FDA grants fast track status to ervogastat plus clesacostat for NASH
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The FDA has granted fast track designation to Pfizer for ervogastat in combination with clesacostat for treatment of patients with nonalcoholic steatohepatitis with liver fibrosis, according to a company press release.
Pfizer’s investigational combination therapy targets key enzymes for the regulation of lipid metabolism, diacylglycerol O-acyltransferase 2 and acetyl-CoA carboxylase. Inhibiting these enzymes has previously been shown to lower liver fat in patients with nonalcoholic fatty liver disease, a benefit that Pfizer believes could be leveraged to improve inflammation and fibrosis.
The FDA based its fast track decision on results of several nonclinical studies from Pfizer as well as a phase 2a clinical study, recently published in Nature Medicine, which demonstrated that ervogastat plus clesacostat reduced liver fat and exhibited a favorable safety and tolerability profile.
“Receiving fast track designation from the FDA reinforces Pfizer’s belief in ervogastat/clesacostat as a potential treatment for NASH, a serious, progressive liver disease with no currently approved therapies,” James Rusnak, MD, PhD, senior vice president and chief development officer of internal medicine and hospital at Pfizer, said in the press release. “We are proud to be advancing this investigational combination as part of our goal to develop innovative medicines to address some of the world’s most widespread health challenges that affect millions of people — including diseases like NASH.”
The FDA provides fast track status to facilitate the development of new products for serious or life-threatening conditions that demonstrate the potential to address unmet medical needs, with the goal of delivering critical new products to patients earlier. Fast track status also will allow the company to work closely with the FDA to expedite the review of aspects of ervogastat in combination with clesacostat to improve the efficiency of product development.
Perspective
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Stephen A. Harrison, MD, FAASLD
Pfizer recently announced that they were granted FDA fast track approval for the development of ervogastat (a diacylglycerol O-acyltransferase 2 inhibitor) and clesacostat (an acetyl-CoA carboxylase inhibitor) for the treatment of NASH with fibrosis. The hope is that these two compounds will work synergistically to improve liver fat content and subsequently affect further drivers of fibrosis to include hepatic inflammation and liver cell injury, with the ultimate goal of improving long-term outcomes in these patients.
NAFLD primarily develops through three different pathways: underlying insulin resistance and subsequent free fatty acid flux from adipocytes, increased de novo lipogenesis and decreased beta oxidation of fatty acids. This combination of agents proposed by Pfizer will target inhibition of de novo lipogenesis. Both mechanisms have been studied together in a recent phase 2a, short-term study of NAFLD patients, in which liver fat content was reduced and the elevation in serum triglyceride content often seen with an ACC inhibitor alone was mitigated (Calle R, et al.).
Our understanding of NAFLD/NASH pathogenesis continues to evolve, and it is becoming clearer that combination therapies targeting different mechanisms of action are likely to be more impactful than single mechanisms alone. In addition to improving histopathology, our collective hope in drug development for NAFLD/NASH is that we also will be able to affect other metabolic comorbidities, such as cardiovascular and renal disease — two common problems seen in association with NAFLD/NASH.
We anxiously await further studies with this combination of liver-targeted compounds.
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Nancy S. Reau, MD, FAASLD, AGAF
It’s exciting to see the NASH pipeline begin to bear potential therapies. The phase 2a data for ervogastat/clesacostat (enzyme inhibitors in hepatic lipid metabolism) demonstrated safety and tolerability, however the study will not be completed until 2024. With nearly one-third of Americans affected by fatty liver disease, it is imperative that we have effective therapies to stabilize and, hopefully, reverse NASH. It is also important to not lose sight of the other metabolic complications of NASH, such as cardiovascular disease and malignancy, which also drive morbidity and mortality in NASH.
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