Shares of Zafgen Inc. (NASDAQ:ZFGN) more than doubled early and trading was heavy after the Boston-based company reported positive efficacy results from the bestPWS ZAF-311 study of beloranib in patients with Prader-Willi syndrome (PWS).

At Wednesday's closing bell, more than 24 million shares were exchanged, with the stock closing at $10.04 for a gain of $4.42, or 78.7 percent.

Data were reported on 74 patients who completed a six-month randomized treatment period in the double-blind, placebo-controlled pivotal phase III trial and another 27 who completed 75 percent of the randomized portion of the study before dosing was suspended in October 2015 following a participant's death. Six patients discontinued early.

The trial achieved its co-primary efficacy endpoints, with the methionyl aminopeptidase 2 (MetAP2) inhibitor demonstrating a statistically significant reduction in both body weight and hyperphagia-related behaviors.

Treatment with the 2.4-mg and 1.8-mg doses of beloranib resulted in reductions in body weight of 9.45 percent (p<0.0001) and 8.2 percent (p<0.0001), respectively, relative to placebo. Patients in the placebo arm showed an average 4.15 percent weight gain over the treatment period.

Treatment with the 2.4-mg and the 1.8-mg doses of beloranib also resulted in reductions of hyperphagia-related behaviors of 7 units (p=0.0001) and 6.3 units (p=0.0003), respectively, relative to placebo, which was stable during the treatment period, as measured by the Hyperphagia Questionnaire for Clinical Trials, or HQ-CT. The PWS-specific study instrument provides an assessment by caregivers of the food-seeking behaviors exhibited by patients.

Patients in the trial averaged 20 years of age and had an average body mass index of 40 kg/m2 and an average hyperphagia score of 16.9 – consistent with moderate to severe hyperphagia – at the time of randomization. Zafgen said baseline characteristics were balanced across the treatment arms.

In its agreement with the FDA, Zafgen analyzed the data using a mixed model repeated measures, or MMRM, approach to account for the missing endpoint data of patients who did not complete the clinical trial. Results remained statistically significant across a handful of analytic methodologies, according to Dennis Kim, Zafgen's chief medical officer.

Both on a conference call with analysts and in an interview with BioWorld Today, Zafgen CEO Tom Hughes emphasized the findings as "a crucial first step" toward meeting with the FDA to discuss a path forward for the drug in PWS, the rare genetic disorder linked to obesity and its co-morbidities and characterized by feelings of constant hunger. Hughes was careful to emphasize both the clinical significance of the results and the weightiness of the disease.

"Prader-Willi syndrome is a very, very serious, life-threatening, devastating illness," he explained. "There is no treatment available, particularly for the two hallmark features of the disease, which are uncontrolled hunger and profound obesity, which really rob these people of a normal life."

The average life expectancy for patients with PWS is just 32 years, he added.

"This is the first study that allows us to look at efficacy, and we saw a very profound and very robust impact on both of these endpoints, of hyperphagia and obesity," Hughes told BioWorld Today. "This is a really important piece of information that shows we might have an opportunity to really help these patients, which strengthens our resolve to find a path forward and move the drug toward approval."

Although the efficacy results represent "a key deliverable" in requesting a meeting with the FDA, resolution of the clinical hold will be "a process," he acknowledged.


Zafgen had seen a meteoric rise in the obesity space, raising sequentially larger private rounds even when competitors stalled. The company pulled in $86.25 million in its 2014 IPO and $138 million last year in a follow-on offering. (See BioWorld Today, Dec. 5, 2012, Dec. 5, 2013, April 22, 2014, and Jan. 26, 2015.)

Then, in October, a strange two-day drop in the company's stock was followed by a brief statement that a patient death was reported in the bestPWS study. Details were scant, as the cause, initially, was unknown. (See BioWorld Today, Oct. 15, 2015.)

Within days, the FDA imposed a partial clinical hold on two phase III studies of beloranib in PWS patients while Zafgen screened patients for existing thrombotic disease. At the time, Hughes said that "what we can't exclude – and this is the point of this screening and monitoring that we're doing – is there may be some potential interaction between the drug treatment that would unmask some latent predisposition for thrombosis." (See BioWorld Today, Oct. 19, 2015.)

The company subsequently elected to close the randomized portion of bestPWS and a phase IIb trial in Australia, known as ZAF-203, that was evaluating the safety and efficacy of beloranib in obese patients with type 2 diabetes, on the basis that a sufficient number of patients completed randomized treatment in both trials to assess the efficacy of beloranib and inform the next steps for the program.

