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Mergers’ Latest Stint In The Hot Seat

Anyone who reads the comments at Derek Lowe’s In the Pipeline knows that drug company mergers are far from favorites among industry researchers. Mergers also took the heat at a pair of high-profile events this month.

At this month’s ACS/Société de Chimie Industrielle panel discussion, former Pfizer Global R&D President John LaMattina laid the blame for ailing pharma pipelines largely on mergers.
From today’s C&EN editorial by Rudy Baum:

LaMattina’s comments focused on the negative impact of mergers and acquisitions on pharmaceutical R&D (Nature, DOI: 10.1038/nrd3514) calling them “a major factor in the decline in R&D productivity.” He pointed out that the Pharmaceutical Research & Manufacturers of America had 42 members in 1988, of which only 11 exist today as independent companies. While there are more than 11 current members of PhRMA, “the fact is , due to industry consolidation as well as some companies dropping their pharmaceutical R&D, there is far less competition in this industry than there was a decade ago.”

“Lilly has announced that they are going to be growing organically, and not through M&A,” Baum says. At the Société event both LaMattina and fellow panelist Ron Breslow of Columbia wished the company well in this strategy, he adds.

LaMattina confirms this, adding via Twitter “I would hope that Pharmas can succeed without the devastating effects of mergers.”

It wasn’t just LaMattina and Breslow calling out mergers. Last Friday, at the Pharmaceutical Strategic Alliances Conference, Bristol Myers Squibb CEO Lamberto Andreotti said that avoiding mergers was part of what’s made his company successful. As tweeted by Pearl Freier, founder of advisory firm Cambridge BioPartners:
PearlF: #PSA11 BMS transform, CEO credits continuity in R+D team working together for 7,8 years + No big mergers in 15 yrs, no disruptions

You can read more about Andreotti’s remarks at Reuters.

Drugs to Stop the “Brain-Eating Amoeba” N. fowleri

Summer can be hot, and many people cool down by jumping in nearby lakes and rivers. However, that’s also where millions of microbes like to play: as reported by multiple news outlets, the third 2011 US death has now been attributed to what the popular press has dubbed “the brain-eating amoeba.”

This “amoeba,” actually a protist called Naegleria fowleri, has been known to medicine since 1965. It belongs to a completely different biological branch from the true amoebas (I won’t go into all the biological background here, but Jennifer Frazier over at The Artful Amoeba has much more to say). This organism’s M.O. sounds like a cross between kuru (a brain-destroying prion disease)and flesh-eating bacteria. When a victim inhales freshwater containing N. fowleri, the organism attacks nasal membranes, working its way up towards the brain. Infected patients’ symptoms mimic those of encephalitis or meningitis, delaying proper drug treatment, while the protist quite literally consumes their nerve tissues.

Sound gruesome? Well, so are the existing therapies to fight it – the CDC Naegleria fact sheet discloses no current best treatment. The infected often receive amphotericin B, an antifungal known to have toxicity issues, in combination with an antibiotic (minocycline, or azithromycin). These combination therapies may improve the overall infection survival rate, but targets for small-molecule inhibition have been sorely lacking.

One promising biological lead to conquering N. fowleri does exist: the Nfa-1 gene. This gene produces proteins that impact the structure of the protist’s food cups, the organs used to digest tissue. A 2011 study indicated that chlorpromazine, an antipsychotic developed in the 1950s, inhibits Nfa-1 gene expression, and a 2008 test showed 75% survival of mice treated with chlorpromazine. Researchers hope this legacy drug can be further optimized to discover new N. fowleri treatments.

Tweaking A Workhorse Anesthetic

In this week’s issue of C&EN, I’ve written about the search for new anesthetic drugs, as well as the accompanying quest for a better understanding of how anesthetics work. Anesthesia is safer than it’s ever been because highly trained physicians and nurses can manage its complications. The drive to improve anesthetics is nowhere near as strong as it is for other drug classes such as oncology drugs, as Imperial College biophysicist Nick Franks told me. But that doesn’t mean the drugs in use are perfect.

