Zafgen Inc.

Discussion in 'Men's Economics' started by Michael Scally MD, Sep 5, 2011.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen Inc.
    Zafgen - Dedicated to the Treatment of Obesity

    [Note: They are PRIVATE.!]

    At Zafgen, we are dedicated to developing novel therapeutics to treat obesity, one of the most critical and widespread health issues, affecting more than 400 million people worldwide. Rates of obesity in developing countries have tripled in the last 20 years, and American obesity rates are the highest in the world:

    Zafgen is the world’s first biopharmaceutical company dedicated to developing novel obesity therapeutics that directly target and shrink fat tissue to help the body regain and sustain a lean, healthy state. Adipose tissue (fat) in obese subjects expands because of an imbalance between fat storage and fat being converted to various other forms of readily utilizable energy, such as ketone bodies. Fat tissue loses its sensitivity to normal control mechanisms that stimulate fat release, and the liver loses its responsiveness to circulating fatty acids and cannot stimulate formation of ketone bodies. Instead, the circulating fatty acids are repackaged by the liver and are returned to the adipose tissue for storage. Consequently, dietary fats are sequestered in the growing fat tissue, and are unavailable to the body as fuel. The nature of the tissue and the interplay between fat cells and hormones plays a critical and active role in determining the overall size of the fat tissue, and therefore, an individual’s weight.

    Zafgen’s groundbreaking approach targets obesity at its biological foundation by safely manipulating and restoring sensitivity of the fat tissue to natural control mechanisms, driving the loss of fat and a return to a more healthy body weight. For more information regarding Zafgen's groundbreaking technology, click here.

    Zafgen is continuing to explore these remarkable insights and their potential application to a breakthrough treatment for obesity and associated co-morbidities. Substantial proof-of-concept data has been demonstrated in recognized, gold-standard animal models of obesity, and our lead molecules are currently being advanced toward clinical testing.

    [​IMG]

    At such low doses, says Thomas E. Hughes, president and chief executive officer of Zafgen, toxicity concerns tend to evaporate, in part because so little opportunity exists to inhibit off-target proteins. Zafgen, a small pharmaceutical company in Cambridge, Mass., sees high selectivity and low toxicity with its covalent molecule for treating obesity, beloranib hemioxalate, also known as ZGN-433.

    “You’re passing a wave of the molecule through the body,” he says. “It hits the different tissues, silences the target enzyme where it finds it, and then it goes away.”

    Zafgen’s drug candidate inhibits an enzyme called methionine aminopeptidase 2 (MetAP2), which had been of interest in oncology circles until it turned out to be a poor target for treating cancer in mice. However, animals treated with a MetAP2 inhibitor lost weight. Zafgen pursued the enzyme as a target for obesity.

    Its drug candidate contains a spiroepoxide that bonds with a histidine in the protein’s active site. ZGN-433 has undergone a Phase I clinical trial, in which obese volunteers lost up to 2 lb per week. It will enter Phase II trials within a year, Hughes says, funded by $33 million the company raised from investors.

    With dosing of up to 2 mg twice per week, ZGN-433 reaches a maximum concentration in the body of just a few nanomolar for several hours before the body quickly eliminates it, Hughes says. During that time, the drug is much more likely to interact with MetAP2 than with anything else.

    “You’re flying under the radar of a lot of concerns,” he says. “Drug-drug interactions are not an issue. There’s just not enough inhibitor to go around. The same is true for off-target inhibition: The chance of off-target toxicity is largely gone.”
     

    Attached Files:

    Last edited: Aug 23, 2013
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov 2010;9(2):107-15. http://ki.se/content/1/c6/02/52/20/nrd3055-1.pdf

    Current pharmacotherapeutic options for treating obesity and related metabolic disorders remain limited and ineffective. Emerging evidence shows that modulators of angiogenesis affect the expansion and metabolism of fat mass by regulating the growth and remodelling of the adipose tissue vasculature. Pharmacological manipulation of adipose tissue neovascularization by angiogenic stimulators and inhibitors might therefore offer a novel therapeutic option for the treatment of obesity and related metabolic disorders. This Perspective discusses recent progress in understanding the molecular mechanisms that control adipose tissue angiogenesis and in defining potential new vascular targets and approaches for the treatment of this group of diseases.
     
