Novel Drug May Offer Hope in Prader-Willi Syndrome, Obesity

Miriam E Tucker

April 06, 2016

BOSTON — The novel investigational drug beloranib (Zafgen) has produced significant weight loss and reduction of hyperphagia in a phase 3 randomized trial of patients with Prader-Willi syndrome.

The first-in-class injectable small molecule inhibits methionine aminopeptidase 2 (MetAP2), thereby reducing the production of new fatty-acid molecules by the liver and facilitating the conversion of stored fats into energy. It may also have a satiety effect on the hypothalamus.

"Although its primary action isn't in the brain, it does appear to reduce hunger, food uptake, and hyperphagia-related behaviors, with patients losing weight and feeling less hungry," said Merlin G Butler, MD, PhD, professor of psychiatry, behavioral sciences, and pediatrics at the University of Kansas Medical Center, Kansas City.

Dr Butler presented the new data on April 3, 2016 in a late-breaker session at the annual meeting of the Endocrine Society, ENDO 2016.

Prader-Willi syndrome is the most common genetic cause of extreme obesity, affecting about one in 10,000 to 30,000 people. It is characterized by relentless pathologic hunger, leading to dangerous food-seeking behavior and morbid obesity. The annual mortality rate is 1% to 4%, and typically patients don't live past their late 40s. There are no approved treatments for it.

Zafgen is developing beloranib for Prader-Willi syndrome and for general obesity. However, both the phase 3 Prader-Willi syndrome trial and a phase 2 trial in people with severe obesity complicated by type 2 diabetes were halted early following the deaths of two Prader-Willi patients due to pulmonary emboli, one in the randomized trial and the other in an open-label extension, both taking the active drug. And a small number of additional patients from both trials developed nonfatal thrombotic events while on beloranib.

Development of beloranib is now on clinical hold until further data and a risk mitigation strategy can be discussed with the US Food and Drug Administration (FDA), a Zafgen representative told Medscape Medical News.

In an interview, Dr Butler, who chairs the scientific advisory board for the Prader-Willi Syndrome Association in the United States, said that the adverse events might be due to the condition rather than the drug. Thromboembolic events are known to be more common among obese people, and they may be even more so among Prader-Willi syndrome patients, he noted.

"This may be part of the syndrome....The company is investing lots of time and resources trying to find out the natural history of the complications in Prader-Willi. I think it's underreported, but we just don't know."

Asked to comment, session moderator Gary D Hammer, MD, PhD, director of the Endocrine Oncology Program and the Center for Organogenesis at the University of Michigan, Ann Arbor, said: "Prader-Willi is a devastating disease….From my perspective as an endocrinologist, it's exciting to see drugs being developed for rare endocrine disorders and also for the common endocrine disorders."

Dr Hammer called the Prader-Willi syndrome trial results "incredibly promising….However, the unfortunate side effect of increased thromboembolic disease requires detailed science to see how important that is."

Significant Reductions in Weight, Overeating

The trial reported by Dr Butler, bestPWS, was a phase 3, randomized, double-blind, parallel comparison of either 1.8-mg or 2.4-mg beloranib or placebo, all injected twice weekly for 26 weeks. The co–primary end points were change in percent body weight and total score on the 9-item Hyperphagia Questionnaire for Clinical Trial (HQ-CT).

A total 107 Prader-Willi syndrome patients were randomized to the three arms. They had a mean age of about 20 years, a mean body-mass index about 40 kg/m2, and weighed approximately 100 kg. About two-thirds had chromosome 15q deletions.

As expected, the subjects in the placebo group had gained weight at 26 weeks, by an average 4.2%. In contrast, those in the 1.8-mg beloranib group lost 4.1% of their body weight from baseline, while the 2.4-mg group lost 5.3%. Compared with placebo, the differences were -8.2% for the 1.8-mg dose (P < .0001) and -9.5% for the 2.4-mg dose (P < .0001).

The HQ-CT consists of nine questions, scored by caregivers on a scale of 0 to 4 (giving a score range 0–36). Examples include assessments of the degree to which patients "[are] upset when denied food," "up at night to seek food," "steal food," and whether the condition "interferes with activities." Patients in the trial all had HQ-CT scores greater than 12 at baseline.

Total HQ-CT score remained stable in the placebo group (-0.4 at 26 weeks). In contrast, it dropped by 6.7 with 1.8-mg beloranib and by 7.4 with the 2.4-mg dose, both significant differences compared with placebo (P = .0003 and .0001, respectively).

Among the secondary end points, the proportions of patients achieving at least 5% body weight loss were 36.1% for 1.8 mg and 51.4% for 2.4 mg of beloranib vs zero with placebo (P <. 01 and P < .0001 for change from baseline vs placebo, respectively). Loss of at least 10% body weight occurred in 11.1% and 18.9%, respectively, with 1.8 mg (P < .05) and 2.4 mg of beloranib (P < .01).

Total body mass dropped by 2.9 kg with the 1.8-mg dose and by 5.7 kg with 2.4 mg of beloranib, while rising by 3.4 kg in the placebo group (P < .0001 for both for change from baseline with beloranib vs placebo). Reduction in fat mass accounted for 90% of this total, whereas little change occurred in lean mass, Dr Butler noted.

Data presented in a separate poster at ENDO 2016 also showed that beloranib significantly reduced total cholesterol, LDL cholesterol, and high-sensitivity C-reactive protein in the Prader-Willi syndrome patients.

Safety Question

Treatment-related adverse events resulting in withdrawal from the study prior to its halt in October 2015 were reported for four patients in the 1.8-mg group (11.1%) and two in the 2.4-mg group (5.4%) vs none of the placebo patients. During the study, the death occurred in the 1.8-mg group.

Other adverse events occurring in more than 10% of study subjects included injection-site bruising (in 16.2% of the 2.4-mg group vs 2.9% with placebo), aggression, hyperphagia, fatigue, and headache. None were seen in more than 17%.

In all, about 400 patients have been exposed to beloranib in the Prader-Willi syndrome and obesity trials. Of these, there have been 11 venous thrombotic events (pulmonary embolism, deep vein thrombosis, and superficial thrombophlebitis) in beloranib-treated patients and none with placebo.

The FDA put a partial hold on the development of beloranib after the first death in October 2015 and a complete hold after the second death was announced in December.

A complete clinical hold is an order that the FDA issues to a sponsor to suspend all clinical work requested under the company's investigational new drug application.

Nonetheless, CEO Thomas Hughes said in a statement at the time: "We remain committed to advancing beloranib as a potential new therapy for this underserved patient population."

Dr Hammer told Medscape Medical News that the company has some work to do. "Once you have a fatal effect like this…the onus is on you to prove that it's the randomness of the selection….You have to prove it happens with placebo as well. The FDA is very skittish about these things, appropriately."

Dr Butler said that the Prader-Willi community is very much hoping for a positive resolution. "We understand why it's on hold, but once that's resolved I think there's certainly support for this."

The study was funded by Zafgen, and Dr Butler received funding from the company. Disclosures for the coauthors are listed in the abstract. Dr Hammer is a consultant for Atterocor, Orphagen, HRA Pharma, and Embara, and is founder of Atterocor.

ENDO 2016; April l3, 2016; Boston, Massachusetts. Abstract LB-OR02-7

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