by NOVA in 2001. A film clip may be found within that site.
Folkman was one of those scientific giants who was also a charismatic and accessible man. His passing is a tremendous loss to the biomedical community, but he has left us with a rich legacy.

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George Clooney, You, and Chantix

One of the more recent offerings in the pernicious practice of direct-to-consumer (DTC) advertising from Big Pharma is a tortoise and a hare hawking a smoking cessation med: Chantix. The drug, varenicline tartrate, has a dual action in that it acts as both a partial agonist (enhancing activity but not by too much) and antagonist (blocker) of the alpha2beta4 nicotinic acid acetylcholine receptors. These are ligand-gated ion channel receptors, a major class of receptors in the CNS which comprises the targets for many drugs. Here’s an illustration of a nicotinic acetylcholine receptor, ripped off from the Wikipedia entry.
Also, take a look at Corpus Callosum’s (pre-Science Blogs) article on Chantix.
As with any med, Chantix has side effects: some adverse, some not-sot-adverse, and some, well, kind of provocative. The superlative John Mack of the Pharma Marketing Blog(1) discusses his investigation of one of the odd side effects of varenicline tartrate in Chantix Californication Dreamin’: Viagra II. Because Chantix acts as a partial agonist (see Big Papa Pfizer’s notes on Chantix’s mechanism of action), the upregulation of dopamine results in – how should we say – pleasurable dreams. The intrepid Mr. Mack went so far as to investigate what consumers were saying about Chantix on Health Boards.
From his perhaps not comprehensive study (but entertaining all the same). Mr Mack reports

that a good portion of dreams involve Hollywood movie stars like George Clooney. And there’s a decidedly sexual overtone to these dreams.

.

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Taking Notes: Lab Notebooks in the Private Sector

One of my to-do tasks includes making some revisions to a standard operating procedure draft document for lab notebook policies for our division. I’m a member of an “executive lab notebook committee” or as I fondly like to call my assignment, the stinking albatross that hangs around my neck. The confluence of discovery scientists and attorneys is an uneasy one, and acting as an intermediary between the two factions can get pretty stinky in that dead-avian pendant way.

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The (NP)Y’s and Wherefores of Stress and Obesity

When I find myself in times of trouble
Ben and Jerry’s comes to me
Snarfing Chunky Monkey so sweetly, so sweetly.

When stressed, some folks barely eat and consequently lose weight. Others, including myself, reach for high-fat-high-sugar (HFS) foods in an attempt to ameliorate the angst. Although the connection between stress and overeating is not fully understood, the evidence until recently focused on centrally acting (brain & spinal cord) mechanisms, e.g., hypothalamic control of food consumption and metabolism.
However, Lydia Kuo et al. (1) reported recently in Nature Medicine that stress-triggered release of neuropeptide Y (NPY) can stimulate angiogeneis (formation of new blood vessels) in the periphery, i.e., other places in the body than the brain and spinal cord. The researchers also demonstrated that NPY stimulates creation and differentiation of new fat cells (adipogenesis). NPY evidently binds to its receptor (or one of its receptors), NYP2R – a G-protein coupled receptor, and gets the big fat ball rolling.
More below the corpulent fold…

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The (NP)Y’s and Wherefores of Stress and Obesity

When I find myself in times of trouble
Ben and Jerry’s comes to me
Snarfing Chunky Monkey so sweetly, so sweetly.

When stressed, some folks barely eat and consequently lose weight. Others, including myself, reach for high-fat-high-sugar (HFS) foods in an attempt to ameliorate the angst. Although the connection between stress and overeating is not fully understood, the evidence until recently focused on centrally acting (brain & spinal cord) mechanisms, e.g., hypothalamic control of food consumption and metabolism.
However, Lydia Kuo et al. (1) reported recently in Nature Medicine that stress-triggered release of neuropeptide Y (NPY) can stimulate angiogeneis (formation of new blood vessels) in the periphery, i.e., other places in the body than the brain and spinal cord. The researchers also demonstrated that NPY stimulates creation and differentiation of new fat cells (adipogenesis). NPY evidently binds to its receptor (or one of its receptors), NYP2R – a G-protein coupled receptor, and gets the big fat ball rolling.
More below the corpulent fold…

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Hipster “Teh” Hits a Staid Pharma-Journal

The Teh finally hit the conservative pages of Scrip World Pharmaceutical News.

