What Are Your Favorite Non-U.S. Drug Discovery Stories?

Over at my other gig at the Pharma & Healthcare section of Forbes.com, I’ve been covering a few stories of new drugs and improvements on old drugs. Although I’m focusing on natural products like vancomycin and semi-synthetics like lurbinectedin, I’ve been thinking a bit about the stories behind the discoveries of all drugs. Part of my thinking has been driven by my current reading of Happy Accidents: Serendipity in Modern Medical Breakthroughs by Morton A. Meyers, MD, professor emeritus of radiology and internal medicine at SUNY–Stony Brook. Therein, I’m reading stories like that of Gerhard Domagk, who first showed that prontosil was an effective antibiotic in vivo but not in vitro because it liberates sulfanilamide when metabolized. The story was told in even greater detail in the superb Thomas Hager book, The Demon Under the Microscope. This got me to thinking: I hear quite a bit about drug discovery stories in the U.S. but rarely about modern drugs that have been discovered elsewhere. The brain tumor drug, temozolomide, for example, was developed in the laboratory of Malcolm Stevens at Aston University building upon work of the late Tom Connors (expertly told by Kat Arney at Cancer Research UK last summer). But one rarely hears stories like these, even in pharmacology courses at pharmacy schools where the teaching is more likely to be chemistry-oriented. So, chemistry world hivemind: What are your favorite stories of drug discovery and development that didn’t occur in the United States? Bonus points for natural products or...

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The Case Of The Malodorous Metabolite
Apr06

The Case Of The Malodorous Metabolite

Over where I also write at Forbes.com, Matthew Herper, Senior Editor for Pharma and Healthcare, reported on GlaxoSmithKline’s NEJM clinical trial of darapladib in coronary artery disease. The drug had been developed as a small molecule, orally-formulated, subnanomolar inhibitor of lipoprotein-associated phospholipase A2. Lp-PLA2 is associated with apolipoprotein B-containing lipoproteins, such as LDL and non-HDL particles, and is found in the necrotic center of atherosclerotic plaques. Formerly known as platlet-activating factor acetylhydrolase, the enzyme produces pro-apoptotic lysophosphatidylcholine and stimulates the synthesis and release of proinflammatory mediators such as IL-1 beta, IL-6, ICAM-1, and VCAM-1. A meta-analysis of nearly 80,000 patients across 32 trials indicated that Lp-PLA2 was associated with a relative risk for coronary artery disease of 1.10 for each 1-standard deviation increase in activity, even when correcting for other influences. This magnitude of relative risk is similar to that for non-HDL cholesterol or systolic blood pressure.So, the enzyme seemed like a reasonable target for small-molecule inhibition. Darapladib (SB-480848) emerged from screening for inhibitors and a synthesis campaign, each published in 2002 and 2003, and was selected for clinical trials. A study with 330 patients with coronary artery disease, The Integrated Biomarkers and Imaging Study-2 trial, showed that 12 months of darapladib (160 mg daily, p.o.) decreased the progression of atherosclerotic plaques that occurred in the placebo group, even when they were also receiving standard-of-care statin therapy. Last week saw the publication in NEJM of the STABILITY trial to examine efficacy against primary endpoints. Unfortunately, this large, placebo-controlled, randomized trial with 15,828 patients who took 160 mg darapladib once daily showed no benefit of the drug relative to placebo in the primary endpoints of time to cardiovascular death, myocardial infarction, and stroke. However, the drug did show significant differences from placebo in measures of major coronary events (9.3% vs. 10.3 % for placebo) and total coronary events (14.6% vs. 16.1% for placebo). Major coronary events were defined as “a composite of death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia.” Total coronary events were defined as “a composite of death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization procedure.” But when looking at other aspects of the paper, Herper noted that a small but significant subset of patients reported an unpleasant odor from their skin, urine, or feces while taking darapladib. In discussing the side effects relative to the modest effects on secondary endpoints, Herper wrote, [T]he leading side effects were diarrhea (3.2% vs. 0.8%), feces odor (2.2% vs. 0.1%), urine odor (1.4% vs. <0.1%), and skin odor (2.2% vs. 0.1%). Would such a small difference be enough to...

