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Roche’s GA101 (obinutuzumab): Engineering an antibody to beat Rituxan

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

Survival rates for people with B-cell driven blood cancers, such as non-Hodgkin’s Lymphoma and chronic lymphocytic leukemia, have vastly improved in the last decade thanks to the introduction of Rituxan, marketed by Biogen Idec and Genentech. But the drug, a chimeric monoclonal antibody targeting CD-20, a protein that sits on the surface of B-cells, has its limitations: not all patients respond at first, and others become resistant to the drug over time.

As a result, companies are tinkering with the sugar molecules that decorate antibodies in hopes of coming up with a drug that binds better to its target and, ultimately, is more effective at battling cancer. At the American Society of Clinical Oncology annual meeting, held earlier this year in Chicago, Roche offered Phase III data showing its glycoengineered antibody GA-101 worked better than Rituxan at delaying the progression of CLL. If all goes well with FDA, the drug could be approved by the end of the year.

BACKGROUND:

Although the CD20 antigen is expressed on both normal and malignant cells, it has proven to be a useful target therapeutically.  Rituximab, ofatumumab and most of the anti-CD20 antibodies in earlier development are Type I monoclonal antibodies, which means that they have good complement-dependent cytotoxicity (CDC) and Ab-dependent cell mediated cytotoxicity (ADCC), but are weak inducers of direct cell death.

In contrast to Type I monoclonal antibodies, next generation monoclonals are increasingly Type II, such as GA101 (obinutuzumab) in CLL and NHL and mogamulizumab (anti-CCR4), for T-cell leukemias and lymphomas.  They have little CDC activity, but are much more effective at inducing ADCC and also direct cell death, at least based on in vitro studies performed to date.

How does glycoengineering make a difference?

Glycoengineering is the term used to refer to manipulation of sugar molecules to improve the binding of monoclonal antibodies with immune effector cells, thereby increasing ADCC.

Obinutuzumab is a very different molecule from rituximab, in that it is a novel compound in its own right (originally developed by scientists at Glycart before being bought by Genentech).  It is not a biosimilar of rituximab.  It is also a glycoengineered molecule designed specifically to improve efficacy through greater affinity to the Fc receptor, thereby increasing ADCC activity.GA101

The overall intent with the development of obinutuzumab was to significantly improve efficacy over rituximab and Type I monoclonal antibodies in B-cell malignancies using glycoengineering techniques.

At the recent ASCO annual meeting, data from a phase III trial was presented to evaluate rituximab or obinutuzumab in combination with the chemotherapy chlorambucil versus chlorambucil alone in newly diagnosed CLL.  Patients elderly and had co-existing co-morbidities, excluding them from standard chemotherapy with fludarabine and cyclophosphamide (FC).

This two part trial sought to compare both combinations to the chemotherapy initially, and then against each other in a head-to-head comparison once the survival data matured in the second phase.  Data from the first phase of the study was reported at this meeting.

What did the results show?

When looking at the response rates, both obinutuzumab and rituximab combinations had a higher overall response rate (ORR) than chemotherapy alone (75.5% and 65.9% vs. 30.2% and 30.0%).  Importantly, the combinations had a great proportion of complete responses (CR) i.e. 22.2% and 8.3% compared to 0% in the chlorambucil arms.

Minimal residual disease (MRD), a measure of the number of leukemia cells remaining in the blood, was 31.1% in the peripheral blood of the obinutuzumab combination compared with 0% in the chemotherapy arm.  Corresponding values in the rituximab and chlorambucil arms were 2.0% and 0%, respectively.

Median progression-free survival (PFS) i.e. the length of time during which people lived without their disease worsening for the obinutuzumab plus chlorambucil arm were impressively higher than chemotherapy alone.  PFS was more than doubled (23 months compared to 10.9 months, HR=0.14, p <.0001) when compared to chlorambucil alone.  The corresponding outcome data for the rituximab combination were 15.7 versus 10.8 months for chlorambucil alone (HR=0.32, p <.0001).