Wyeth’s new antipsychotic receives FDA non-approvable letter after fatality
August 13, 2007
Scrip
The US FDA has issued a non-approvable letter for Wyeth/Solvay’s new-generation atypical antipsychotic bifeprunox, which was under review for the acute treatment of schizophrenia and the maintenance of stable adult patients.
Wyeth’s share price on teh New York Stock Exchange closed at $46.59, down by 6% on August 10th. (emphasis mine)

OK, it may just be a typo, but I’d like to think it’s an oh-so-hip ironic reference to Teh NYSE.
I will inflict you with a little sidebar on the drug…just because I can:
The majority of atypical antipsychotics on the market are dopamine receptor antagonists. Bifeprunox is a partial agonist of the D2 dopamine receptor, a G-protein coupled receptor (GPCR). Like aripiprazole (Abilify), another D2 partial agonist, bifeprunox is believed to act as a dopamine stabilizer, that is, decreasing overactive dopaminergic response in some areas of the brain and increasing it in others.
The FDA issued the non-approval letter because of a patient’s death (multi-organ failure) in an acute (six-week) trial. It was noted that the case was complex and that it is not known if the patient’s death was related to the drug.
Yeah, so that explanation of D2 partial agonists was teh lame. You know what I have to say to that?
Meh.

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Thumbs Down on Rimonabant

Following up on the wacky tobaccy post, the FDA advisory panel voted 14-0 against recommendation of rimonabant to move forward as a treatment for obesity, citing the need for further safety studies. As noted, the primary concerns are psychiatric/neurological issues.
I really can’t resist a “No shit, Sherlock!” as pertains to the psychiatric and neurological issues. The endocannabinoid system is under scrutiny for psychiatric indications, i.e., new antidepressants and anxiolytics. It’s not exactly unexpected that such adverse effects might arise given the different responses among patient populations to other neuro-GPCR agonists and antagonists. Just as there are allelic variations in the 5HT receptors, I’d expect one would find the same among the CB-1 receptors.
So, there will be no quick pharma-fixes for the godly fast food f(r)iends of Jim’s post.
Here’s the report from the NYTF: F.D.A. Panel Rejects Drug for Obesity
Some noteworthy pharmabloggery related to rimonabant:
From Pharmalot

FDA Panel Rejects Acomplia Fat Pill

From Derek Lowe of In the Pipeline:
Rimonabant, Out In the Light
And finally from PharmaGossip:
Now that’s what I call a black box warning!

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CB-1 Antagonists: Wacky Tobaccy’s Pharmacological Legacy


Today, the FDA’s Endocrinologic and Metabologic Advisory Committee reviews rimonabant, the cannabinoid receptor antagonist developed by Sanofi-Aventis, for recommendations, or lack thereof, as an anti-obesity medication. Rimonabant was approved in Europe for limited cohorts of obese patients, but rejected as an anti-smoking medication. Approval for marketing rimonabant in the US is pending next month, and the advisory committee’s assessment will weigh heavily on this decision.
There are other ‘bants in the pharma pipeline so it should be interesting to see how today’s decision plays out. A major concern is the increased incidence of psychiatric effects, e.g., from the NJ Star Ledger, 06/12/2007, FDA links obesity drug to suicides: Sanofi-Aventis studies reveal psychiatric events.
As we await the FDA’s decision, our adipocytes aquiver with anticipation, please allow me to distract you from that box of Hostess Twinkies and the nearby six pack of Bud with my scintillating historical bloggery on cannabinoid receptors, accompanied by my usual gentle measured opinion on obesity drugs.

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Peter Rost: Big Pharma’s PITA.

Three pant-hoots and a grooming session to my very favorite cheeky pharma-insider monkey over at PharmaGossip (see the Chimp Refuge Blogroll) for the following, Can Peter Rost be silenced? including the link therein which led me to…
…the reprint of the article on Peter Rost in Fortune Magazine, posted on Dr. Rost’s blog: Fortune: “Peter Rost has become the drug industry’s most annoying – and effective – online scourge.
As a pharma discovery scientist, I regard marketing as the Devil Incarnate in its current form, and it’s refreshing to see someone pitbulling them. But will Rost can hold out? Jim Edwards over at BrandweekNRX seems to think so.
If you’re not familiar with Rost, here’s an excerpt from the Fortune article:

The ridicule comes easy for Rost. In his former life, the 48-year-old physician earned $600,000 a year conjuring up marketing plans for companies like Pfizer, Pharmacia, and Wyeth. That’s all behind him. Since Pfizer fired Rost from his post as a vice president of marketing in December 2005, he has been blogging from the basement of his suburban New Jersey home. Rost’s blog, Question Authority With Dr. Rost (peterrost.blogspot.com), is one part mocking rant, two parts investigative chronicle. A recent week’s headlines included PFIZER, VIAGRA, AND THE MOB; and FORMER U.S. ASTRAZENECA CEO LARS BILDMAN: THE CRAZIEST BIG PHARMA CEO EVER? He has also published an exposé of his years in the drug industry, The Whistleblower: Confessions of a Healthcare Hitman.