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Must-See ACS Webinar: Superbugs and Drug Development
Feb26

Must-See ACS Webinar: Superbugs and Drug Development

One of science journalism’s expert voices, author Maryn McKenna, will be the guest on this Thursday’s ACS Webinar Joy of Science series at 2:00 – 3:00 pm Eastern time. Free, as always, you can sign up to participate at this link. McKenna’s book, SUPERBUG: The Fatal Menace of MRSA, is a thorough and accessible investigation of the reemergence of lethal bacterial infections while new drug development lags. The book, now in paperback, received the 2011 Science in Society Award from the the National Association of Science Writers. McKenna had spent much of her career at the Atlanta Journal-Constitution as the only U.S. reporter assigned full time to the Centers for Disease Control and Prevention. In fact, her first book, Beating Back the Devil, detailed her experiences with CDC’s Epidemic Investigation Service (EIS), the team dispatched anywhere in the world that’s experiencing an unusual infectious disease event. From her book’s website: I was following a group of disease detectives from the Centers for Disease Control and Prevention, the CDC, through an investigation of bizarre skin infections in Los Angeles. The CDC wanted to know where men were picking them up. I wanted to know something more fundamental: How could a minor problem — something that the victims all described as looking like a tiny spider bite — blow up into massive infections that ate away at skin and muscle, put people into the hospital for weeks and drained their health and their bank accounts? Where had it come from? And if it could do that, what else was it capable of? Maryn’s one of the best science writers in the world in terms of mastering her subject and making it widely accessible. Of course, her webinar will be of interest to anyone concerned about the proliferation of drug-resistant infectious diseases and how to design drugs to stay a step ahead of evolution. But she’s also a great model to emulate for anyone trying to make their scientific work more approachable to non-experts. You might even learn a thing or two about telling a gripping story. And, thanks to your American Chemical Society, dialing into the webinar is FREE. Go here to register. You don’t even need to be an ACS member! You can thank me later. The webinar will be archived but you can also hear from Maryn McKenna on a regular basis at her Wired Science blog, Superbug and on Twitter...

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Elion-Hitchings Building Tour: A Storify
Oct22

Elion-Hitchings Building Tour: A Storify

As discussed in my post last week, I had the opportunity on Saturday to tour the old Burroughs-Wellcome US headquarters building in Research Triangle Park, NC. Designed in 1969 by architect Paul Rudolph, the building was completed in 1972. The building became known as the Elion-Hitchings Building after BW scientists Trudy Elion and George Hitchings shared the 1988 Nobel Prize in Physiology or Medicinewith Sir James Black.The building was acquired by Glaxo when they merged with Wellcome in 1995 (Glaxo had built its US headquarters in RTP in 1983, just north of the BW property.). Now GlaxoSmithKline (GSK), the company began liquidating buildings and consumer products over the last two years. When they announced their intent to sell the Elion-Hitchings Building in April, 2011, I suggested that someone purchase it to fashion into hipster condominiums. My hopes were dashed when United Therapeutics purchased it and two other buildings for $17.5 million in late June of this year. United Therapeutics has a 55-acre lot adjacent to the GSK property where they’ve constructed a new headquarters building of their own. What follows is a Storify compilation of my tweets from Saturday with photos that I sent out. I’ll post other photos later. Triangle folks: You can still come to tour the Elion-Hitchings Bldg in RTP today 9:00 – 12:40 for $15 at door http://bit.ly/T5YrxE David Kroll Sat, Oct 20 2012 05:15:07 ReplyRetweetFavorite Just arrived at former GSK-held Elion-Hitchings Bldg, now owned by United Therapeutics. http://pic.twitter.com/qOiH8kf7 David Kroll Sat, Oct 20 2012 06:34:40 ReplyRetweetFavorite @davidkroll It looks like the building is held up by giant lab jacks Matthew Hartings Sat, Oct 20 2012 07:11:50 ReplyRetweetFavorite You can’t erase the GSK. Logo outline on frosted glass. #elionhitchings http://pic.twitter.com/RiJPqN3a David Kroll Sat, Oct 20 2012 06:46:47 ReplyRetweetFavorite I wonder if GSK was still paying these 1996-97 wages? #elionhitchings http://pic.twitter.com/okKeIVAU David Kroll Sat, Oct 20 2012 06:52:55 ReplyRetweetFavorite This was the view for the executive secretarial pool. RTP requires that 40% of lots remain wooded #elionhitchings http://pic.twitter.com/YGGT75i4 David Kroll Sat, Oct 20 2012 07:12:27 ReplyRetweetFavorite @davidkroll Very cool! Didn’t know that stat! Stephanie Beck Sat, Oct 20 2012 07:36:12 ReplyRetweetFavorite Since Stephanie is a news producer for WRAL-TV in Raleigh, I thought I should do some fact-checking and find the source for this factoid once I got home. Turns out that I was wrong — I underestimated the wooded requirement.According to RTP’s Land Management plan, the built-up area of each lot is limited to 30%, leaving much more of the pine forest than I had originally cited. The #elionhitchings patio where Christopher Walken and Natalie Wood appeared in “Brainstorm”; Burroughs-Wellcome then http://pic.twitter.com/AO67RfIK David Kroll Sat,...