Since ASCO, Roche have announced that the FDA granted Priority Review for obinutuzumab in CLL (in addition to the Breakthrough Designation already received in May, when the company filed a new drug application for obinutuzumab), meaning that the PDUFA date is set as December 20th.  In addition, the Data Monitoring Committee decided that the interim data analysis was sufficient to meet the primary endpoint of the trial, ahead of schedule.  The data confirms that obinutuzumab was superior to rituximab in terms of the disease worsening (PFS).  The full data will be presented at ASH in December, when overall survival data (ie did the patients live longer) may be available.

The adverse event profiles were slightly different between the monoclonal antibodies.  Patients in the obinutuzumab arm experienced more infusion site reactions, and a slightly higher degree of myelosuppression (thrombocytopenia and neutropenia), but lower infection rates.

Overall findings

The study demonstrated that both obinutuzumab and rituximab were more beneficial to elderly patients living with CLL and co-existing medical conditions than chemotherapy alone.  The final head to head analysis of the two combinations will be available once the second stage of the study has mature data.  Based on the progress to date, the signs are very encouraging that the chemical engineering behind the development of obinutuzumab may potentially have produced a superior compound to rituximab for treatment of B-cell malignancies.

Should the mature outcome data show a positive survival advantage in obinutuzumab’s favour over rituximab, we may well see similar glycoengineering techniques applied to other monoclonal antibodies in the near future, potentially leading to further improvement in outcomes.

 

Biotech, Pharma, & VCs Offer Rare Disease Patient Groups Some Advice

Today’s issue examines the surge of interest in rare disease drugs, which in the past few years have attracted significant interest from biotech firms, big pharma, and venture capitalists alike. In addition to exploring the business and policy drivers behind increased investment in orphan drugs, the multi-part story looks at the critical role patient organizations play in drawing attention to rare diseases. As such, it seemed worth highlighting advice from various stakeholders on what patient groups can do to entice drug developers to work on their disease:

Organize yourselves. Find as many patients as possible, and establish a registry that will make it easy for a drug firm to begin a clinical trial. “Beginning to identify people, getting them into a registry, and collecting natural history data is one of the most valuable things a developer can have when they’re thinking about a program,” says Genzyme’s CEO David Meeker. “Among the most helful things that patient advocates can do is to help us to understand the natural history of disease,” agrees Kevin Lee, CSO of Pfizer’s rare disease unit. “Without that understanding of how the disease progresses, and what the endpoints can be, its almost impossible to do drug development.”

–Find a way to collaborate with one another. In even the smallest of diseases, patient groups tend to proliferate. And while its natural and understandable for advocates to want to do all they can to help their own child or family member, it can lead to duplicative efforts. The disparate groups can also make it tougher for drug developers to access. “We all need to give everybody a lot of space here to do what they think is best, but in an optimal world, there are tremendous advantages to being coordinated,” Meeker says.

Be connectors. Patient organizations have the amazing ability to bring together academics who had previous not collaborated. “What I have found over and over again is that patient advocates know the investigators in their field far better than the investigators themselves do,” says Christopher Austin, director of NIH’s National Center for Advancing Translational Science (NCATS). “They can be instrumental there.”

Get the right researchers interested. Often only a handful of academic researchers are working on a given rare disease, and drug developers say attracting new scientists into the field, while also giving careful consideration about who to fund is key. Patient groups should look for someone who can use advocacy funds to attract larger grants. “If they can get some grant support, you’ll get more done,” says Emil Kakkis, CEO of Ultragenyx. “If they can’t get any grant support, you’ll have to wonder if it was just because the disease is rare, or another reason.”

Don’t cut corners. As more patient groups directly fund and organize natural history studies and early clinical trials, they need to make sure the work they support is of the same caliber as that done by biotechs or pharma. “Every data point they generate may some day be helpful in getting a drug approved,” says Philip Reilly, venture partner at Third Rock Ventures.

