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Category → Pharma

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.

Darapladib (SB-480848; N-[2-(diethylamino)ethyl]-2-(2-{[(4fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1 H-cyclopenta[d]pyrimidin-1-yl)-N-{[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide

Darapladib (SB-480848; N-[2-(diethylamino)ethyl]-2-(2-{[(4fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide

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Must-See ACS Webinar: Superbugs and Drug Development

Maryn McKenna.

SUPERBUG author, Maryn McKenna.

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?

A multidrug-resistant Staphylococcus aureus (MRSA) plushy from GiantMicrobes.com, personalized for the author by Maryn McKenna. Photo credit: DJ Kroll

A multidrug-resistant Staphylococcus aureus (MRSA) plushy from GiantMicrobes.com, personalized for the author by Maryn McKenna. Photo credit: DJ Kroll

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 @marynmck.

Elion-Hitchings Building Tour: A Storify

  1. 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.

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 Powder.

FDA Withdraws Avastin Approval for Breast Cancer

Schematic of humanized anti-VEGF antibodies. Credit: Steinbrook R. NEJM 2006; 355:1409-1412. Click on illustration for the source article.


 
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.

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“Pick A Powder” RIP?

BC Powder Historic Site, Durham, NC. Photo: David Kroll

I wrote this post on April 15th for my monthly gig at the Science-Based Medicine blog but just thought of it again this weekend as I drove past the BC Powder historic building in downtown Durham, NC. One thing I’ve observed since bringing Terra Sig to CENtral Science last summer is that we get a readership that is distinctly different than what I have seen when blogging in more biomedical environs (at least as far as institutional IP address hits tell me on SiteMeter.)

So, I wanted to update this post for you – Dear C&EN/CENtral Science reader – and add a few pictures. Truth be told, I really like this post in part because I love the pharmacy history of the American South. I also think that we could do a better job down here of using NASCAR enthusiasm to promote careers in science, technology, engineering, and mathematics (STEM).

The following is adapted from a post that appeared originally on 15 April 2011 at Science-Based Medicine.

After spending the first 21 years of life in New Jersey and Philadelphia, I ventured to the University of Florida for graduate school. For those who don’t know, UF is in the north-central Florida city of Gainesville – culturally much more like idyllic south Georgia than flashy south Florida.

It was in Gainesville – “Hogtown” to some – that I first encountered the analgesic powder. I believe it was BC Powder, first manufactured just over 100 years ago within a stone’s throw of the Durham, NC, baseball park made famous by the movie, Bull Durham. I remember sitting with my grad school buddy from Kansas City watching this TV commercial with hardy men possessing strong Southern accents enthusiastically espousing the benefits of BC. I looked at Roger – a registered pharmacist – and asked, “what in the hell is an analgesic powder?”

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GSK to sell iconic Elion-Hitchings building

On the heels of last week’s announcement that GlaxoSmithKline was selling off 19 consumer products comes news today by Laura Oleniacz from the Durham Herald-Sun that the drugmaker is liquidating some of its facilities on its Research Triangle Park campus.

The GSK Elion-Hitchings Building, formerly Burroughs-Wellcome headquarters, Research Triangle Park, NC. Photo: Joseph Molitor, Paul Rudolph Foundation.

One of these buildings is the futuristic structure built in 1972 for then Burroughs-Wellcome as designed by famed architect, Paul Rudolph. Now known as the Elion-Hitchings building in honor of the Nobel prize-winning chemists, the facility is one of the most recognizable landmarks in pharmaceutical history.

Click here for a fantastic series of copywritten photos from architect Kelvin Dickinson of The Paul Rudolph Foundation. You may recognize the building from the movie, Brainstorm, with Christopher Walken and the late Natalie Wood. (Her final film, the movie was released almost two years after her Wood’s death.)

