Dr Deepak Bhatt Discusses Results From the ENTRIGUE Trial

Deepak L. Bhatt, MD, MPH, who in the past year became director of Mount Sinai Heart and the Dr Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, has multiple presentations during the upcoming 72nd American College of Cardiology (ACC) Scientific Sessions, to be held March 4-6 in New Orleans, Louisiana.

Bhatt’s presentations Saturday include additional results from the phase 2 ENTRIGUE trial, which is evaluating pegozafermin (89bio) in severe hypertriglyceridemia. Bhatt presented phase 2 findings last fall at the European Society of Cardiology (ESC) that showed the investigational therapy reduced triglycerides more than 50% at various doses.

His follow-up presentation at ACC will be, “Pegozafermin Provides Beneficial Lipid Effects in Subjects with Severe Hypertriglyceridemia (SHTG) Regardless of Background Lipid Modifying Therapy Status: An Analysis of the Phase 2 ENTRIGUE Study.” He previewed the presentation with The American Journal of Managed Care^® earlier this week.

Transcript

Can you describe the unmet need in severe hypertriglyceridemia?

There remains a really great unmet need in severe hypertriglyceridemia. By that I'm referring to hypertriglyceridemia, meaning triglycerides greater than or equal to 500 mg/dL. Different people use different thresholds and various circumstances; here, though, I'm really talking about severe, so that's greater than or equal to 500 mg/dL. The risk there is that it increases the risk of acute pancreatitis. 

That's why, in general, that sort of level of triglycerides is always treated. There’s, of course, a role of triglycerides in other disease processes, such as cardiovascular disease—that risk probably starts at a much lower level—but here we're talking about severe hypertriglyceridemia greater than 500. And what we can do to reduce pancreatitis risk—and the belief is that level of pancreatitis-associated triglycerides should always be treated—obviously, first-line therapy is lifestyle modification, and things like weight loss and alcohol cessation can sometimes be useful. But in many patients that have triglycerides in that range, pharmacotherapy is needed.

There are therapies, such as fibrates, that have historically been used. Those, of course, are now known not to provide cardiovascular benefit in patients that are statin treated. There's also high doses of omega-3 fatty acids that can reduce triglycerides in that range. Some of the compounds have been shown to reduce cardiovascular risk, specifically EPA, or icosapent ethyl. Others, the mixtures of omega-3 fatty acids haven't. But still, even with those therapies that are available, lots of times patients’ triglycerides aren't well controlled when they're in that range. Oftentimes, it's necessary to use 2 agents.

I think there's really an unmet need for treating severe hypertriglyceridemia for those reasons.

Can you explain the unique technology and the mechanism of action of pegozafermin?

The drug now that you and I are speaking about—pegozafermin—it is an FGF21 agent….First of all, maybe I should explain what FGF stands for: That’s fibroblast growth factor 21. What that is, is an endogenous hormone regulating lipid and glucose metabolism and energy-expenditure–type agent. It occurs in nature and people.

What pegozafermin is, is a glycopegylated FGF21 analogue. So, it's specifically been designed to have a longer half-life than just the native FGF21 that we've got running through our systems right now. This ability to create a longer half-life analogue, hopefully, then does even more of what FGF21 would normally be doing. Again, it's regulating glucose and lipids and energy expenditure and other important things that seem to be very important and fundamental in human biology.

This analogue has been designed and is being tested for treatment of severe hypertriglyceridemia—what you and I just discussed. Also, it's being tested for nonalcoholic steatohepatitis, or NASH, as it's called, which is separate from this and a big health problem as well, where there's a lot of need for new therapies.

How will the results you are presenting this week at ACC build on the earlier findings?

Some of these data regarding pegozafermin and severe hypertriglyceridemia from the ENTRIGUE study, which was a phase 2 trial, there was a late-breaker at ESC where I presented the overall results, which showed a very significant and large reduction in the level of serum triglycerides. Interestingly, it also showed a variety of other beneficial effects on biomarkers. And I will say, importantly, also in the subset of patients who had MRIs of their liver, looking at liver fat, produced pretty large, dramatic, and I'll say quick effects on liver fat—that is, reducing liver fat—in these patients with severe hypertriglyceridemia.

So, there are 2 messages from that part of the study. One, is that this drug works in taking fat out of the liver. Two, is that in patients with severe hypertriglyceridemia, in fact, have a lot of fat in their liver. That is, it may not be the case that physicians widely appreciate that patients with severe hypertriglyceridemia are really at risk for things like NAFLD—that is, nonalcoholic fatty liver disease—or NASH or alcoholic steatohepatitis.

These are interesting observations from the trial, even just beyond the fact that the drug works, that this is a big problem to begin with. That is, I don't think most physicians when they see someone's severe hypertriglyceridemia realize that there's trouble brewing in the liver and, for that matter, trouble brewing in the cardiovascular system as well. That part, I think, is more commonly appreciated. In the main results presentation—again, this was at the European Society of Cardiology as a late-breaker—we presented those results and showed rather large reductions in triglycerides.

What I'm going to be presenting at ACC now gets into the benefits in patients who were or were not on background lipid-lowering therapy, including statins. And what we find there is a very consistent benefit on both types of patients: Patients on background lipid-lowering therapy and those who weren't patients, as well, who are on high-intensity statin, we see a significant reduction in triglycerides.

I would say that most patients with severe hypertriglyceridemia probably should be on a high-intensity statin; not all of them will be, not all of them are going to tolerate it. But even in those patients who are on high-intensity statins, we're seeing significant reductions in hypertriglyceridemia. And by significant—just to contextualize that—I'm talking about 50-ish percent reductions in triglycerides.

We studied a number of doses. This is a phase 2 trial primarily designed for safety, which we established. But of course, we were also looking at efficacy, and all the different doses did produce large reductions in triglycerides.