Take propofol, or 2,6-diisopropylphenol, which is marketed as Diprivan by AstraZeneca. It’s arguably the most commonly used injectable anesthetic for surgeries in developed nations. It even has a nickname around the operating room, “milk of amnesia”, because of its effects on memory, and because of the milky appearance the sparingly water soluble compound takes on in the oil-water emulsion needed to deliver it to the bloodstream.

But propofol has side effects. Several firms have made adjustments to propofol or its formulation in order to address the limitations, and they’re finding out whether those chemical tweaks translate into benefits for patients. Continue reading →

Ensemble Hits Macrocycle Milestone

Today, Ensemble Therapeutics announced it has developed experimental drugs with molecular structures containing a large ring, which the company calls Ensemblins, against one of 8 key drug targets laid out in a 2009 agreement with Bristol-Myers Squibb Company (BMS). As a result, the drug development program will be handed off to BMS and Ensemble will receive a milestone payment. Neither the drug target nor the milestone payment amount have been disclosed.

I first became acquainted with Ensemble in 2008, when I wrote about a symposium extolling the potential benefits of compounds containing rings of 12 or more atoms, also known as macrocycles, in drug discovery. Continue reading →

Structures May Not Solve Everything

This week’s C&EN cover story is about how X-ray crystal structures of G-protein coupled receptors (GPCRs) help the hunt for new drugs. GPCRs are already a major target for drugs (if not the most popular drug target), but until recently, researchers knew little about the finer points of their structures.

As I mentioned in that story, those high-resolution protein pictures aren’t a panacea, and they won’t replace established drug-discovery technology so much as complement it. I didn’t have room to flesh out that idea in print, so I’m posting a few researchers’ thoughts on this area here today.

Some scientists thought that GPCR X-ray structures are so far of limited utility for discovering allosteric drugs, a class of GPCR-targeted drugs that can dial activity up or down rather than turning it on or off. Some GPCR-targeted drugs on the market already work this way, such as the HIV medication Maraviroc, and many more are in development. (As an aside, I feel as though every time I attend an ACS meeting talk about GPCRs, the room is packed).

“It’s the chicken and the egg story,” says Robert Lutjens, head of core biology at Addex Pharmaceuticals, which specializes in GPCR drug discovery. To get an X-ray structure of an allosteric molecule binding to a GPCR, which would be useful for developing virtual screens, one would first need to find just the right allosteric molecule—one that stabilizes the GPCR sufficiently to enable it to be crystallized. That’s difficult to do, so powerful biological assays are still critical for finding molecules that act at allosteric sites, Lutjens says. Continue reading →

Genetic Tests And Rimonabant: Coulda, Woulda, Shoulda

Here’s something I missed while finishing up that blood thinner cover story. Last week Reuters reported that genetic testing might have helped save rimonabant, the ill-fated obesity medication once touted as a future blockbuster. Rimonabant, which blocks the cannabinoid-1 receptor, the target of marijuana’s psychoactive ingredient, appeared to help people lose weight. But it also increased the risk of psychiatric side effects, as we wrote back in 2009. The drug never won US approval and was pulled from the market in Europe in 2008.

Reuters’ story was based on this report from The Lancet. The report (and accompanying press release) decribe CRESCENDO, a large clinical trial of rimonabant which was halted midway through because regulatory authorities were concerned about suicides in people taking the drug.

The story actually focused on a small part of the Lancet paper’s discussion section, where Topol describes the lessons drugmakers should take away from the CRESCENDO trial.

Endocannabinoid blockade could have proven viable, if a genome-wide association study had been done to establish what sequence variants are linked with suicides, suicide attempts, or significant neuropsychiatric side-effects.

And here’s what Topol told Reuters about genetic testing.

“Finding the gene for severe adverse drug reactions is a lot easier than we ever thought it would be,” Topol said in a telephone interview.
Topol thinks if they had thought to collect genetic information on the study’s more than 18,000 participants, they might have spared the drug.
“We probably could have figured out genomically who was susceptible and that drug could be quite viable,” Topol said in a telephone interview.

I guess a genome-wide association study might have been interesting. It’s a shame one doesn’t seem to have been conducted. Still, I’m not sure it would have been guaranteed to determine which patients were more susceptible to suicide. These types of studies have limitations, which this article from JAMA describes best:

GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors.