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The Man Who Gave Us Epo

Professor Eugene Goldwasser (center) and future Nobel laureate Prof Harald zur Hausen (left) with King Bhumibol Adulyadej of Thailand (right) after receiving the 2005 Prince Mahidol Award. Source: Prince Mahidol Award Foundation.

I learned over the weekend via this tweet from Serena Stockwell at Oncology Times that Eugene Goldwasser passed away on Friday at age 88. The biochemist and renal physiologist who spent most of his career at the Argonne National Cancer Hospital and Department of Biochemistry and Molecular Biology at the University of Chicago (web page) demonstrated that a hormone made in the kidney could increase the number of new red blood cells, a major advance in physiology. His laboratory purified the protein hormone, erythropoietin (or Epo), from sheep in 1971 and from humans in 1977.

While a remarkable discovery of its own, Goldwasser’s partnership with then-Applied Molecular Genetics (Amgen today) led to the first- and second-generation recombinant biopharmaceuticals, erythropoietin and darbopoietin, and other versions such the the PEGylated EPO, Mircera. These drugs have transformed the lives of kidney dialysis and cancer patients, raised a furor in competitive sports – cycling in particular – and have been central to some of the most robust legal wrangling and medical costs discussions of our generation.

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Apixaban trial halted, eight others continue

After writing this week about the new, direct-acting antithrombotic drugs that threaten to replace the stalwart anticoagulant, warfarin, comes news that the joint BMS/Pfizer development of apixaban has hit a snag. From Jonathan Rockoff and Kathy Shwiff in the Wall Street Journal:

Pfizer Inc. and Bristol-Myers Squibb Co. said they’ve halted one the key trials for an experimental blood-thinning drug that is one of their brightest pipeline prospects, though other pivotal studies remain on course.

The phase III study of apixaban was examining whether the pill reduces the incidence of strokes or heart attacks caused by coronary heart disease, but early results indicated it didn’t while raising the risk of bleeding. The companies said they had acted at the recommendation of an independent data-monitoring committee. All patients will be taken off the drug and the results evaluated and made public, the companies added.

Eight other trials of apixaban are ongoing in other patient populations.

Mechanistically, apixaban is most similar to rivaroxaban (Xarelto, Bayer/J&J) a direct Factor Xa inhibitor discussed this week at the American Heart Association meeting. Rivaroxaban exhibited efficacy similar to warfarin in reducing clots of atrial fibrillation patients but had caused fewer spontaneous bleeding episodes.

A careful examination of the opposite effect of apixaban in patients with coronary heart disease will be essential to understanding whether this is a function of the drug (relative to rivaroxaban) or peculiar to the patient populations studied.

Blood Clotting and Benzamidine

Benzamidine, humble servant to many a successful Western blot, has given rise to one of two exciting developments in cardiovascular medicine.

Now that I don’t have to be graded on my memorization of the blood clotting cascade, let me just step back for a second and express awe for the physiological process of hemostasis. Think about this: we have to maintain our blood in a freely circulating form 99.999% of the time but as soon as there is a breach in the system, we have to quickly mobilize a cascade of events to prevent catastrophic blood loss. Pharmacological fiddling with this exquisitely controlled process is bound to have complications. But we have learn to walk this tightrope with drugs to prevent blood clots following stroke, orthopedic surgery, vascular stent implant, and other procedures and disorders that might cause such emboli to travel to our lungs, heart, or brain.

News yesterday from the American Heart Association meeting in Chicago brought our attention to a new class of anticoagulant drugs that may finally knock the coumarin, warfarin (Coumadin, racemic mixture), off its lofty pedestal as the oral antithrombotic drug of the last six-plus decades. Yes, the standard of care for about 65 years. The large, ROCKET AF trial presented yesterday had investigated the efficacy and side effect profile of warfarin relative to rivaroxaban (Xarelto, Bayer/J&J), a once-daily, oral inhibitor of the clotting factor, Factor Xa (part of a complex that converts prothrombin to the endogenous coagulation protein, thrombin).

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