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From Blog: The Haystack

Heptares solves first X-ray structure of Family B GPCR, but full details not yet public

GPCR family tree

The new structure adds a new section of GPCR space amenable to computer modeling (big blue circle), a space which includes sought-after drug targets. Previously determined GPCR structures, which are all from the same family, are highlighted in small blue and red circles. Image courtesy Heptares

In what might be the year’s biggest molecular teaser, Heptares Therapeutics has announced that it has solved the first X-ray crystal structure of a G-protein coupled receptor in the Family B subclass. The work provides the first structural insights into a protein family that includes sought-after drug targets such as GLP-1 for diabetes and CGRP for migraine.

Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank.

The structure, Weir says, is another success for Heptares’ GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the “off” state.

The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1′s architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. “The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors,” he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation.

“This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away,” says Monash University’s Patrick Sexton, an expert in Family B GPCRs who was at Friday’s talk. The structure, he says, confirmed researchers’ expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. “There was a very open and relatively deep extracellular binding pocket, with the receptor having a ‘V’ shaped appearance,” he says. This open pocket likely contributes to medicinal chemists’ difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests.

That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs’ molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but “it would appear that deleted globular N-terminal domain would fit quite nicely into the open pocket.”

The CRF-1 receptor is a drug target for depression and anxiety, but at least one CRF antagonist failed to show benefit compared to placebo in a clinical trial. Weir says the impact of the CRF-1 structure for drug discovery will not necessarily be in CRF-1 drug discovery per se, but in the ability to develop relevant computer models of related targets.

It hasn’t been possible to make accurate models of Family B receptors with Family A information, explains Ryan G. Coleman, a postdoctoral fellow at UCSF who develops GPCR models, but who was not in attendance at the talks. Quality models could streamline small molecule drug discovery for the entire family, he explains. Most of the natural ligands for Family B receptors are long peptides, which are notoriously tough to replace with small molecule drugs.

Experts like Coleman will have to wait for some time to learn about the structure for themselves, unless they happened to have a friend in the audience at Heptares’ talks. It’s not unheard of for there to be a gap of several months to two years between a structure’s announcement and publication.

“We’re delighted to have such an informative structure,” Weir says. “It’s very exciting.” He adds says Heptares is progressing toward a structure of the biggest fish in family B, GLP-1, in the “on” state.

From Blog: The Haystack

Lilly Diabetes Setbacks Mount

Lilly’s diabetes pipeline is taking its lumps this week, a situation that has all but quashed any notions of earnings growth in coming years.

The first setback came on Tuesday, when FDA issued a complete response letter for Bydureon, a long-acting form of the diabetes treatment Byetta. Lilly and its partner Amylin won’t be able to submit a response to the CRL until late 2011, significantly pushing back the much-needed new revenue stream.

Now, along with today’s third-quarter earnings report, Lilly said teplizumab, an anti-CD3 antibody, had failed Phase III trials in Type 1 diabetes. Although expectations for the treatment were modest, the latest disappointment doesn’t do much for confidence in the company’s pipeline.

Further, the setbacks of Bydureon and teplizumab are not the only challenges to the company’s diabetes portfolio. Last month, in a move that was not entirely surprising, Lilly and Transition Therapeutics dropped development of TT-223, a gastrin analogue that failed to meet its goals in a small study testing the drug in combination with a Lilly GLP-1 analogue in Type 2 diabetes.

Meanwhile, news this week that Pfizer was paying $200 million for Biocon’s biosimilar insulin program caused some to worry that Lilly’s generous slice of the insulin market was at risk.

On a call with analysts this morning, Enrique Conterno, president of Lilly Diabetes, tried to quell investor concerns. Bangalore, India-based Biocon “basically sells when it comes to insulin about 1% of what Eli Lilly sells today,” he noted. Conterno acknowledged that Pfizer could put some heft into the Indian biotech’s commercial infrastructure, but suggested that innovation around delivery devices would differentiate players in diabetes. “Clearly this is something we will watch, but we feel very confident in our ability to be effective with our insulin portfolio,” he added.

But Lilly’s pipeline woes are not limited to diabetes. In August, the company experienced a major blow when it ended development of semagacestat after the compound worsened cognition in people with Alzheimer’s disease. Semagacestat, a gamma secretase inhibitor, had been viewed as a leading contender to be the next big Alzheimer’s drug on the market.

As it stands, Lilly’s profits through 2014 will be driven by what is in its pipeline and efforts to rein in costs. Last fall, the company said it would eliminate 5,500 jobs, and for those keeping track of industry-wide layoffs, today said it was only about halfway through that process and has no immediate plans to expand the cuts. The company is staring down a wave of patent expiries on key products, and with the recent pipeline setbacks, earnings growth is “moving into sharply negative territory from 2012-2015,” Bernstein Research analyst Tim Anderson said in a note to investors today.

As such, Lilly will likely need to buy-in growth. After the Bydureon news, Leerink Swann analyst Seamus Fernandez noted that “the pressure on Lilly to either do a deal and/or partner some of its pipeline products and reduce its cost structure likely will intensify.”

So, dear readers, who are potential M&A candidates? Is there any deal that could even fill this gap?

From Blog: The Haystack

Is Oral Insulin on the Horizon?

The Haystack wanted to point readers to a nice piece on oral delivery strategies for biotherapeutics by our colleague Ann Thayer. An injection or IV drip may be perfectly reasonable for diseases like cancer, where drugs are usually given in a hospital setting, but for chronic diseases like diabetes or multiple sclerosis, which require daily or weekly injections, a pill would be much more palatable. That said, it is awfully tough to get effective oral delivery of a big, unwieldy protein. As Thayer writes, “Acids and enzymes in the gastrointestinal tract will chew up a valuable therapeutic protein as easily as they’ll tear into a bite of steak.

Companies are especially keen to develop alternative delivery solutions for insulin. Not only would it represent a major advance for patients, but the market for a better-acting and easier-to-use insulin would be gigantic—insulin sales account for about $15 billion of the global diabetes market. Attempts at inhaled insulin have been a colossal failure. Thayer goes on to describe some of the methods biotech companies are using to enable oral delivery of insulin. Among the players:

–India’s Biocon is developing IN-105, an insulin molecule conjugated to a short-chain polyethylene glycol derivative. The technology was originally developed at N.C.-based Nobex, which Biocon bought in 2006.

–Ireland’s Merrion Pharmaceuticals is using technology acquired from Elan Corp. to enhance gastrointestinal permeation. In 2008, the company began working with Novo Nordisk on solid oral forms of insulin analogs; the first such analog was put into Phase I trials by Novo in late 2009.

–N.J.-based Emisphere Technologies is working with Novo Nordisk on GLP-1 analogs. In January, Novo started a Phase I trial of the first candidate using Emisphere’s Eligen technology.

–Isreal’s Oramed is using capsules with an enteric coating, which controls where in the intestinal tract a pill is absorbed. A Phase IIb trial of ORMD-0801 conducted in South Africa showed the drug to be safe and to have a clinical impact on insulin and gluose levels. Oramed hopes to do a Phase II study in the U.S. late this year.

–Dallas-based Access Pharmaceuticals is using insulin-containing nanoparticles coated with vitamin B-12 analogs, which pull the complex into circulation.