Zafgen gets one last fat chance

Zafgen’s second-generation obesity project ZGN-1061 looks safer than its abandoned candidate beloranib, if phase I results are anything to go by. But longer-term safety remains to be proven for the drug, which is now Zafgen’s sole clinical asset.

Investors were encouraged, with shares up 11% in premarket trading today. The company has enough cash to last it until the end of 2018, by which time it should have phase II data for ZGN-1061 – and a hit will be vital for the group.

Better profile?

Zafgen seems confident that ZGN-1061, a second-generation MetAP2 inhibitor, will not be associated with the thromboembolic events seen with beloranib, which led to patient deaths and the suspension of its pivotal trial.

Although the two projects have the same mechanism of action, the company pointed to a better pharmacokinetic profile with ZGN-1061, which is cleared faster than beloranib. Biomarker data from the phase I trial also hint at ZGN-1061’s improved safety profile, according to Zafgen. Notably, ZGN-1061 had no impact on D-dimer levels at 14 and 28 days. This marker of blood clotting was elevated with beloranib.

However, D-dimer data were collected retrospectively in the beloranib trial, and only at three and six months. The only way to confirm that ZGN-1061 is differentiated from beloranib on D-dimer levels will be at the three-month time point in the phase II trial, the company's chief medical officer, Dennis Kim, conceded during a conference call to discuss the phase I data.

That study, slated to start in the second half of this year, will enrol around 120 patients with obesity and type 2 diabetes, and will evaluate 12 weeks of treatment.

Stacking up efficacy

The data available so far suggest that ZGN-1061 is less efficacious than beloranib, which though plagued with safey issues did hit its efficacy endpoints in the pivotal trial (Zafgen surprises again, but bigger questions remain, January 20, 2016). 

But cross-trial comparisons are always risky, and Roth Capital Partners analysts noted that patients in studies of beloranib started off with a higher BMI at baseline, which is associated with greater weight loss.

More concerning could be a lack of dose response with ZGN-1061, but Zafgen blamed this on dosing above the threshold for efficacy. The company, which evaluated doses of 0.2mg, 0.6mg and 1.8mg in phase I, plans to include a lower dose in the phase II trial to investigate this.

Zafgen execs were keen to stress that the primary aim of the phase I study had been to show safety, and that it was not powered to detect significant differences in efficacy metrics.

Even so, after beloranib’s problems it will be ZGN-1061’s safety that will be most closely watched in phase II.

To contact the writer of this story email Madeleine Armstrong in London at or follow @ByMadeleineA on Twitter

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