Memorandum
1.8 mg dose shows 1.1% A1c reduction and 5.1 lbs weight loss at 12 weeks (both placebo-adjusted); No treatment-related SAEs but FDA clinical hold for CV risk remains; Full results in 2019
Zafgen announced positive results from the second cohort of its phase 2 trial for MetAP2 inhibitor ZGN-1061, headlined by a 1.1% placebo-adjusted A1c reduction at 12 weeks for with the 1.8 mg dose (p<0.0001). A significant reduction in A1c was also seen with 0.9 mg at 12 weeks (p=0.0003 v. placebo).
Both doses showed continuous reductions in A1c through 12 weeks, hinting at potentially larger A1c reductions in a longer trial. A significant reduction in weight was also seen with the 1.8 mg dose, with placebo-adjusted weight loss of 2.3 kg (5.1 pounds) at week 12 (p=0.0002) – this is great to see. As a reminder, this 1.8 mg dose was added in a trial expansion based on the absence of treatment-related serious adverse events and safety signals with lower doses (0.05, 0.3, and 0.9 mg) in the first part of the phase 2 trial (interim data presented at ADA 2018).
No treatment-related serious adverse events occurred, and adverse events that did occur were “mild to moderate,” including upper respiratory tract infection, injection site bruising, contusion, and nasopharyngitis. Notably, no elevation in D-dimer concentrations (a biomarker of thrombosis) were seen at any doses – a reassuring sign given two thrombosis-related deaths in a phase 3 trial of Zafgen’s previous MetAP2 inhibitor, beloranib, led to its 3Q16 discontinuation. Compared to beloranib, ZGN-1061 has a lower duration of exposure, thought to enhance it clinical safety profile.
In its press release, Zafgen notably quotes Dr. John Buse touting ZGN-1061’s mechanism of action as “novel and unique” and pointing toward the significant improvements in both A1c and weight as “very encouraging.” Of high note, at TCOYD/The diaTribe Foundation’s 12th Annual Diabetes Forum during ADA 2018, Dr. James Gavin made a point to mention that “[ZGN-1061] is absolutely wonderful in terms of mechanism of action. It can actually reduce weight and glycemia in type 2 diabetes…so this is a wonderful technology that combines well with other things and could be a whole new class.”
Looking ahead, full results from this phase 2 trial will be presented at an “upcoming medical meeting in 2019.” Notably, this study occurred outside the US, and FDA placed a clinical hold on Zafgen’s IND for ZGN-1061 in November 2018, citing potential CV risk based on beloranib. What would be needed to assuage FDA’s concerns? Will the clinical hold impact progress into phase 3 , and will ZGN-1061 be otherwise stymied by fear of CV risk?
--by Martin Kurian, Ann Carracher, and Kelly Close