Zafgen’s ZGN-433 shows promise for obesity- so what’s it look like?
Jan05

Zafgen’s ZGN-433 shows promise for obesity- so what’s it look like?

Just in time to coincide with January's massive uptick in gym-going, Cambridge, MA startup Zafgen has announced good news about its experimental weight-loss drug for severe obesity. The molecule, ZGN-433, helped a small group of severely obese women (with body mass index of 32-45) lose weight- more so than a placebo. Weight losses varied from person to person, but the midpoints of the range of weight loss results were attention-getting: weight loss of 1 kilogram (2.2 pounds) per week, and 3.1 percent of body weight after 26 days, when the trial concluded. Women taking ZGN-433 in the 24-person study also experienced meaningful changes to their triglyceride levels and levels of LDL cholesterol, the so-called "bad cholesterol". The news spurred coverage at FierceBiotech, Xconomy, and many other news outlets. It's too early to tell whether ZGN-433 will become an FDA-approved weight loss drug. But it's encouraging to see companies still plugging away at the obesity problem even in light of the challenging year obesity drugs had in 2010. And Zafgen's announcement today contains some additional tidbits that point interested medicinal chemists toward the kinds of structures Zafgen might be working on. When we last covered Zafgen, the company had revealed the target of its experimental drugs, methionine aminopeptidase 2. And we learned that in animal studies, Zafgen was using a naturally-occurring molecule as a methionine aminopeptidase 2 blocker- fumagillin, or ZGN-201 in the company's parlance. We knew Zafgen was using another molecule in human trials (that's ZGN-433), but at the time the company didn't disclose the molecule's structure, or the name of the company they licensed the molecule from. In today's announcement, Zafgen unveiled that company's name: ZGN-433 was initially developed at Korea's Chong Kun Dang (CKD) Pharmaceuticals. So I decided to perform a Google Patents search to see what kind of structures CKD has patented. My very cursory search revealed four patents but as you can see below, some of the sample structures in the patents differ quite a bit from fumagillin. Zafgen's president and CEO Thomas Hughes told us that fumagillin's long double bond rich tail is troublesome, and it looks like it's gone in both these possibilities. Images: Zafgen and U.S. Patent Office UPDATED: corrected image...

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Takeda Keeps On Truckin’ With Obesity Drug Research
Dec28

Takeda Keeps On Truckin’ With Obesity Drug Research

This year's additions to the pile of setbacks in the obesity drug arena are enough to make anybody wonder whether big pharma companies will continue to invest in the field (was it already two years ago that Pfizer exited obesity research entirely?!). But news today of a pact between Takeda and Sanford-Burnham Medical Research Institute suggests the Japanese drug maker is in it for the long haul. Takeda's agreement with Florida Hospital and Sanford-Burnham Medical Research Institute creates a partnership to evaluate potential new obesity drug targets. Today's deal is the latest in a string of obesity-related investments for Takeda. Haystack readers may recall that Takeda is Orexigen's partner for the development of Contrave, the weight-loss drug that is awaiting a decision from FDA in the wake of a thumbs-up from the agency's advisory panel. The company also has a stake in peptides from Amylin Pharmaceuticals as potential obesity treatments, and it is conducting clinical development in Japan for Alizyme's lipase blocker cetilistat, a next-generation pill to Xenical (orlistat), the drug sold over-the-counter as alli. Takeda's interest in obesity makes sense given its strong history with type 2 diabetes drugs, a class with close ties to the obesity area. A quick look at Takeda's pipeline is a whirlwind tour of diabetes drug targets, like glucokinase activators and dipeptidyl peptidase-4 inhibitors. The company has also discovered a protein, TGR5, that could be a target for drugs that mimic gastric bypass surgery's ability to control diabetes. And they are behind Actos, the well-known diabetes medication which shares its mechanism of action with Avandia. Unlike Avandia, Actos remains on the market, although FDA is currently investigating its safety. Will Takeda's strategy pay off? Time will tell- beginning with FDA's official decision on Contrave by the end of...

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Haystack 2010 Year-In-Review
Dec17

Haystack 2010 Year-In-Review

This Friday, we're looking back at 2010's big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon's Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen's drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen's Contrave and Vivus's Qnexa are both combinations of already-approved drugs, whereas Arena's Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA's panels didn't always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus' Qnexa. The fact that FDA's panel voted favorably for Orexigen's Contrave, a drug that's thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott's Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn't fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency's formal decision on Contrave. And if you're interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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Good News for Contrave, Qnexa Could Be Next
Dec08

Good News for Contrave, Qnexa Could Be Next

Apparently, third time’s a charm in the obesity drug world. Yesterday afternoon, an FDA advisory panel recommended approving Contrave, an obesity pill being developed by Orexigen Therapeutics and Takeda. The positive vote came just months after two other obesity drugs, Vivus’ Qnexa and Arena Pharmaceutical’s Lorqess, were rejected. There are plenty of caveats to the good news. First, FDA doesn’t always follow the advice of its advisory committees, although most analysts seem confident Contrave will make it onto the market. But Orexigen and Takeda will likely need to conduct a large, post-approval study to track cardiovascular issues, the details of which would be hammered out with FDA. Second, excitement over the next pill for obesity should be tempered with the reality that Contrave has shown only minimal weight loss. Contrave is a combination of two already-approved drugs, the antidepressant buproprion and the addiction treatment naltrexone. All that said, Orexigen stands to collect more money from Takeda if Contrave makes it to the finish line. Takeda paid just $50 million upfront to license the obesity drug, and will take on the lion’s share of the costs of a post-approval study. The thumbs up for Contrave could also be good news for Vivus’ Qnexa, also a combination of two existing drugs (phentermine and topiramate). In July, an FDA advisory committee, concerned about the lack of long-term safety data for the drug, voted against its approval. FDA backed up that decision in October, issuing a complete response letter (its version of a rejection) citing birth defect worries and cardiovascular risks. But yesterday’s panel was mainly focused on the cardiovascular risks associated with Contrave, and Qnexa is a cleaner drug on that front. One panel member, University of California, Davis, neurologist Michael Ragowski, even said he’d rather prescribe Qnexa versus Contrave. Vivus plans to submit a formal response to the CRL later this month, and FDA would provide its feedback in January. If all goes well, Vivus could gain approval for Qnexa in the second half of 2011, analysts say. Investors seemed optimistic on its chances, as Vivus' stock is up over 20% in pre-market trading. Orexigen is holding a conference call at 4:15pm this afternoon, to discuss the panel. If anything interesting comes out of it, we'll be sure to update...