  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Beloranib A Novel Methionine Aminopeptidase 2 (MetAP2) Inhibitor Appeared Safe and Showed Dose Responsive Weight Loss [~10 kg (22 pounds)] Over 12 Weeks in Interim Analysis of Ongoing Phase 2 Trial
    ADA 2013


    Beloranib is a MetAP2 inhibitor that increases fatty acid oxidation and reduces hunger. Previous proof of concept studies over 4 weeks showed ~4% weight loss with 1-3 mg subcutaneous (SC) beloranib in obese women. This is a double-blind placebo-controlled study to investigate the safety/tolerability PK/PD and metabolic effects of SC beloranib.

    Obese men and women were randomized to 0.6 (n=37) 1.2 (n=36) or 2.4 mg (n=34) of SC beloranib vs. placebo (N=38) twice-weekly for 12wks. Body weight (BW) sense of hunger and cardiometabolic biomarkers were measured. Results are based on pre-specified interim analysis of first 19 patients who completed 12 weeks of treatment duration (n=5 6 3 and 5 for 0.6 1.2 2.4mg and placebo respectively). Patients were white females (mean age 40.3 yr BW 101.2 kg and BMI 37.9 kg/m2).

    The most common adverse events (AEs) with higher incidence during beloranib treatment were sleep disturbance nausea and vomiting (resulting in 2 drop-outs from the 2.4 mg group). There were no severe AEs serious AEs or deaths. There were no clinically significant abnormal laboratory measures vitals or ECG findings.

    After 12wks subjects on 0.6 1.2 or 2.4mg lost an average (±SEM) BW of -3.8±0.8 -6.1±1.5 and -9.9±2.3 kg vs. +1.8±0.4 kg for placebo (all p<0.005 vs. placebo). Hunger LDL-c TG and hs-CRP decreased in the beloranib groups vs. placebo.

    Beloranib treatment for 12wks was generally well-tolerated by SC administration resulted in rapid and sustained clinically meaningful BW loss of up to ~10% improved sense of hunger and cardiometabolic risk markers in this interim analysis of an ongoing Phase 2 study which is scheduled to be completed by May 2013.
     
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    New entrant in obesity drug race targets body, not the mind
    New entrant in obesity drug race targets body, not the mind | Reuters

    * Zafgen's drug designed to make body produce less fat, burn excess
    * Trials show privately owned company's approach may give it an edge
    * Safety profile also appears better than current treatments
    * Drug still years away from hitting the market
     
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen Announces New Weight Loss and Safety Data from Phase 2 Study of Beloranib in Obesity - Final Study Results Demonstrate Treatment with Beloranib Led to Significant Weight Loss and Improvements in Multiple Cardiometabolic Risk Factors in 147 Obese Subjects.
    Zafgen Announces New Weight Loss and Safety Data from Phase 2 Study of... -- ATLANTA, Nov. 15, 2013 /PRNewswire/ --

    Beloranib A Novel Methionine Aminopeptidase 2 (MetAP2) Inhibitor. Beloranib, a novel obesity therapy that utilizes a unique mechanism of action, is being studied for its ability to reduce body weight and improve cardiometabolic risk factors in obese patients.

    The study presented was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of a dose range of beloranib administered as twice-weekly subcutaneous injections for 12 weeks. The trial enrolled 147 patients, of which 122 completed the study.

    Subjects were mostly obese women with mean age 48.4 years, body weight (BW) 100.9 kg, and body mass index (BMI) 37.6 kg/m2, who were enrolled into one of the four arms of the trial (N=37 in 0.6 mg, 37 in 1.2 mg, 35 in 2.4 mg and 38 in placebo arm).

