Lipid changes and liver fat reductions
Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.
“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”
Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.
Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.
As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.
During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”
Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.
“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.
Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.