Category → Meetings
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.
We wanted to point Haystack readers to an upcoming event hosted in conjunction with our parent organization, the American Chemical Society, and Société de Chemie Industrielle: On September 14, our own Rudy Baum will moderate a panel discussion between former Pfizer R&D head John LaMattina and Columbia University chemistry professor Ron Breslow. The topic? “New Business Paradigms for Pharmaceutical Companies.” If the lively discussion today on twitter over the arrival of the “niche blockbuster” (or as Chemjobber coined “nichebuster”) model for pharma is any indication, folks are pretty interested in how drug firms are going to survive in a post-blockbuster era. For those living in the NY/NJ area, you can witness what is sure to be some great banter in person; for everyone else, feel free to sign up for the webcast.
As reported by Nature News and Forbes’ The Medicine Show on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI).
Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note:
So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope. Continue reading →
This is the first Haystack post from C&EN Intern Aaron Rowe. You may recognize Aaron from Twitter (@soychemist) or from his contributions to WIRED and its science blog.
Isis Pharmaceuticals showed off its latest strategy for improving the potency and pharmacokinetics of antisense oligonucleotides at its annual shareholder meeting, held last week. Their structure, called cET (structure at bottom right), should bring the size of a dose down to 5-40 mg per week and allow oral delivery of antisense molecules for some diseases. In its drugs, Isis uses a mix of several different modifications. They call these molecules gapmers. For instance, its cholesterol-lowering phase 3 compound, mipomersen (molecular model at top), has 2’-methoxyethyl modifications on each end (see structure at bottom left) and central DNA region, and it also has a phosphorothioate backbone. The newer cEt modification will be featured in a cancer drug that targets STAT3, a transcription factor that is overactive in many different malignancies. Here’s more on the cET story.
In the last year we’ve covered many up-and-coming drugs for controlling the delicate balance between clotting and bleeding. But what happens when something—an injury or a major surgical procedure—overwhelms that system?
Controlling big bleeds is big business, from the battlefield to the operating room. This Monday, at the American Chemical Society’s Middle Atlantic Regional Meeting (MARM) in College Park, Maryland, I heard from Matthew Dowling, CEO of a startup looking to make its mark in that space. The company is called Remedium Technologies, and it’s developing chemically modified versions of a natural biopolymer to make improved materials for stanching blood flow.
Remedium is one of several companies getting on its feet with help from technology incubation programs the University of Maryland. Representatives from several of those companies, including Dowling, gave talks at a MARM symposium on the science of startups. Look here for the MARM session’s program- it includes other companies in the drug and vaccine space, including Azevan Pharmaceuticals (which C&EN wrote about in 2001 when it was called Serenix), Leukosight, and SD Nanosciences.
The biochemical pathway that regulates clotting can’t support severe injuries that lead to profuse bleeding, Dowling said Monday. While several treatments exist for this kind of severe injury, where sutures might not work to close a wound, they have drawbacks that Dowling thinks Remedium’s technology can address.
The company’s material of choice is chitosan, a biopolymer that can be scavenged from waste shells of shrimp or crabs. Chitosan wound dressings are already on the market, but they become saturated with blood and quit sticking to tissue after about 30 minutes, which can lead to more bleeding. As a bioengineering graduate student at Maryland, Dowling developed an alternative chitosan modified with hydrophobic groups that help it stick to tissues longer. This modified biomolecule is the basis of Remedium’s technology. The company likens the material to Velcro because it is the sum total of weak interactions between hydrophobic groups and tissue that help the material stick around, Dowling explains. Once the wound has had time to heal, the material can be gently peeled away. The chemical structure of Remedium’s hydrophobic groups is proprietary; Dowling used benzene n-octadecyl tails in graduate school.
The company has two products in development- a modified chitosan “sponge” and a spray-on blood clotting foam. Neither of those products is yet available for purchase. In College Park, Dowling showed a video demonstrating how the modified chitosan makes blood congeal quickly, and how the effect can be reversed by applying alpha-cyclodextrin. In a second video, the sponge is tested on a bleeding pig that’s had a major blood vessel cut open. This presentation is similar to what Dowling gave Monday.