    Results from this study showed that after 12 weeks of treatment, subjects on 0.6 mg, 1.2 mg, or 2.4 mg of beloranib lost on average (+/- standard error of mean) -5.5 +/- 0.5 kg, -6.9 +/- 0.6 kg, and -10.9 +/- 1.1 kg, respectively vs. -0.4 +/- 0.4 kg for those on placebo (all p<0.0001 vs. placebo).
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Obesity play Zafgen files for IPO
    Obesity play Zafgen files for IPO - BioCentury.com

    Zafgen Inc. (Cambridge, Mass.) [http://www.zafgen.com/] filed to raise up to $86.3 million in an IPO on NASDAQ underwritten by Leerink; Cowen; Canaccord; and JMP Securities. Zafgen is developing beloranib, a subcutaneous formulation of a methionine aminopeptidase 2 (MetAP2) inhibitor. Form S-1

    This year, Zafgen plans to start Phase III testing to treat Prader-Willi syndrome, a severe form of genetic obesity with a prevalence of about 5,000-7,000 people in the U.S. Next half, Zafgen plans to start a Phase IIb trial in severely obese patients.
     
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen priced 6 million shares at $16 in its public debut Wednesday night.https://www.google.com/finance?q=NASDAQ:ZFGN

    Its lead drug beloranib works in the liver to reset or normalize a patient's metabolism. http://www.zafgen.com/

    Obese people, especially those who are morbidly obese, have livers that work overtime converting food into stored fat instead of energy to be burned off by muscle.

    When these obese patients are treated with beloranib, their livers stop making fat and instead start converting food into energy, like the metabolism of a lean person.

    Zafgen isn't really close to advancing beloranib towards an FDA filing for severe obesity. Another phase II study and large phase III studies still need to be conducted.

    However (and this is important) Zafgen is also developing the drug as a treatment for Prader-Willi Syndrome (PWS), a rare genetic disorder which causes patients to become obsessed with food and eating.

    PWS patients have enormous appetites, and to prevent them from literally eating themselves to death, they have to be monitored constantly.
     
  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Kim DD, Krishnarajah J, Lillioja S, de Looze F, Marjason J, et al. Efficacy and Safety of Beloranib for Weight Loss in Obese Adults: A Randomized Controlled Trial. Diabetes, Obesity and Metabolism. http://onlinelibrary.wiley.com/doi/10.1111/dom.12457/abstract

    Aim 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.

    Methods This Phase 2, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2, and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily White females) with obesity. No diet or exercise advice was administered.

    Results At Week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6, and -10.9 ± 1.1 kg for the 0.6, 1.2, and 2.4 mg beloranib doses, compared to -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs. placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, hsCRP, and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than placebo; these were generally mild to moderate, transient, and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib.

    Conclusions In this 12-week Phase 2 study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe and the 0.6 and 1.2 mg doses were generally well tolerated; the 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.
     
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen Issues Statement
    http://finance.yahoo.com/news/zafgen-issues-statement-160001458.html


    BOSTON, Oct. 14, 2015 (GLOBE NEWSWIRE) -- Zafgen, Inc. (ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, today issued the following statement:

    "Zafgen recently learned of a patient death which occurred in the Company’s ongoing double-blind, randomized, placebo-controlled Phase 3 bestPWS study of beloranib in Prader-Willi Syndrome, a rare genetic disorder with a high rate of mortality linked to obesity and its co-morbidities. The cause of death remains unknown at this time. According to normal practice, the event was reported to the U.S. Food and Drug Administration, at which point the Agency initiated a discussion with the Company. The Company is working with the Agency to expedite a review and understanding of this event, and to determine implications of the event on the conduct of the trial, and anticipates providing an update as its discussions with the Agency progress. The thoughts of the Company are with the family of the patient at this time. Zafgen remains committed to ensuring the safety of all patients enrolled in its studies.”
     