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Orexigen And Takeda’s Contrave To Face FDA’s Panel Tuesday
Dec03

Orexigen And Takeda’s Contrave To Face FDA’s Panel Tuesday

Today FDA released its briefing documents for Orexigen and Takeda's experimental obesity drug Contrave. And they've got more than one news outlet wondering whether the third time will be the charm in the obesity drug race. On Tuesday, FDA's outside advisers will meet to review the potential drug and make recommendations on whether to approve it. You can read our ongoing coverage of Contrave as well as Arena's Lorqess and Vivus's Qnexa, the other two obesity drug candidates FDA reviewed, here. At first glance, the documents don't contain any big surprises in terms of safety or efficacy. And Orexigen's had time to learn from what happened at the Lorqess and Qnexa panel meetings. That said, Adam Feuerstein makes an interesting comparison- to Meridia, Abbott Labs' diet pill that was pulled from the market this fall because of its cardiovascular risks. We've known that Contrave can raise blood pressure, but the memory of Meridia may influence some of FDA's outside experts. Contrave's cardiovascular risk profile somewhat resembles Abbott Lab's Meridia, which was recently pulled off the market after a September advisory panel meeting. Eight of the 10 experts who will be reviewing Contrave Tuesday voted to recommend Meridia's withdrawal from the market due to the drug's cardiovascular risks. These eight experts are the people Orexigen needs to be most worried about Tuesday. An analyst at Rodman & Renshaw in New York had similar concerns in an interview with Bloomberg. “They may have to do a thorough cardiovascular study before approval,” said Elemer Piros, an analyst at Rodman & Renshaw in New York, in a telephone interview today. “The clear precedent is Meridia. It’s so fresh in our minds that I don’t think the FDA wants to embark on a public experiment in an uncontrolled setting without this information.” So if more studies will be needed, it's a good sign that Leerink Swann analysts Joshua Schimmer and Steve Yoo are impressed with Orexigen's long-term safety strategy, according to a note sent to investors. While no FDA panel is without risk and the track record of obesity drugs at the Endocrine Division is unquestionably poor, we have been impressed with OREX's strategic approach to tackling Contrave's safety-issues head on and its rational explanation for a post-approval study commitment. That's important because at least some of what sank Vivus's Qnexa at its FDA advisory panel evaluation was a desire for more long-term data. But at the end of the day, panelists who voted ‘no’ felt like more long-term safety data was in order. From Feuerstein’s liveblog: one of the “no” votes says obesity is a chronic disease, so tell me what happens to...

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GSK Abandons Resveratrol, Focuses on Next Generation Compounds
Dec01

GSK Abandons Resveratrol, Focuses on Next Generation Compounds

GlaxoSmithKline has reportedly abandoned work on SRT501, or resveratrol, the controversial drug based on the ingredient found in red wine that has been said to reverse the aging process. The news came as no real surprise—the company has been quiet about the compound since May, when it halted a clinical trial of the drug in multiple myeloma after cases of kidney failure occurred. (find background on that news and other controversies around the drug here, here, and here.). But confirmation that SRT501 is officially done for is prompting many to wonder about what else Sirtris has up its sleeve—specifically, what exactly is going on with the follow-on compounds it has put in the clinic. The news is also reinvigorating a debate over the value of Sirtris. As you’ll recall, GSK paid $720 million for Sirtris in 2008, and industry folk have been questioning the hefty price tag ever since. Just before Thanksgiving, GSK had a group of reporters into the Sirtris offices to provide an overview of its externalization strategy for R&D. Given the very public debate over the value of its technology, it was an interesting choice of venue. But their offices were spacious, and we got a tour of their labs, which house about 70 people who operate fairly autonomously from the overall GSK operation. I can attest that there were indeed chemists in lab coats makin’ compounds while I was there. The day included a presentation by George Vlasuk, former vice president of metabolic disease and hemophelia research at Wyeth who last year came over to GSK to lead Sirtris. He was brought on to keep pursuing "the dream," of resveratrol, "but do it in a slightly different way," Vlasuk said. Prior to GSK's purchase of Sirtris, "the science, in some regards, didn’t get as fully elaborated as it could have," he acknowledged.  His job was to "make sure the science was solid and we were going down a path you could really develop drugs from. From the presentation, it was clear that work on SRT501 was dead in the water, as the focus of Vlasuk’s talk was squarely on the next set of compounds. Sirtris has developed a library of over 6,000 molecules that turn on SIRT1, the target of resveratrol, that are chemically unrelated to resveratrol, Vlasuk said. The company also recently published a paper on SIRT1 modulation, which can be found here. The first molecules to come out of that work are SRT2104 and SRT2379. Sirtris is wrapping up a series of clinical trials of those compounds and plans to discuss results from those early-stage studies in the first half of next year, he...

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