Take the reins. With the passage of FDASIA last year, FDA committed to allowing patients more of a seat at the table during regulatory discussions. But the role patient groups will play—how they will be allowed to particulate and how much influence they have—is still to be determined. Ritu Baral, analyst at Canaccord Genuity, thinks there’s opportunity in that vagueness. “Give an inch, take a mile. If they’re going to define it, then we can define it as a patient group,” Baral, who also sits on the board of a disease foundation, says. “We can set the markers where we want to set them.”

Help drug developers understand your needs. Drug companies are partnering with patient organizations earlier on in the drug process than in the past, convening patient advisory boards to understand how best to design a clinical trial, says Amy Waterhouse, vice president of regulatory affairs at Biomarin. That design ins’t just about regulatory practicalities, but about what families need out of the design in order to participate—a three day visit to a hospital instead of four, for example, can make all the difference. “We learn so much from discussions [with patient groups] that we wouldn’t get from the literature,” Waterhouse says.

 

 

 

 

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead.
NOLAblog-program
1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go!
2:29PM
IMG_3813
BMS-906024
Company: Bristol-Myers Squibb
Meant to treat: cancers including breast, lung, colon, and leukemia
Mode of action: pan-Notch inhibitor
Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546
Status in the pipeline: Phase I
Relevant documents: WO 2012/129353
3:02PM
IMG_3810
LGX818
Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation
Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E
Mode of action: selective mutant B-RAF kinase inhibitor
Status in the pipeline: Phase Ib/II
Relevant documents: WO 2011/023773 ; WO 2011/025927
3:47PM
IMG_3812
AZD5423
Company: AstraZeneca
Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease
Mode of action: non-steroidal glucocorticoid receptor modulators
Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma.
Status in the pipeline: Phase II
Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568
4:17PM
IMG_3811
Birinapant (formerly known as TL32711)
Company: TetraLogic Pharmaceuticals
Meant to treat: cancer
Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death
Status in the pipeline: Phase II
Relevant documents: US 8,283,372
5:00PM
IMG_3814
MGL-3196 (previously VIA-3196)
Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche
Meant to treat: high cholesterol/high triglycerides
Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver
Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site.
Status in the pipeline: completed Phase I trials
Relevant documents: WO 2007/009913 ; WO 2009/037172

And that’s it, folks! Watch the April 22nd issue of C&EN for more on this session.

New Targets in Advanced Prostate Cancer

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

Much hullabaloo has been in the medical news over the past year over new options for the treatment of metastatic castrate resistant prostate cancer (CRPC). FDA approval for two new drugs, abiraterone acetate (J&J’s Zytiga) and enzalutamide (Astellas/Medivation’s Xtandi), has meant a sharp focus on drugs that target the androgen receptor. But at the the American Society of Clinical Oncology Genitourinary (ASCO GU) symposium, held last month in Orlando, intriguing data on new targets for CRPC emerged.

Zytiga and Xtandi target the androgen receptor (AR) in very different ways, but the overall effect is similar, in that they can effectively reduce the levels of prostatic serum antigen (PSA), which is reactivated in tumors with advanced disease. Zytiga acts high up in the steroidogenic pathway and one side effect associated with monotherapy is the development of mineralcorticosteroid effects, leading to over stimulation of the adrenal glands and hypokalaemia.  This toxicity must therefore managed with concomitant prednisone therapy. Xtandi, meanwhile, more directly targets the androgen receptor, which tends to be amplified in advanced prostate cancer. The drug doesn’t have same effect on cortisol production as Zytiga, and can therefore be taken without steroids.