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    ZAFGEN ANNOUNCES PARTIAL CLINICAL HOLD AFFECTING BELORANIB TRIALS
    http://ir.zafgen.com/releasedetail.cfm?ReleaseID=936982

    INVESTOR CONFERENCE CALL TODAY, OCTOBER 16TH, AT 8:30 A.M. E.T.

    BOSTON, Oct. 16, 2015 (GLOBE NEWSWIRE) -- Zafgen, Inc. (Nasdaq:ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, today announced that it received verbal notice late yesterday from the U.S. Food and Drug Administration (FDA) that beloranib has been placed on partial clinical hold.

    This partial clinical hold impacts ongoing or planned clinical trials, including ZAF-311 and ZAF-312.

    A partial clinical hold is an order that the FDA issues to delay or suspend part of a sponsor's clinical work requested under its investigational new drug (IND) application.

    As previously reported, Zafgen learned of a death in the ongoing Phase 3 bestPWS study (ZAF-311) of beloranib in Prader-Willi Syndrome (PWS).

    While the cause of death remains unknown, the patient's treatment assignment has been unblinded and it is now known that the patient was receiving beloranib.

    Due to previously reported thromboembolic events in ongoing and prior clinical trials of beloranib and the unknown nature of the death, the FDA gave verbal notice of a partial clinical hold to institute measures to ensure patient safety.

    Patients currently participating in the ZAF-311 study will be screened for existing thrombotic disease prior to receiving further study drug and regularly monitored through the completion of the study.

    Given that the study is near complete, at this time, the Company expects to report top-line results in the first quarter of 2016. Similar screening and monitoring is being considered for the ongoing Phase 2b study (ZAF-203) in patients with severe obesity complicated by type 2 diabetes.

    The Company now anticipates that the PWS Phase 3 clinical trial, ZAF-312, will be initiated after ZAF-311 is completed and a full assessment of the safety and efficacy of beloranib is performed by the FDA.
     
  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    ZAFGEN ANNOUNCES BELORANIB PROGRAM UPDATE
    http://ir.zafgen.com/releasedetail.cfm?ReleaseID=937850

    BOSTON, Oct. 22, 2015 (GLOBE NEWSWIRE) -- Zafgen, Inc. (Nasdaq:ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, today announced a clinical update for beloranib, the Company's lead MetAP2 inhibitor product candidate.

    After review of its ongoing clinical trials, the Company has elected to proceed with efficacy and safety data analysis and close the randomized portion of its Phase 3 ZAF-311 clinical trial of beloranib in patients with Prader-Willi syndrome (PWS) and its ZAF-203 Phase 2b clinical trial of beloranib in patients with severe obesity complicated by type 2 diabetes. Zafgen believes that a sufficient number of patients have completed randomized treatment in both clinical trials to assess the efficacy of beloranib and help inform next steps for the beloranib program. Following the partial clinical hold announced last week, the Company believes it can best preserve the integrity of the data in each clinical trial by closing the randomized portion of the clinical trials early. The Company, based on consultation with the U.S. Food and Drug Administration (FDA), expects ZAF-311 to remain a pivotal clinical trial. The Company expects to report top-line results from both the ZAF-311 and ZAF-203 clinical trials in the first quarter of 2016.

    Zafgen will continue the six-month open label extension (OLE) of the ZAF-311 clinical trial in PWS to obtain important ongoing efficacy and safety data. As previously planned, the Company is continuing to offer an open-ended, unblinded extension study after patients have completed six months of OLE.

    In consultation with the FDA, a full assessment of the safety and efficacy data from ZAF-311 will be performed to inform the design of ZAF-312, the Company's second PWS Phase 3 clinical trial. The FDA has informed the Company that it will review the ZAF-311 clinical trial results on the basis of an abbreviated data package.
     