Image:C&EN

On Blood Thinners And Rat Poison

C&EN’s cover story this week is about finding replacements for the blood thinner warfarin, something that hasn’t happened in the more than fifty years since the drug went on the market.

Warfarin prevents blood clots from forming and reduces active clots as well. When it works, it’s great for preventing strokes. As a bonus, it’s a dirt cheap pill, costing on the order of a couple of cents a day. But the trouble is that warfarin doesn’t always work well. It is extremely unpredictable in the body. Foods and other drugs affect its activity, as do certain genetic traits.

The last thing you want to do is to take too much or too little warfarin. Too much warfarin could lead to uncontrolled bleeding, something that can be deadly in a place like the brain. And of course too little warfarin won’t be effective at preventing clots. So patients on warfarin must constantly monitor how well their blood is clotting, so their doctor can get their dose just right.

The fact that it’s easy to overdose on warfarin is a pain for doctors and patients. But it comes in pretty handy in warfarin’s other, perhaps less well-known application: rat poison. It seems that messing with rodents’ blood clotting pathways is a very efficient way to off them. My cursory research indicates that we’ve got many rodenticide options, and warfarin isn’t the most common one. I couldn’t find warfarin at three different D.C. hardware stores. But it’s still available online.

YOUR KEYWORD FOR THIS BLOG IS: COMING

As an aside: medical websites seem to use the name “coumadin”, but the rat poison boxes read “warfarin”. I’d love to know the history behind this name divergence. It could be another instance of name-changing to assuage patient fears. I can certainly understand how a patient would find it disconcerting to see a giant box of their blood thinner in the pest control aisle at Home Depot. Think of how a nuclear magnetic resonance spectrometer uses essentially the same technology as a magnetic resonance imaging instrument. But the name you see used in the health field drops the “nuclear”.

Scientists On The Move

I like taking the time to read the fine print in journal articles. When I first read the antibiotic work I posted about yesterday, I noticed that a few of the authors on the paper had little crosses next to their names. If you go to said fine print, you will find that they are no longer at GSK, but are located elsewhere. I’m no Chemjobber or Electron Pusher, but I try to pay attention to researchers’ moves.

Drake S. Eggleston, Fabrice Gorrec, Earl W. May & Alexandre Wohlkonig
Present addresses: Innovalyst, 1000 Centre Green Way, Suite 200, Cary, North Carolina 27513, USA (D.S.E.); MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK (F.G.); OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale, New York 11735, USA (E.W.M.); Vrije Universiteit Brussel, VIB Department of Molecular and Cellular Interactions, Pleinlaan 2, 1050 Brussels, Belgium (A.W.).

Platensimycin On My Mind

Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet ‘potential new antibiotics’ as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly.

There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, “Don’t get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring.”

In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust’s Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot.

Since the news story discussed revisiting old antibiotic targets, I thought I’d spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample.

Here’s an abbreviated platensimycin timeline:

May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic.

October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity.

April 2008: Lisa Jarvis’s C&EN cover story counts platensimycin among the natural product antibiotics in development.

March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin’s target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all.

August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: “As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage pipeline.”

Positive Results for Onyx’s Myeloma Drug Carfilzomib

This morning Onyx Pharmaceuticals shared good news about its multiple myeloma drug candidate carfilzomib- the compound helped 24% of the multiple myeloma patients enrolled in a Phase 2b clinical trial, all of whom have seen other therapies fail. Onyx’s stock was up over 21% on the news, last we checked. The company is hammering out the details of filing a new drug application (NDA) for carfilzomib, something they intend to do by the end of 2010.

Multiple myeloma is a type of blood cell cancer that’s very challenging to treat, with relapses a fact of life. Patients in Onyx’s trial “can expect to respond to therapy only 11 percent of the time and survive for only six to 10 months,” Michael G. Kauffman, M.D., Ph.D., Chief Medical Officer of Onyx Pharmaceuticals, said in a press release. In these patients, when carfilzomib worked, the duration of the response was over seven months.

Carfilzomib is part of a new generation of myeloma drugs that are just starting to emerge, as we wrote about in C&EN last year. Continue reading →