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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.


Sanofi’s MS Pill Aubagio Wins FDA Approval

Another pill for multiple sclerosis has gotten FDA’s stamp of approval. Sanofi’s Aubagio is expected to hit the market in a few weeks, making it only the second oral drug available to people with MS. Novartis’ MS pill Gilenya, which works by a different mechanism of action than Aubagio, has been on the market for two years.

Aubagio will cost roughly $45,000 a year, strategically priced below the leading MS drugs on the market. As Leerink Swann analyst Seamus Fernandez pointed out today in a note, that puts it at about 6.5% lower than Teva’s Copaxone, 8% less than Biogen Idec’s Avonex, and 28% below the price of Gilenya. “We continue to be surprised by the magnitude of price increases within the MS market overall and view Sanofi’s slight discount as reasonable,” he added.

As we described back in 2009, MS is a problem of an immune system gone awry, with lymphocytes first attacking myelin, the protective sheath on nerve fibers, and eventually breaking down the fibers themselves. The first wave of MS drugs—beta-interferons like Avonex and Copaxone–intercept T-cells to slow down the body’s immune response. But that approach is promiscuous—the beta-interferons also prompt widespread gene expression, and cause flu-like side effects.

The latest wave of MS treatments take a more refined approach to reining in the immune system. Biogen’s Tysabri, for example, blocks alpha-4-beta-1 integrin, which signals immune cells to leave the bloodstream and enter the brain and spinal cord. Gilenya keeps some T-cells out of the bloodstream by binding to sphingosine-1-phosphate receptor, thereby preventing some white blood cells from leaving the lymph nodes. Aubagio, meanwhile, inhibits dihydroorotate dehydrogenase, a critical enzyme in the synthesis of pyrimidine, which activated white blood cells need to survive. Whereas the beta-interferons have a sweeping effect on the immune system, some pathways are maintained with Aubagio’s activity.

Aubagio has a few advantages over Gilenya and Tysabri: namely, it does not carry the same safety risks associated with those drugs (see here and herefor more on that), and is taken orally just once a day.

But Aubagio also has its downsides. On the efficacy front, its milder interaction with the immune system renders it less effective than the more hard-hitting treatments. And it can cause hair loss and birth defects, a serious limitation for women of childbearing age—as Fernandez points out in his note, a large population in the MS community.


Trouble Brewing for New HCV Meds

In a blow to the Hepatitic C drug development arena, Bristol-Myers Squibb last night pulled the plug on BMS-986094, an NS5B inhibitor in mid-stage trials. The decision comes just weeks after the company reported a patient suffered from heart failure during a Phase II study of the compound. Nine patients were eventually hospitalized, with varying symptoms of kidney and heart toxicity, according to BMS’s release (See more coverage by Adam Feuerstein at The Street and by Andrew Pollack at the NYT)

BMS-986094? You might know this molecule better as Inhibitex’s former nucleoside INX-089. The molecule came to BMS through its $2.5 billion purchase of Inhibitex in 2011, as we wrote last year here at the Haystack.

The molecule belongs to a family of new nucleosides with fairly common structural motifs: a central sugar appended to a nitrogen heterocycle (usually purine- or uracil-based) and an elaborate phosphoramidate prodrug. These new drugs’ similarities may also prove to be their Achilles heel – Idenix Pharmaceuticals announced an FDA-requested partial clinical hold on their IDX-184 lead. This cautious approach aims to protect patients; though the drugs are similar, 184’s main structural difference – a thioester-based, slightly more-polar prodrug – seems to be enough to distance it from the cardiac side-effects seen with BMS-986094.

For a fairly in-depth look at the chemistry behind these inhibitors, as well as dozens of other analogues that never made it to prime time, check out US Patent 7,951,789 B2, issued to Idenix just last year.


What Pfizer’s Bapineuzumab Failure Means for Parkinson’s Disease Research

The spectacular—and largely anticipated—failure of the Alzheimer’s treatment bapineuzumab has caused an outpouring of stories questioning what went wrong and what it means about pharma’s approach to R&D. Pfizer, Johnson & Johnson, and Elan, the developers of bapineuzumab, are taking a beating in the press for investing so heavily, not to mention raising the hope of so many patients, in a therapy that had not shown strong signs of efficacy in early trials.

Most stories are focused on the implications for Alzheimer’s research and, more generally, the pharma business model given the hundreds of millions of dollars the three companies sank into bapineuzumab. But news of its failure also resonated in research communities focused on other neurogenerative diseases, like Parkinson’s disease and Huntington’s disease, marked by protein aggregation.

I checked in with Todd Sherer, CEO of the Michael J. Fox Foundation to understand what Parkinson’s researchers might learn from the disappointing data from bapineuzumab. Sherer believes there are scientific and business ramifications of the results, both of which might have a chilling effect on neuroscience research.