The other shoe-drop occurred in December, when a second patient death was reported in the open-label extension portion of bestPWS. The cause was reported as bilateral pulmonary emboli. At that point, the FDA placed the beloranib investigational new drug application on complete clinical hold due to an imbalance in severe venous thromboembolic events, including the patient deaths. (See BioWorld Today, Dec. 3, 2015.)

At the time, Leerink Partners LLC analyst Joseph Schwartz wrote that the "silver lining," if it could be called that, was the second patient's elevated risk was identified by Zafgen's heightened screening process and was considered before the patient opted to resume treatment following consultation with family members and a physician.

On Wednesday, Zafgen reported other safety findings. The most common adverse events in bestPWS ZAF-311 were injection site bruising, aggression and hyperphagia, which the company said were generally mild and transient in nature.

Five serious adverse events (SAEs) included aggression (placebo, 2.4 mg beloranib), ankle fracture (placebo), mental status change (1.8 mg beloranib) and pulmonary embolism (1.8 mg beloranib). The company said that many SAEs, especially psychiatric disorders, are associated as background co-morbidities in PWS and that no clinically significant abnormal patterns in laboratory values, vital signs or electrocardiography findings were observed at the end of randomized treatment.

Zafgen officials said they plan to present full safety and efficacy data from the bestPWS trial, including the impact of beloranib treatment on body composition, cardiovascular disease risk markers, metabolic endpoints and quality-of-life measures, at upcoming medical meetings.

The company's top priority, however, is to resolve the clinical hold. Zafgen plans to meet with the FDA "as soon as possible," Hughes said, to present the efficacy and safety data from the bestPWS study, data from the ZAF-203 trial, expected later this quarter, and a proposal for a risk mitigation strategy for beloranib in PWS.

"We're starting to prepare our materials for the FDA now," he added, with the goal of moving swiftly to discussions with the agency once the ZAF-203 data report.


Although beloranib also is envisioned to treat hypothalamic injury-associated obesity and severe and complicated obesity, Zafgen plans to restrict its talks with the FDA to PWS, at least for now.

"It's a large conversation to have to get forward movement on this first indication, so that would be a good, serious and very positive step forward for us," Hughes said. "We'll take on the rest of this discussion in due course."

The company continues to study the mechanisms and incidence of underlying thromboembolic disease in PWS and any potential impact of beloranib on thrombosis as part of its effort to develop a risk mitigation strategy.

"We remain committed to understanding why these events happened and what we can do to ensure patient safety in future trials," Kim told analysts on the company's call, adding that Zafgen is working to gain a better understanding of thrombosis in the PWS setting.

As part of its thrombosis risk mitigation strategy, the company is assessing prophylactic measures that might be adopted for patients. Officials declined to offer specifics but noted that other drugs have been approved, launched and marketed successfully despite their potential to increase the risk of thrombotic events.

"We're working with the best minds in the field and collecting all thoughts around this," Hughes said.

Zafgen also hopes to enlist the support of patient advocates that previously worked for the re-introduction of human growth hormone (HGH) as a treatment for PWS when that therapy was approved but later pulled by the FDA following patient deaths.

"The field learned how to cope with" adverse events associated with HGH, now widely used in PWS, Hughes pointed out. "That experience is a great and very illustrative example of what we hope to have in terms of a partnership with this community. Having a drug that now shows a benefit in these two unsolved issues in Prader-Willi syndrome – uncontrolled hyperphagic behaviors and body weight – provides a first opportunity for a new therapy to be advanced, and we expect that we'll have a very collaborative interaction."

Analysts were optimistic that beloranib could have legs. Leerink Partners LLC analyst Joseph Schwartz called the bestPWS efficacy data "compelling," adding that they "surpassed expectations" despite lower patient numbers and underpowering.

And Cowen and Co. analyst Phil Nadeau characterized the efficacy data as "impressive," noting that hyperphagia-related behaviors in PWS are not controlled by available treatments, including HGH and weight loss drugs.

"While the efficacy data are striking, beloranib's approvability and place in treatment will depend on it demonstrating a positive benefit-risk," he added. "While today's data do not make it clear that the risk-benefit is positive, there seems little question that beloranib's benefits are substantial in a very serious condition that has a short life expectancy and high unmet need. Therefore we are encouraged that there may still be a path to approval of beloranib in Prader-Willi."