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen Provides Clinical [2ND DEATH] Update on Beloranib
    http://ir.zafgen.com/releasedetail.cfm?ReleaseID=945102

    On December 1, 2015, the Company learned that a patient receiving beloranib as part of the open label extension (OLE) portion of the study was diagnosed with bilateral pulmonary emboli and has died.

    Six weeks after Zafgen ($ZAFG) finally broke an uncomfortable silence and acknowledged that a patient taking its experimental obesity drug beloranib had died, the company is reporting that a second patient has died--this time from bilateral pulmonary emboli.

    Boston-based Zafgen has been probing the death of the first patient, trying to determine what triggered that death, which prompted the FDA to place a partial hold on the study. The company said earlier it would start screening patients for thromboembolic events (blood clotting), which has afflicted patients in earlier studies. The study enrolled patients suffering from a rare eating disorder known as Prader-Willi syndrome, which can be lethal.

    The biotech maintained an awkward, stony silence in early October as rumors about trouble in the pipeline spread after execs at the biotech suddenly canceled a planned roadshow with investors. Only days after its stock plunged did the company finally admit that a patient taking beloranib had died, leaving Zafgen under a cloud of suspicion on a safety issue, which can be particularly troublesome for an obesity drug.

    Beloranib inhibits MetAP2, an enzyme involved in metabolism. Zafgen had attracted considerable attention for its effort, which aimed at coming up with a therapeutic that could have the same profound impact as gastric bypass surgery. The company has reported dramatic weight loss among patients taking the drug, but faces a high hurdle on safety if it expects to gain regulatory approval.
     
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen’s Epoxide Adventure [2012]
    http://blogs.sciencemag.org/pipeline/archives/2012/10/17/zafgens_epoxide_adventure

    Zafgen is a startup in the Boston area that’s working on a novel weight-loss drug called beloranib. Their initial idea was that they were inhibiting angiogenesis in adipose tissue, through inhibition of methionine aminopeptidase-2. But closer study showed that while the compound was indeed causing significant weight loss in animal models, it wasn’t through that mechanism. Blood vessel formation wasn’t affected, but the current thinking is that Met-AP2 inhibition is affecting fatty acid synthesis and causing more usage of lipid stores.

    But when they say “novel”, they do mean it. Behold one of the more unlikely-looking drugs to make it through Phase I:

    [​IMG]

    Natural-product experts in the audience might experience a flash of recognition. That’s a derivative of fumagillin, a compound from Aspergillus that’s been kicking around for many years now. And its structure brings up a larger point about reactive groups in drug molecules, the kind that form covalent bonds with their targets.

    I wrote about covalent drugs here a few years ago, and the entire concept has been making a comeback. (If anyone was unsure about that, Celgene’s purchase of Avila was the convincer). Those links address the usual pros and cons of the idea: on the plus side, slow off rates are often beneficial in drug mechanisms, and you don’t get much slower than covalency. On the minus side, you have to worry about selectivity even more, since you really don’t want to go labeling across the living proteome. You have the mechanisms of the off-target proteins to worry about once you shut them down, and you also have the ever-present fear of setting off an immune response if the tagged protein ends up looking sufficiently alien.

    I’m not aware of any published mechanistic studies of beloranib, but it is surely another one of this class, with those epoxides. (Looks like it’s thought to go after a histidine residue, by analogy to fumagillin’s activity against the same enzyme). But here’s another thing to take in: epoxides are not as bad as most people think they are. We organic chemists see them and think that they’re just vibrating with reactivity, but as electrophiles, they’re not as hot as they look.

