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. Remedies, enhancer and even natural steroids, also 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? Online Headshop | Smoke Cartel – Glass & Vape Superstore says 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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