The androgen receptor isn’t the only valid target in CRPC, however.  Aldo-keto reductase 1C3 (AK1C3), an enzyme that can facilitate androstenedione conversion to testosterone, is also over-expressed in advanced prostate cancer. Several new agents in early development appear to specifically target AK1C3. At ASCO GU, a couple of abstract particularly caught my eye and are worth highlighting here:

1) Bertrand Tombal et al., presented the initial data on Xtandi monotherapy in advanced prostate cancer in the hormone-naive setting, that is prior to CRPC.  Traditionally, Androgen Deprivation Therapy (ADT) is given to patients with high risk disease.  In the US, LHRH antagonists are used first-line, followed by AR antagonists such as bicalutamide, giving a basis for the rationale testing Xtandi, which is a more complete antagonist of the AR than bicalutamide.

In this trial, the single arm design sought to determine whether not enzalutamide would have activity in patients who had not received standard ADT therapy. The waterfall plots in this study (n=67) were impressive. The results showed that:

a) Ninety-three percent of study participants experienced a ≥80% PSA decrease at week 25.

b) Median change in PSA was -99.6% (range -100% to -86.5%).

In other words, most of the men in this trial responded well to Xtandi, suggesting that a randomized trial is well worth pursuing next.

You can read more about the specifics of this new development and what Dr Tombal had to say here.

2) Ramesh Narayanan et al., presented an intriguing poster on a new preclinical compound from GTX Inc that specifically targets AK1C3. The results demonstrated some nice inhibitory activity of AKR1C3, with reduced androgen signaling and CRPC tumour growth. It is important to selectively inhibit C3 and not the C1 and C2 isoforms, since the latter are involved in production of the sex hormones.  Inhibition of C1 and C2 is also counter-productive because it can increase the androgenic signal and deprive ERβ of its ligand. To date, the challenge has been to develop a C3 isoform specific inhibitor, making GTX-560 a compound that may be worthwhile watching out for in the clinic.

Recently, Adeniji et al., (2011) observed that, “AKR1C3 plays a pivotal role in prostate tumor androgen biosynthesis, inhibitors of this enzyme have the potential to be superior to abiraterone acetate, a CYP17/20 hydroxylase/lyase inhibitor.”

Clearly, this is a promising development in CRPC, however, it is early days yet and we will have to wait and see how the clinical trials progress with this new agent.

New developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 2

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

In my last post on The Haystack, we discussed the phase III data from the Abraxane MPACT trial in advanced pancreatic cancer that was presented at the recent ASCO GI meeting in San Francisco. Two other late-stage studies in pancreatic cancer caught my eye—fresh data for AB Science’s kinase inhibitor masitinib and Sanofi’s multidrug pill S1.

Masitinib is an oral tyrosine kinase inhibitor from AB Science that targets KIT, PDGFR, FGFR3 and has shown activity in gastrointestinal stromal tumours (GIST). A different version of the drug (Masivet, Kinavet) is also approved in France and the US for the treatment of a dog mast cell (skin) cancers, which are also known to be KIT-driven.

S1 is multidrug pill from Sanofi and Taiho that consists of tegafur (a prodrug of 5FU), gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. Previous Japanese studies have demonstrated effectiveness of this agent in gastric and colorectal cancers, so a big unaswered question is whether it is effective in pancreatic cancer.

So what was interesting about the latest data at this meeting?

At the ASCO GI conference in 2009, French oncologist Emmanuel Mitry presented data from a small Phase II study of the effect of combining masitinib and Eli Lilly’s Gemzar in advanced pancreatic cancer. The study had just 22 patients, but the median overall survival of 7.1 months in was not a large improvement over what is often seen with the standard of care, Gemzar given alone, or with a combination of Gemzar and Genentech’s Tarceva. Over the years, many combination therapies based on Gemzar have failed to show superiority over single agent therapy. It’s both a high unmet medical need and a high barrier to beat.  Thus, the phase III data for the combination of masitnib and Gemzar was highly anticipated at this year’s ASCO GI meeting.