    That’s been demonstrated by several papers from the Cravatt labs at Scripps. (He still is at Scripps, right? You need a scorecard these days). In this work, they showed that some simple epoxides, when exposed to entire proteomes, really didn’t label many targets at all compared to the other electrophiles on their list. Andhere, in an earlier paper, they looked at fumagillin-inspired spiroexpoxide probes specifically, and found an inhibitor of phosphoglycerate mutase 1. But a follow-up SAR study of that structure showed that it was very picky indeed – you had to have everything lined up right for the epoxide to react, and very close analogs had no effect. Taken together, the strong implication is that epoxides can be quite selective, and thus can be drugs. You still want to be careful, because the toxicology literature is still rather vocal on the subject, but if you’re in the less reactive/more structurally complex/more selective part of that compound space, you might be OK. We’ll see if Zafgen is.
     
    Last edited: Dec 2, 2015
  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen Announces Beloranib IND Placed on Complete Clinical Hold
    http://finance.yahoo.com/news/zafgen-announces-beloranib-ind-placed-002505350.html

    BOSTON, Dec. 02, 2015 (GLOBE NEWSWIRE) -- Zafgen, Inc. (ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, today received verbal notice from the U.S. Food and Drug Administration (FDA) that its beloranib investigational new drug (IND) application has been placed on complete clinical hold, affecting the ongoing open label extension (OLE) portion of the pivotal Phase 3 ZAF-311 bestPWS clinical trial in patients with Prader-Willi syndrome (PWS). A complete clinical hold is an order that the FDA issues to a sponsor to suspend all clinical work requested under the Company’s IND application.
     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Zafgen's Pivotal Phase 3 Trial of Beloranib in Prader-Willi Syndrome Achieves Co-Primary Efficacy Endpoints
    Zafgen's Pivotal Phase 3 Trial of Beloranib in Prader-Willi Syndrome Achieves Co-Primary Efficacy Endpoints


    Note: On December 2, 2015, the Food and Drug Administration (FDA) notified Zafgen that the beloranib investigational new drug (IND) application had been placed on complete clinical hold due to an imbalance in severe venous thromboembolic events, including two patient deaths. In order to address the clinical hold, Zafgen plans to present to the FDA the efficacy and safety data from the bestPWS ZAF-311 study, data from the Phase 2b trial of beloranib in severe obesity complicated by type 2 diabetes, ZAF-203, expected later this quarter, and a proposal for a risk mitigation strategy for beloranib in PWS.
     
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Lose Weight But Die] Zafgen's Phase 2b Trial of Beloranib in Severe Obesity Complicated by Type 2 Diabetes Achieves Primary Efficacy Endpoint
    Zafgen's Phase 2b Trial of Beloranib in Severe Obesity Complicated by Type 2 Diabetes Achieves Primary Efficacy Endpoint (NASDAQ:ZFGN)

    Zafgen has rolled out a fresh set of upbeat efficacy data for its obesity drug beloranib, trumpeting evidence of significant weight loss among diabetics while taking a much more low key approach to pointing to fresh evidence of the safety issues that forced the FDA to halt all use of the drug.

    Zafgen's 1.8 mg and 1.2 mg doses of beloranib in the Phase IIb study triggered a 12.7% and 13.5% drop in body weight, compared with a 3.1% drop for the placebo arm. And there was an average reduction in HbA1c of 2% for the two drug arms compared to a reduction of 0.6% for placebo.

    That's all to the good for the biotech, which has been bullish about this drug's ability to take off pounds in a way currently marketed therapies can't. But the past three months have been brutal on the company, which initially chose to stay mum about a patient death in their Phase III study for Prader-Willi syndrome which they subsequently determined was caused by a pulmonary embolism. Subsequently another patient taking the drug died, also from a pulmonary embolism, forcing the FDA to order a complete stop to any further dosing.

    The company, though, was far enough along with its two most advanced studies to wrap the trials and report out data. Now Zafgen plans to assemble a risk mitigation plan and take that to the FDA in an attempt to open the door to moving ahead.

    That's going to be a tall order, though, as this latest study offered fresh evidence of the lethal side effects triggered by a drug that's being advanced for both rare diseases as well as big patient populations like diabetes, where the bar on safety is set very high by regulators.

