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Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity

Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a┬áMetAP2 inhibitor that showed remarkable┬áweight loss efficacy both in patients with Prader-Willi Syndrome┬áas well as┬áhypothalamic obesity. Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a┬árisk mitigation strategy. As announced by the company in a press release┬áearlier this week, “Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.” The press release also describes the new compound ZGN-1061 as a, “…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class.┬áLike other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source.┬áZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.” According to the press release, “The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.” Screening of patients for┬áa Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway. @DrSharma Edmonton, AB Disclaimer: I have served as a consultant to Zafgen.


Belanorib: Good Weight Loss Efficacy But Troubling VTE Risk

Yesterday, Zafgen released data from its phase 2b trial of beloranib in patients with severe obesity complicated by type 2 diabetes. Zafgen recently announced that its phase 2b trial (ZAF-203) of the MetAP2 inhibitor beloranib in 152 patients with severe obesity complicated by type 2 diabetes. Accompanying an impressive 12.7 and 13.5% weight loss on 1.8 mg and 1.2 mg beloranib (vs 3.1% for placebo), respectively. Unfortunately, these results are marred by the ongoing concern over potential thrombogenic adverse effects. Thus of the nine serious adverse events identified in eight patients during the trial, one was a pulmonary embolism in the 1.2 mg treatment group. A subsequent screening process (following the FDAÔÇÖs partial clinical hold on the trial) identified silent pulmonay emboli in two additional patients in the beloranib treatment arms. Currently Zafgen is working to better understand the potential mechanisms underlying the apparent thrombogenic risk as well as developing a risk-mitigation strategy (at least for studies in patients with Prader-Willi Syndrome) that would help resolve the complete clinical hold the FDA placed on the beloranib for now. Thus, the future remains uncertain for what would otherwise certainly be a big step forward to fill the continuing gap of more effective medical treatments for obesity. @DrSharma Gurgaon, Haryana Disclaimer: I have received consulting honoraria from Zafgen, the makers of belanorib


MetAP2 Inhibitor Beloranib Produces Weight Loss in “Simple” Obesity

Readers may recall a previous post on the remarkable efficacy of beloranib, a methionine aminopeptidase 2 (MetAP2 ) inhibitor, in patients with hypothalamic obesity. Now, a paper by Dennis Kim and colleagues present the results of a phase II study in individuals with “simple” obesity, published in Diabetes, Obesity and Metabolism. The study included 147 participants with moderate obesity, who were randomised to 0.6, 1.2, and 2.4 mg beloranib or placebo for 12 weeks, with no specific diet or exercise recommendations. At 12 weeks, participants had on average lost between 5.5 and 10.9 Kg in a dose-dependent fashion. This reduction in body weight was associated with relevant improvements in waist circumference, lipids and blood pressure. Adverse effects included dose-dependent increase in sleep latency and mild to moderate gastrointestinal symptoms. Beloranib is an investigational weight loss therapy with a novel mechanism of action. This study assessed the efficacy, safety, and tolerability of beloranib treatment for obesity. This is certainly a most remarkable degree of weight loss seen at 12 weeks and it will be interesting to see the results of the longer-term studies that are currently underway. @DrSharma Edmonton, AB Disclaimer: I have received consulting honararia from Zafgen, the maker of belanorib.


Hope For Hypothalamic Obesity And Beyond?

Hypothalamic obesity, is a rare but serious condition that occurs in about 50% of individuals who have suffered injury to their hypothalamus (e.g. because of a craniopharyngoma or trauma). Severe weight gain in these patients may not be all that surprising given that the hypothalamus plays a key role in the regulation of hunger, satiety and other aspects of energy balance. Now, Zafgen, a US┬ábiopharmaceutical company, announces surprising early results of treating such patients with beloranib,┬áan inhibitor of methionine aminopeptidase 2┬á(MetAP2), an enzyme that modulates the activity of key cellular processes that control metabolism.┬á According to┬áZafgen, their small proof-of-principle trial (ZAF-221), conducted in┬á14 obese patients (nine women and five men) who were confirmed by magnetic resonance imaging (MRI) to have had hypothalamic injury, the results look most promising. Here is the description of their findings taken from their press release: “ZAF-221 was a randomized, double-blind, placebo controlled study of twice-weekly subcutaneous injections of 1.8 mg beloranib or placebo in patients with HIAO to evaluate weight reduction and safety over four weeks, followed by an optional four week open-label extension. Beloranib treatment resulted in mean weight loss of 3.4 kg and 6.2 kg in patients with HIAO after four and eight weeks of treatment with beloranib, respectively, in contrast to 0.3 kg mean weight loss in patients treated with placebo for four weeks (p = 0.01). Improvements in cardiovascular disease risk factors of lipids and inflammation (measured by C-reactive protein) were also observed. Beloranib 1.8 mg was well tolerated in this population, with no serious or severe adverse events reported. Safety measures such as laboratory, electrocardiogram, and vital sign measurements revealed no signals of concern, and all subjects randomized to beloranib completed the trial.” What I find most surprising about these findings, is that this drug appears┬áto work in people where key centres for appetite regulation are no longer intact. This points to the existence of a non-hypothalamic mode of action for this drug – an action that is powerful enough to work independently of the centres in the brain known to┬áplay a key role in energy regulation. The company is also pursuing beloranib┬áfor individuals with Prader-Willi Syndrome, another hypothalamic form of obesity as well as patients with severe obesity. Needless to say, this finding may well also hold promise for other forms of obesity, reason enough to closely watch the further development of this compound. @DrSharma Edmonton, AB Disclaimer: I… Read More »


Obesity Drugs at the ADA

I am currently attending the 72th Scientific Meeting of the American Diabetes Association, here in Philadelphia, where, not surprisingly, obesity is a major topic. While I presented data on the finding that the new phentermine/topiramate combination drug for obesity, currently awaiting approval from the FDA, has the same weight-loss efficacy, irrespective of obesity stage (about 10% at the highest dose for participants with EOSS Stage 1-3), I was also intrigued by the presentation of new findings from Zafgen, the maker of belonarib, a novel antiobesity drug with most interesting properties. In fact, based on early randomised controlled double-blind Phase 1 trials, belonarib appears so effective, that the company is currently focussing on developing this compound specifically for the treatment of severe obesity. Thus, according to the data presented at this meeting, based on the trials that were primarily designed to test safety, tolerability and efficacy of twice-weekly intravenously administered beloranib, the injection of belonarib in severely obese women over just a 25 day period resulted in a mean weight loss of about 4 kg, despite the fact that participans were allowed to eat normally and were not counseled to change their exercise habits. The trial enrolled 34 subjects of which 28 completed the study. In addition to losing weight, the beloranib-treated subjects also showed marked improvements in cardiometabolic risk factors including reduced triglycerides, diastolic blood pressure, and C-reactive protein. The most common adverse events were nausea, infusion site injury and headache. Most events were of mild/moderate intensity and tended to be self-limiting. Beloranib, works through a novel mechanism that targets a methionine aminopeptidase 2 (MetAP2), a key enzyme that controls the production and utilization of fatty acids. In animal studies, inhibitors of MetAP2 reduce the production of new fatty acid molecules by the liver and help to mobilised fat stores. Currently, Zafgen hopes to develoep beloranib as a twice-weekly subcutaneous injection for the treatment of patients with severe obesity. Certainly, a most interesting mode of action and results, which of course now need to be documented in longer-term studies. AMS Philadelphia, PA Disclaimer: I have served as a paid consultant to Vivus and Zafgen, the makers of the compounds discussed in this post.