Dowling has been running Remedium full-time since he obtained his doctorate from Maryland in 2010—the company was founded while he was still in graduate school, and several classmates are also in the company’s management. The company has an exclusive license for the chitosan technology from the university, and has four patents pending. It has also won several business competitions, including Oak Ridge National Laboratory’s (ORNL) 2010 Global Venture Challenge. Dowling says the university’s technology incubation resources are what made it possible for him to start a company while still in grad school, from providing office space in a building just off campus, to regular meetings with staffers knowledgeable about navigating the regulatory and funding process.
1PM Pacific: There’s one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs’ structures unveiled for the first time. Watch this space for updates.
2:39PM Pacific: CEP-26401
This drug candidate now has a name: irdabisant
meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer’s and schizophrenia
mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory
medicinal chemistry tidbits: Cephalon’s goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates’ lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011, advancing to Phase II
structure coming soon!
UPDATED 3/29 with structure:
3:16PM Pacific: BMS-663068
company: Bristol-Myers Squibb
meant to treat: HIV
mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors
medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency.
status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year.
meant to treat: irritable bowel syndrome
mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut.
medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain.
status in the pipeline: Completed Phase IIa clinical trials.
5:30PM Pacific: MK-0893
meant to treat: type 2 diabetes
mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels.
medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team’s big breakthrough was adding a methyl group to the benzylic position of a promising compound, which greatly improved potency. This methyl group strategy hadn’t worked for previous compound series, but the team revisited it anyway.
status in the pipeline: Completed some Phase II trials, according to clinicaltrials.gov
meant to treat: Alzheimer’s disease
mode of action: blocks gamma-secretase, a key enzyme in the production of amyloid-beta, the peptide behind the plaques that mar Alzheimer’s patients’ brains.
medicinal chemistry tidbits: Adding a cyclopropyl group and a trifluoromethyl group enhanced molecules’ metabolic stability.
status in the pipeline: discontinued because of adverse liver side effects unrelated to its mode of action.
5:31PM Pacific: That’s all for now, folks. I hope to update with more structure information later. Watch for my full story on this symposium in a mid-April issue of C&EN.
Medicinal chemists, it’s that time of year once again. Time for the ACS National Meeting, and the accompanying symposium where drug companies reveal the structures of drug candidates in clinical trials for the first time. I’ll be on the ground in Anaheim and will be posting from that session (which lasts from 2PM-5PM Pacific Sunday the 27th) and others. Here is the Anaheim Division of Medicinal Chemistry program (pdf).
And here is the list of disclosures:
- Discovery and characterization of CEP-26401: A potent, selective histamine H3 receptor inverse agonist: R. Hudkins, Cephalon
- Discovery of BMS-663068, an HIV attachment inhibitor for the treatment of HIV-1: J. Kadow, Bristol-Myers Squibb
- Discovery and development of LX1031, a novel serotonin synthesis inhibitor for the treatment of irritable bowel syndrome: A. Main, Lexicon
- Discovery of MK-0893: A glucagon receptor antagonist for the treatment of type II diabetes: E. Parmee, Merck
- Discovery of ELND006: A selective γ-secretase inhibitor: G. Probst, Elan
Just about every time C&EN covers a newly-solved structure of a G-protein coupled receptor, we throw in a sentence about how the structure has big implications for drug discovery. And rightly so- G-protein coupled receptors (GPCRs) are one of the top types of proteins targeted by drugs. But just what does that statement mean? It’s not like a medicinal chemist can look at that structure and instantly come up with a drug that controls the protein and treats a disease.
I’m in Taos, New Mexico, at a Keystone Symposium called “Transmembrane Signaling by GPCRs and Channels”, where I’m talking to researchers who take the information from pretty pictures of membrane-spanning proteins and use it to build viable drug candidates. Take a look at the Keystone Symposium’s program, and you’ll see a handful of speakers from industry. For instance, I’ve already heard a talk from Fiona Hamilton Marshall at Heptares Therapeutics and today (Wednesday) I will hear one from Kenneth E. Carlson at Anchor Therapeutics.
I’ve also had the pleasure of meeting two folks who I’ve only spotted before on Twitter- Peter Nollert (@reducentropy) of Emerald Biosystems and UCSF postdoc Ryan G. Coleman (@rgcjk).
This conference is already giving me more information than I can handle about solving GPCR structures- start drinking from the firehose with this overview of the tricks of the trade.