From a scientific perspective, some are declaring the failure of bapineuzumab the nail in the coffin of the amyloid hypothesis, the theory that the beta-amyloid, the protein responsible for the plaque coating the brains of people with Alzheimer’s disease, is the primary cause of neuron death in the disease. Bapineuzumab, which blocks beta-amyloid, was one of a handful of treatments to test the hypothesis in the clinic. So far, every drug to reach late-stage trials has failed.

Sherer isn’t convinced bapineuzumab is the nail in the amyloid hypothesis coffin. “Obviously the results are very disappointing given the level of interest and investment that’s been put forward for this therapy,” Sherer says. “I don’ think that the result is a definitive answer to the amyloid hypothesis because there are many different ways to target amyloid aggregation therapeutically.”

Parkinson’s researchers are also trying to learn from the setbacks in Alzheimer’s and apply that to studies of drugs targeting alpha synuclein, the protein that clumps together in the brains of people with Parkinson’s disease. “One of the things that is a learning for us in Parkinson’s is really to try to be as smart and informative as we can be in the early clinical trials,” he says.

In Alzheimer’s, for example, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a collaboration between government, academic, and industry scientists, was formed in 2003 to identify biomarkers that can be used both in the diagnosis of the diseases and in the clinical development of Alzheimer’s drugs. However, Sherer points out that while progress in the ADNI initiative has been promising, it was started too late for many companies, which had already jumped into larger clinical trials of Alzheimer’s therapies.

The Fox Foundation already has a biomarker initiative for Parkinson’s ongoing. The goal is that when the first clinical trial for a vaccine alpha-synuclein, to be led by the Austrian biotech Affiris with support from the non-profit, starts later this year, the tools will be in place to conduct a highly informative study.

On the business side, Sherer worries about the impact of more bad news in Alzheimer’s at a time when many companies are already moving out of drug discovery in many areas of neuroscience. “One of the concerns I have is that investors like big pharma companies and others are already showing a trend towards risk aversion,” Sherer says. “That will just get reinforced by these large trials not succeeding.”

Although basic research is uncovering new therapeutic avenues in diseases like Alzheimer’s and Parkinson’s, companies may decide the bar for understanding the biological relevance for each drug target needs to be set much higher. But when it comes to Parkinson’s disease, he adds, “we are not going to have the luxury of knowing everything about the disease and the biochemical pathways before we need to push forward with therapies.”

One hope Sherer has is that companies will make much of the data from these failed trials available to the research community to try to understand what didn’t work, and what the results really mean. “It’ll be a goldmine of information for other Alzheimer’s trials, but also for other genetic diseases like Parkinson’s disease and Huntington’s disease.”

 


BMS Cuts R&D Jobs

The ax is falling on more pharma R&D jobs. Earlier today, Derek Lowe brought word from readers that research jobs were being cut at Bristol-Myers Squibb. The company just confirmed that “fewer than 100″ positions were being eliminated in the U.S. Here’s the official word from BMS:

“Bristol-Myers Squibb is strategically evolving the company’s Research focus to ensure the delivery of a sustainable, innovative drug pipeline in areas of serious unmet medical need and potential commercial growth.
The Company is aligning and building internal capabilities to support the evolution of its Research focus. In doing so, certain research areas will be streamlined and there will be investment and growth in other areas. This strategic evolution has resulted in job eliminations in the short term to allow longer term investment. This initiative will result in a reduction in employee headcount of fewer than 100 people in an R&D organization of more than 7,000 employees. Impacted employees were notified on August 1, 2012 and transitions will take place within two weeks of this date.”

The company will not confirm whether they are, as Derek’s sources suggest, in the metabolic disease area or limited to New Jersey. If indeed they are all coming out of its N.J. labs, today’s announcement will add to challenging times for the state.  As we wrote last month after Roche announced plans to shutter its Nutley site, costing some 1,000 jobs, the number of drug industry jobs in N.J. fell by 22.4% between 2007 to 2010, according to a report by Battelle and the Biotechnology Industry Organization.


Rigged Reactions: Biocatalysis Meets 13C NMR

When you think of reaction screening, what comes to mind? Most would say LC-MS, the pharma workhorse, which shows changes in molecular polarity, mass, and purity with a single injection. Some reactions provide conversion clues, like evolved light or heat. In rare cases, we can hook up an in-line NMR analysis – proton (1H) usually works best due to its high natural abundance (99.9%).

Please welcome a new screening technique: 13C NMR. How can that work, given the low, low natural abundance of ~1.1% Carbon-13?

Researchers at UT-Southwestern Medical Center have the answer: rig the system. Jamie Rogers and John MacMillan report in JACS ASAP 13C-labeled versions of several common drug fragments, which they use to screen new biocatalyzed reactions.

Biocatalysis = big business for the pharma world. The recent Codexis / Merck partnership for HCV drug boceprevir brought forth an enzyme capable of asymmetric amine oxidation. Directed evolution of an enzyme made sense here, since they knew their target structure, but what if we just want to see if microbes will alter our molecules?

