Zafgen Optimistic, But No Clear Path For Beloranib
This article was originally published in Scrip
Zafgen investors are clinging to any bit of hope they can, pushing the stock up after the obesity drug maker announced positive clinical trial data. Yet, safety signals still linger and an FDA clinical hold remains the largest obstacle to Zafgen moving beloranib forward.
The biotech's stock jumped 78.65%, or $4.42, to close at $10.04 on Jan. 20 after Zafgen announced that results of the Phase III bestPWS ZAF-311 trial were finally available. While the trial showed statistically significant efficacy on both clinical endpoints when compared with a placebo in patients with Prader-Willi syndrome (PWS), the death of two patients during the trial and concerns about pulmonary embolisms threaten to derail the program permanently.
Zafgen CEO Tom Hughes expressed optimism on a call with analysts, saying he expects things to move swiftly now. Yet, the elephant in the room was the complete clinical hold that the regulatory agency imposed on Dec. 2 after a second patient taking beloranib died from a pulmonary embolism.
The biotech reported the first patient death in October when a patient taking the drug in the blinded portion of the study died from blood clots in the lungs. The second patient death occurred during an open-label extension phase of the trial; two other patients also experienced non-fatal pulmonary embolisms. Patients in the open-label extension study were screened to make sure they weren't at increased risk of developing blood clots.
Due to the clinical hold, the trial was never completed, but Zafgen was able to compile data from the patients that did finish the full 26 weeks of treatment, as well as from those patients that completed 75% of the treatment period. The company, under advisement from experts of the disease and FDA, conducted a sensitivity analysis to determine efficacy. Hughes noted that there was still statistical significance regardless of how the analysis was conducted.
"Of note, these efficacy results remain statistically significant regardless of the sensitivity analysis applied. These robust and compelling efficacy data demonstrate the potential of beloranib in this difficult-to-treat syndrome. Along with the overall safety data, the efficacy results continue to inform the benefit risk profile of beloranib in PWS," said Hughes on the call.
The bestPWS ZAF-311 trial included 107 patients with PWS, a rare disorder that causes people to chronically overeat and exhibit compulsive behavior with food, eventually leading to morbid obesity and often death. The patients in the study had an average body mass index of 40 and were generally about 50% body fat. Typically, people with a body mass index greater 27 is considered overweight and over 30 is considered obese.
Patients in the trial were given two injections a week of either 1.8mg of beloranib, 2.4mg of beloranib, or placebo. Those in the placebo group gained 4.15% of their bodyweight form baseline, while patients in the lower dose group lost 4.05% and those in the higher dose group lost 5.3% of their bodyweight.
Patients in the trial were also given a questionnaire to determine habits about eating and behavior. Those in the treatment groups showed dramatic improvement in behavior, according to the surveys, while those in the placebo group remained stable in their negative behaviors.
What Does It Mean?
Zafgen spent little time on the conference call with analysts emphasizing the clinical hold, despite that being the major roadblock to development at this point.
The company said it is currently working with experts in PWS, as well as parts of the PWS community to better understand the disease. The biotech is hoping to prove that the risk of blood clots is higher in the PWS population due to the disease and not due to the drug. Zafgen is looking at blood parameters, genetic risk factors and concomitant medications that could affect the development of blood clots in these patients.
"We're in active dialogue with a number of PWS and thrombosis experts to better inform our approach to this effort. We've thoroughly reviewed our existing pre-clinical and clinical data sets and are also conducting additional studies to further elucidate any potential mechanistic reasons why we might be seeing this imbalance," said Hughes.
FDA has made it clear that Zafgen will need to present a clear risk mitigation plan, along with any other clinical data it has for the agency to consider lifting the clinical hold – some drugs never move beyond a clinical hold.
"We're hopeful that with proper screening and monitoring protocols in place, potential thrombotic risks can be effectively managed," said the exec. Yet, he admitted that the company is still assessing the data and has not yet determined what their risk mitigation strategy will be.
The next steps will be to finish collecting and assessing data – the company expects further Phase II data to be announced in coming months, and then book another meeting with FDA.