Gael Deplanque and colleagues compared masitinib plus Gemzar to Gemzar plus placebo.  Although the overall trial results for median overall survival were slightly higher than in the phase II study, they were not significant (7.7 versus 7.0 months, P=0.74; HR=0.90).

Some promising data was observed, however, in a subset of the population identified by a profile of biomarkers that the authors vaguely described as, “a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes.” No other details on the actual genes or biomarkers were was provided, but the subset was described as having an improved MOS to 11.0 months compared to the Gemzar and placebo arm.

They also noted that patients with high pain, who usually do poorly on standard chemotherapy, also saw improvement with the masitinib combination. AB Science might have found a particularly aggressive subset that respond to masitinib, in which case, a biomarker would be useful in selecting those patients most likely to respond, as opposed to a catch-all approach where everyone is treated regardless of the predictive value.

AB Science has asked European regulatory authorities for approval, but the Phase III data will not be sufficient for US approval. The company will need to validate the biomarker panel in a large-scale randomized study, and a new phase III trial is now recruiting patients. The outcome of that study won’t be known for awhile, but the hope is for more insight into how to choose the right patients to respond to masitinib in combination with Gemzar.

The other compound featuring late-stage results in pancreatic cancer was Sanofi’s S1. The compound is interesting, but so far its development has been limited to Asian patients, particularly people of Japanese origin. Studies in caucasians have not seen any benefit over standard 5FU therapy.

Katsuhiko Uesaka, medical deputy director at Shizuoka Cancer Center Hospital in Japan, presented encouraging data for the use of S1 as adjuvant therapy in combination with Gemzar after surgical resection (relevant in stage I-III pancreatic cancer). They compared S1 and Gemzar in a head to head non-inferiority trial (with 385 patients. In the interim analysis reported at this year’s ASCO GI meeting, the hazard ratio for S-1 to Gemzar was 0.56, while the 2-year survival rates were 53% for Gemzar and 70% for S-1. The percentage of serious side effects were similar to previously reported studies with Gemzar and S-1, including fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1).

Overall, the authors concluded that S-1 adjuvant chemotherapy was shown to be as good as, perhaps even better than Gemzar, even suggesting that S-1 could be considered the new standard treatment for resected pancreatic cancer. It should be noted, however, that this data is only applicable to patients of Japanese origin since no caucasian data was included in this analysis.

 

New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

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

The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest.

With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1.

Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma.

At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care.

A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar.

As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.”

However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy.

Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the protective stroma surrounding the tumor, thereby providing better penetration of the tumor.  The phase II data led to a promising 12.2 months improvement in median overall survival.

In general, results from randomized phase III trials tends to be lower than that reported in the smaller studies. This is exactly what happened in the MPACT trial, with the Abraxane combination showing a MOS of 8.7 months versus 6.7 months for Gemzar alone, a highly statistical significant finding (P<0.000015). The hazard ratio (HR) was 0.72, suggesting that the combination gave a 28% reduction in the risk of death versus gemcitabine.

Kindler is eager to use and learn more about the combination and notes that it will be another option for oncologists rather than a new standard of care.

This is encouraging data and met the primary endpoint. Celgene is expected to file for approval for Abraxane in advanced pancreatic adenocarcinoma in the second half of the year. Data on a previously identified biomarker (SPARC expression) was not yet available and is expected to be presented at the annual ASCO meeting in June.  The audience at the GI meeting were clearly expecting survival to be higher in those patients with high SPARC expression, but we will see what happens.

Advanced pancreatic cancer is a particularly devastating disease – the incidence and prevalence are approximately equal, with patients typically having a year of life left.  The symptoms are vague and insidious plus there are no useful screening approaches approved for earlier detection, so the emergence of potential biomarkers for selecting patients most likely to respond to Abraxane or Tarceva in combination with gemcitabine would be a most welcome advance, especially given the toxicities associated with FOLFIRINOX.

 

 

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.

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.”