Enter the labeled substrates: the researchers remark that they provide an “unbiased approach to biocatalysis discovery.” They’re not looking to

13C Proof-of-Concept

Credit: JACS | UT-Southwestern, 2012

accelerate a certain reaction per se, but rather searching for any useful modifications using the 13C “detector” readout. One such labeled substrate, N-(13C)methylindole, shows proof-of-concept with their bacterial library, producing two different products (2-oxindole and 3-hydroxyindole) depending on the amount of oxygen dissolved in the broth. NMR autosamplers make reaction monitoring a snap, and in short order, the scientists show biotransformations of ten more indole substrates.

This paper scratches multiple itches for various chem disciplines. Tracking single peaks to test reactions feels spookily close to 31P monitoring of metal-ligand catalysis. Organickers, no strangers to medicinally-relevant indole natural products, now have another stir-and-forget oxidation method. Biochemists will no doubt wish to tinker with each bacterial strain to improve conversion or expand scope. The real question will be how easily we can incorporate 13C labels into aromatic rings and carbon chains, which would greatly increase the overall utility.


J&J Could Score Priority Review Voucher with Bedaquiline NDA

Janssen Research and Development, part of J&J, has asked the FDA to approve bedaquiline, a diarylquinoline to treat multi-drug resistant tuberculosis. If given the green light, bedaquiline would be the first drug with a new mechanism of action to be approved for tuberculosis in over four decades. Janssen points out that the pill would also be the first drug approved for multi-drug resistant TB.

If approved, Johnson & Johnson will score a Priority Review Voucher, an incentive created in 2007 to prompt more R&D in neglected disease. A PRV, given to a company that wins U.S. approval for a new drug for neglected disease, is a coupon good for shaving the review time for another new drug application. The value of that coupon depends on the drug its applied to—in theory, if a drug has lofty sales potential, gaining a few extra months (as we’ve written, it could shorten the FDA’s decision time by anywhere from four to 12 months) could translate into hundreds of millions of dollars.

To date, Novartis has been the only company to be granted a PRV, which it gained through the U.S. approval of the malaria drug Coartem. But that first test of the incentive had some questioning its value, as Novartis cashed in its PRV for a supplemental new drug application for Ilaris, an antibody for auto-inflammatory disorders that brought in just $48 million last year.

So, readers, any thoughts on how J&J might cash in its PRV if granted?

 


#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.

However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.

At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?

An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.

One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.

Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Continue reading →


#ASCO12 Data Digest: Combating Resistance in Lung Cancer

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.

Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.

Today we’ll focus on advances in non-small cell lung cancer (NSCLC). ASCO brought data from several new agents—most notably, Boehringer Ingelheim’s afatinib, AstraZeneca’s selumetinib, and Novartis’ LDK378—as well as new combinations of existing drugs.

First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.

Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.

At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations: Continue reading →


#BIO2012: Pfizer’s academic push by the numbers

The evolution of the model for academic-pharma collaboration has been a topic of much discussion as more companies try to tap into university talent for early-stage research (recent examples of collaborations can be found here and here). Industry observers question whether anything tangible will come out of the efforts (see here for a recent critique), believing the divergent missions and cultural differences of each organization inevitably sidelines these pacts.

Pfizer is making one of the more aggressive pushes through its Centers for Therapeutic Innovation. Under the CTI model, Pfizer has set up labs in research hotbeds like Boston and San Francisco, where, through partnerships with various academic institutions, its scientists work side-by-side with university scientists to discover new biologics-based drugs. This week at BIO, I sat down with Tony Coyle, CTI’s chief scientific officer, to talk about CTI’s progress. A more in-depth look at the CTI model will come in the pages of the magazine, but in the meantime, I wanted to share some facts and figures that came out of our chat:

Number of CTIs formed: Four (San Francisco, San Diego, New York, Boston)

Number of academic centers involved: 20

Number of Pfizer scientists across each of its dedicated labs: roughly 100 (Coyle says about 75% were hired from the outside, coming from biotech, academia, with a few from big pharma)

Number of proposals reviewed in the last year: 400

Percentage of proposals overlapping with internal Pfizer efforts: <5%

Number of proposals funded so far: 23

Number of therapeutic areas being studied: 4 (rare diseases, inflammation, cardiovascular disease, and oncology)

Facts and figures aside, Pfizer is trying to move as quickly as possible given the learning curve of teaming with academia. Coyle said he’s promised his bosses that by the third year of the effort, at least four drugs will be in human studies across multiple therapeutic areas. “We’re well on our way to identifying a number of candidates, and I have no doubt that in the next 18 months, we’ll be in our first patient studies,” he added.

Those numbers could change in 2013, when Pfizer potentially expands its CTI outside the U.S. “Ex-U.S is still our ambition,” Coyle says. “2012 has been a period of ‘lets build the group, get the programs and start executing on the pipeline.’ For 2013, we will be and are looking at opportunities ex-U.S., and have had some pretty good discussions to date externally.”



From The CENtral Science Blogs