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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

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: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown.

So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.   Continue reading →

Sensible Antisense RNA Modifications


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.

Remedium Technologies Gets A Grip On Severe Bleeding

Maryland is serious about nurturing startups. Drahl/C&EN

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.

Drug Candidate Structures Revealed At #ACSAnaheim

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
company: Cephalon
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:

CEP-26401

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.

BMS-663068

4:24PM Pacific:LX1031
company: Lexicon
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
company: Merck
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

ELND006
company: Elan
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.

First Time Drug Disclosures at #ACSAnaheim

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

How Do You Get From Picture to Pill?

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.

Big Pharma Talks Emerging Markets Strategy

Last year’s JP Morgan Healthcare conference brought a flood of proclamations and projections about growth in emerging markets. Although the topic is now more of a given rather than a new arm of drug companies’ strategies, it seemed worth compiling some of the comments on emerging markets made at this year’s event. Of note? With many of the best assets in developing countries already snatched up and so much attention on what remains, prices are rising. Several big pharma CEOs underscored the need to grow at a profit, instead of just for the sake of growing. Time will tell if companies can heed their own advice.

GlaxoSmithKline is very deliberately shifting resources away from the U.S. and into emerging markets. In just a few years, the number of sales reps in the U.S. is down to 5,000 from 9,000, while the number of reps in emerging markets has grown from about 8,500 to 13,000, said GSK’s chief strategy officer David Redfern.

Of the 17 significant M&A deals undertaken by GSK since mid-2008, nine were in emerging markets. When asked whether that pace would continue, Redfern said the company no longer needed acquisitions to gain entry into those markets. And while bolt-on deals are still possible, he notes that

“There’s no doubt prices are going up in emerging markets and we’ll maintain our discipline,” Redfern said. “In 2008 we did quite a few deals. We’ve walked away from a lot more deals last year.”

Sanofi-Aventis is also bolstering its sales force in emerging markets at the expense of jobs in the U.S. and Europe. Chris Viehbacher said there has been a 40% reduction in pharmaceutical operations between 2009 and 2011, and a significant overhaul of its European operations is underway. Meanwhile, headcount in emerging markets is expected to increase by 40% in that same timeframe. As a result, “in 2011, we expect to sell more in emerging markets than we do in Europe or the U.S.”

Merck said it had also “significantly reduced” the number of sales reps in developed markets. The company’s goal is to grow sales in emerging markets from 18% to 25% by 2013.

“We’ve been frank to say that companies are ahead of us,” Merck’s CEO Ken Frazier said. However, he pointed out that it’s still an open field: the leading player in China only has about 3% of the market share.

Frazier also stressed the importance of achieving profitable growth in those regions, a nod to the rising prices for assets. “We think value-creating partnerships are the right way to go, because that way our partners have a strong stake in the growth and success of our business,” he added.

Eli Lilly & Co. is avoiding pure generics, and instead is trying to expand its presence in emerging markets by increasing sales of its existing product portfolio in six key markets–China, Russia, Brazil, Mexico, Turkey, and Korea. After doubling its sales force in China, among other efforts, the company has doubled sales in emerging markets in the past five years. Sales in emerging markets, now over 10% of total Lilly revenues, are expected to double again in coming years, said Lilly CEO John Lechleiter.

“We will add nominally medicines to our offerings, primarily in our core therapeutic areas, through product acquisitions, licensing deals, or co-marketing arrangements,” Lechleiter said. “We will pursue alliances, possibly including company acquisitions, to bolster our ability to capture growth in areas where our infrastructure is not fully developed.”

Lastly, big biotech is starting to at least think about, if not fully outline its strategy to expand globally. In a passing comment during his presentation, Amgen CEO Kevin Sharer said emerging markets will be an important part of the company’s future, but “not the future tomorrow morning, but the strategic future.”

From Pisces To Prodrugs: An Obesity Story

Sockeye salmon (Shutterstock)

When it comes to obesity, the drug race between Arena’s lorcaserin, Vivus’s Qnexa and Orexigen’s Contrave is at the forefront of folks’ minds these days.

But yesterday at the ACS National Meeting in Boston, I sat in on part of a session in the Division of Medicinal Chemistry that gave me a broad overview of other strategies for developing treatments for obesity. I heard a neat story from Donald L. Hertzog of GlaxoSmithKline that I thought I’d share.

GSK is focusing on the melanin concentrating hormone receptor protein as a target for obesity drugs. When I read the abstract, I thought I’d made a mistake. What in the world could the pigment melanin have to do with obesity?

It turns out there’s a fascinating connection. Continue reading →

First-time disclosure of Clinical Candidate live tweeting-UPDATED

UPDATED: Sep. 7- You can now find structures for the drug candidates disclosed at the symposium in this pdf document.