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GSK Sells Off BC and Goody’s Powders

My friends, today is a dark day in the history of traditional, old-timey pharmacy in North Carolina. According to Raleigh News & Observer reporter David Ranii, GlaxoSmithKline has sold their interest in two legendary analgesic powders and other over-the-counter products to Prestige Brands Holdings in Livingston, New York and Cody, Wyoming. Cue the old Pace Picante advertisement about the competitor’s “Mexican” salsa made in New York City. GSK even sold off Tagamet. Yes, Sir James Black’s cimetidine – the founding histamine H2 receptor antagonist for which Sir James shared the 1988 Nobel Prize in Physiology or Medicine with Trudy Elion and George Hitchings. Hell, they even sold Beano. If you want to know what I’m talking about, seriously, please see my explainer from April on the rich North Carolina history of analgesic powders. A shorter distillation of my post is this story at the North Carolina History Project. The $660 million sales price will put $375 million directly in the hands of shareholders (*check TIAA-CREF mutual funds to see if I hold any $GSK). Sorry, I can’t type anymore – I’ll be in mourning. In fact, I think I need me a BC...

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FDA Withdraws Avastin Approval for Breast Cancer
Nov18

FDA Withdraws Avastin Approval for Breast Cancer

  As reported around the wires today, US FDA Commissioner Dr. Margaret A. Hamburg formally revoked the accelerated approval of the antiangiogenic drug Avastin (bevacizumab) for breast cancer treatment. Avastin is a humanized mouse antibody that binds and inactivates the vascular endothelial growth factor VEGF-A, a mediator of blood vessel growth. Andrew Pollack at The New York Times does a nice job condensing this episode for us. The highlights are that Avastin was approved based on the surrogate endpoint of progression-free survival in metastatic breast cancer, meaning that it appeared to increase the time from treatment to return of the growth of cancer metastases. However, the true endpoint is long-term patient survival. There, subsequent studies showed that Avastin had no benefit. Moreover, Avastin also use appears to increase the risk of hemorrhage and bowel perforation. These are potentially life-threatening side effects and are considered too great of a risk when no statistical benefit of survival or quality of life are apparent. Of course, there are cases of individual patients who have benefited from Avastin and many questions remain for them. In the 69-page ruling made available today (PDF), Dr. Hamburg includes a well-articulated Q&A for patients and their caregivers. I doubt seriously that the full text of this section will be published in the mainstream media, although Pollack does provide the hyperlink. I found this quite valuable as someone who cares about family and friends with breast cancer. But the text also provides an espeically close look at the rationale behind the US drug approval process. As this rich information is buried in a 69-page federal document, I wanted to provide this text here for ease of reading by those concerned about this ruling. This following statement is from US FDA Commissioner Dr. Margaret Hamburg. The full text is in the public domain and can be accessed here.   I. AN EXPLANATION FOR PATIENTS AND THOSE WHO SUPPORT THEM This document, which lays out the basis for my decision, has several purposes. It is an explanation, for physicians, scientists, patients and the public in general, of the data available on the metastatic breast cancer indication for Avastin and of FDA’s evaluation of those data. It also describes how FDA has applied the law and its regulations in making the decision to withdraw the approval for that indication. I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients and those who support them, to ask hard questions and to demand explanations concerning the drugs that are recommended to...

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