    "In the clinical trial," Zafgen reported today, "there were a total of nine serious adverse events identified in eight patients, one in the 1.8 mg group, six in the 1.2 mg group, and two in the placebo group. As previously disclosed, one of the SAEs was a pulmonary embolism in the 1.2 mg treatment group. During the VTE (venous thromboembolism) screening process that followed the FDA's partial clinical hold of the beloranib IND in October 2015, two additional VTEs were identified in patients in this clinical trial: deep vein thrombosis in a patient who had received 1.8 mg of beloranib, and superficial thrombophlebitis in a patient who had received 1.2 mg of beloranib."
     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    ZAFGEN REFOCUSES RESOURCES ON DEVELOPMENT OF DIFFERENTIATED SECOND-GENERATION METAP2 INHIBITOR ZGN-1061
    Zafgen Refocuses Resources on Development of Differentiated Second-Generation MetAP2 Inhibitor ZGN-1061 (NASDAQ:ZFGN)

    - ZGN-1061 in Phase I Development for Severe and Complicated Obesity Indications-
    - Suspending Development of Beloranib; Implementing Strategic Restructuring to Align Operations with Clinical Development Priorities-
    -Strong Cash Position Sufficient to Fund Operations through Phase 2a Clinical Trials for ZGN-1061-
    -Company to Host Conference Call at 5:00 PM Eastern Time-

    BOSTON, July 19, 2016 (GLOBE NEWSWIRE) -- Zafgen Inc. (NASDAQ:ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, announced today that, following a comprehensive review of its assets and clinical programs, as well as feedback from regulatory authorities, the Company is refocusing its resources on development of a differentiated second-generation MetAP2 inhibitor, ZGN-1061, in severe and complicated obesity.

    "As the leader of the MetAP2 inhibitor field, we have spent many years validating the tremendous potential of this pathway for the treatment of complicated obesity with beloranib, which in multiple clinical trials demonstrated robust reductions in body weight, improvements in glycemic control, and other benefits related to cardiovascular disease risk," said Thomas Hughes, Ph.D., President and Chief Executive Officer of Zafgen. "However, given the heightened complexity and future cost of beloranib development, balanced against the emerging product profile of ZGN-1061, we believe that the long-term opportunity for ZGN-1061 is more robust than for beloranib. Given our deep knowledge of this new and exciting drug class, and our strong cash position, we believe we are well-positioned to advance ZGN-1061 as a potential new treatment for prevalent obesity-related indications."

    The beloranib Investigational New Drug (IND) application was placed on full clinical hold in December 2015 by the U.S. Food and Drug Administration (FDA). To address the clinical hold, Zafgen recently held a Type A meeting with the FDA to discuss the clinical and preclinical data for beloranib as well as a proposed risk mitigation strategy for beloranib in Prader-Willi syndrome (PWS). 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.

    ZGN-1061, like beloranib, is a fumagillin-class MetAP2 inhibitor that was discovered by Zafgen's researchers as part of a multi-year campaign to identify novel compounds that avoided limiting preclinical safety concerns observed with beloranib, including teratogenicity and effects on testicular function. 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.

    Zafgen is currently screening patients to initiate a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment, and currently expects Phase 1 clinical data by the end of the first quarter of 2017. Based on the clinical data demonstrating beloranib's significant effect on body weight and glycemic control in patients with severe obesity complicated by type 2 diabetes, Zafgen plans to focus later-stage development of ZGN-1061 in severe and complicated obesity.

    As part of the strategic restructuring, the Company plans to reorganize its operations to align with its new priorities focused on ZGN-1061 development. Zafgen's workforce is being reduced by approximately 34%, to a total of 31 employees, by December 2016. Zafgen expects the restructuring to result in approximately $4.8 million in reduced annualized workforce expenses once the plan is fully implemented. The Company also expects to incur a non-recurring charge of approximately $2.4 million in the third quarter of 2016 related to the restructuring.