UPDATED: Aug. 24- Structure of Pfizer drug is incorrect. Will re-post shortly.
2:01:27 PM: Hello, this is Leigh Krietsch Boerner live tweeting from the First-time Disclosure of Clinical Candidate session at #acs_bsoton #acsmedi

2:02:31 PM: First up is David Millan from Pfizer #acs_boston #acsmedi

2:04:11 PM: The name of the drug is PF-03715455

2:04:32 PM: The name of the drug is PF-03715455 #acs_boston #acsmedi

2:05:51 PM: It’s used to treat chronic obstructive pulmonary disease (COPD), which affects 30 million people worldwide #acs_boston #acsmedi

2:07:41 PM: It’s a p38 inhibitor, which is expressed and activated in the lungs of COPD patients #acs_boston #acsmedi

2:33:35 PM: Structure of Pf-03715455 #acs_boston #acsmedi

2:34:39 PM: Next up is Michael Sofia from Pharmasset, Inc. #acs_boston #acsmedi

2:35:29 PM: The name of the drugs are PSI-352938 and PSI-353661 #acs_boston #acsmedi

2:36:14 PM: It’s to treat Hepatitis C, or HCV, which affects 180 million people worldwide. #acs_boston #acsmedi

2:48:51 PM: The target is NS5B-RdRP, which is part of the RNA genome of the HCV virus #acs_boston #acsmedi

3:07:11 PM: Both drugs are 2′-alpha-F, 2′-beta-C-methyl nucleoside class #acs_bsoton, #acsmedi

3:09:44 PM: PSI-352938 is in phase 1b clinical trials, PSI-353661 entering phase 1 #acs_boston #acsmedi

3:10:18 PM: Next up is Dr. Orn Almarsson #acs_boston, #acsmedi

3:11:54 PM: He is from Alkermes, which is a biotechnology company #acs_boston #acsmedi

3:13:07 PM: They are working towards treatments for reward/impulse control disorders ie substance abuse, binge eating, etc #acs_boston #acsmedi

3:14:35 PM: Target is opiod modulation #acs_boston #acsmedi

3:16:05 PM: Will discuss ALKS 33 #acs_boston #scsmedi

3:27:26 PM: Attenuates dopamine release in the NAc shell stimulated by ethanol, AMPH and cocaine #acs_boston #acsmedi

3:27:55 PM: Range from phase 1 studies to phase 2/3 #acs_boston #acsmedi

3:31:52 PM: Phase 2/3 is in alcohol dependance adaptive trial. #acs_boston #acsmedi

3:32:55 PM: Partial kappa-opiod agonist, partial delta-opiod agonist/antagonist, potent mu-opiod antagonist #acs_boston #acsmedi

3:33:53 PM: Next talk is Vincent Mascitti, discovery of nes class of SGLT2 inhibitors, from Pfizer #acs_boston #acsmedi

3:34:34 PM: Phase 2, bridged ketal series, dioxa-bicyclo[3.2.1]octane motif #acs_boston #acsmedi

3:35:19 PM: SGLT2 is sodium glucose co-transporter 2 to treat type 2 diabetes #acs_boston #acsmedi

3:37:09 PM: for review of natural product synthesis, see Washburn, W.N. J Med Chem 2009 52, 1785 #acs_boston #acsmedi

3:50:59 PM: Another paper on these molecules is V. Mascitti & C. Prville Org Lett, 2010, 12 (13), pp 2940–2943 http://bit.ly/bvdHNS #acs_boston #acsmedi

3:59:59 PM: Last talk of the session is Paul Watson from Inspire Pharmaceuticals, Inc. #acs_boston #acsmedi

4:01:01 PM: The drug is INS115644 (latrunculin B) #acs_boston #acsmedi

4:01:36 PM: It’s to treat glaucoma, which is an optic neuropathy that can cause vision loss. #acs_boston #acsmedi

4:07:54 PM: Target inhibitors of actomyosin contractilily and inhibitors of microfilament assembly #acs_boston #acsmedi

4:10:30 PM: Naturally found latrunculin B is an actin plolymerication inhibitor, found in the red sea sponge #acs_boston #acsmedi

4:11:48 PM: That is actin polymerization inhibitor…#acs_boston #acsmedi

4:23:49 PM: Drug has gone through phase 1 clinical trials for proof of concept. #acs_boston #acsmedi

4:28:32 PM: That concludes the session.

Follow @LeighJKBoerner 8/22 For New Drug Info #acs_boston #acsmedi

Don’t forget- this Sunday, August 22, from 2PM to 4PM Eastern, Leigh Boerner (of Just Another Electron Pusher) will be tweeting from the ACS Meeting’s medicinal chemistry session on “First Time Disclosures of New Drug Candidates“.

In San Francisco, Paul Docherty of Totally Synthetic was kind enough to promote my tweets from this session. Time, unfortunately, got away from me this time around. So I neglected to ask him the favor again. Instead, I’m going the last-minute route and sending a trackback to his blog. If you’re visiting from TotSyn, welcome! And I hope you find information that’s useful to you here.

Follow Leigh on Twitter (@LeighJKBoerner) or here on The Haystack for updates on structures, targets, etc. I’m also adding Leigh’s tweets to my FriendFeed for viewing from there.