According to Fortune “Peter Rost has become the drug industry’s most annoying – and effective – online scourge.” Peter Rost, M.D., is also the author of “THE WHISTLEBLOWER, Confessions of a Healthcare Hitman” and “THE WOLFPACK.” His blog is designed to be provocative, confrontational, irreverent, mocking, impertinent, flippant, impudent, bold, enlightening, naughty, mischievous, funny and tongue-in-cheek. If you have no humor or if you are a boring person you are not supposed to read this blog.

Hmmm… Rost – an irreverent. mocking, impudent gadfly and thorn in the side of the pharma-hands that feed me. I think I’m in love!** I have added his blog to the “Just Say ‘Yes’ to Drugs!’ section of the Refuge’s blog roll.
**But no one will supplant my undying devotion to the cheeky monkey at PharmaGossip.

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Big Pharma: A Startlingly Accurate Depiction!

Orac clearly knows too much. For an accurate look at a Big Pharma board room, check out The pharma conspiracy acts against a threat. Orac, with his delightful and respectful insolence, reveals why Dan Olmsted, Thimerosal-Conspiracy- Crusader Extraordinaire, is actually Pharma’s Best Friend.
Orac’s characterization of MegaPharmCo’s head honcho, ESB, is pretty accurate, too, e.g.,
Dr_Evil.jpg
+
eye-of-sauron.jpg
=
.Most Big Pharma CEOs

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Sip from me and obey!

As much as it pains me (1) to honor the request (2) by Dave of The World’s Fair, I’ll play:
1. Can you show us your coffee cup?
Here’s my work-a-day mug at my desk flanked by its friends (see answer to item 3). This photo, taken with the marginal little camera in my PDA, is in violation of DOPI (3) policy since I am revealing the kind of printer we use, proprietary information which I am sure will set back our competition by 20 years.
Doc_Bushwells_desk.jpg
2. Can you comment on it? Do you think it reflects on your personality?
The text on the mug says “She Who Must Be Obeyed.” It was purchased for me from the Signals public TV/radio catalog back in the heyday of “Rumpole of the Bailey.” Rumpole routinely referred to his wife as “she who must be obeyed.” At the time, I was the leader for a prostate cancer program, and I was also the only woman in the ranks of the sr. scientists on the project team. Apparently, my team thought it was an appropriate gift, and accurately reflected my personality and leadership style. I am inclined to agree although I tend to view myself as a warm and fuzzy kind of winged harpy.
3. Do you have any interesting anecdotes resulting from coffee cup commentary?
The vast majority of commentary I have received on the cup has been knowing chuckles, as in, “Yep, that’s you.” The squishy stress balls flanking the mug have a moderately more amusing history.
The blue stress ball contains a floating yellow smiley face ball within it, and you can just make out the logo of Prozacasaurus, Inc. on its cheap plastic display stand. This ensemble was given to me at my last place of employment (let’s call it “Club V”) as a reward for an ill-fated collaboration. My response when our project leader gave it to me:
“What? Prozacasaurus, Inc. can only give me one happy best smiley breast implant?”
The stress balls were henceforth known as the “commerative breast implants” by the team members at Club V. It warmed my heart to know I could make such a valuable contribution to drug discovery.
The Blinky the Three-Eyed Fish on the right is pale and flaccid compared to its turgid twin on the left. When I was speaking with a particularly obtuse IT dude at DOPI’s “Help” desk, I squeezed Blinky I too hard, The hapless superfish erupted and ejaculated goo and glitter all over me, my computer monitor and my keyboard. I kept its skin as a meaningful reminder not to put too much stress on a stress reliever.
3. Can you try to get others to comment on it?
Obey, or do not obey (at your own risk). There is no “try.” Not that I am an overbearing micromanager or anything.
*********************
Foornotes:
(1) Yes, really, it pains me. I am recovering from epi-LASIK surgery, and the old orbs are freakin’ irritated. But I couldn’t resist answering this. And the 72 pt expansion of my browser’s font helps.
(2)Thankfully, the request was not called a “meme.”
(3)DOPI = Dark Overlords Pharmaceuticals, Inc.

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Objective 2007: Become Goddess of PowerPointery

Long time no see.
I took something of a hiatus from the hootacular environs of the Refuge due to the Most Wonderful Time of the Year at DOPI:* performance reviews for 2006 and objectives setting for 2007. I know. I shouldn’t whine and bitch about this, seeing how much work you academics put into the grant writing process in the unending effort to suck at the NIH/NCI/NSF/IYAH** teat, and I can appreciate how difficult that is. After seeing my grad advisor lose a significant grant (since regained) during the heyday of Ronnie Reagan years when 0.0000037% of all NIH grants were funded, I was utterly convinced there was no f’ing way I would be hippity hopping down the academic trail.

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