How an abandoned Pfizer NASH drug gave rise to a Novartis-teamed follow-on

Back in early 2018, Pfizer axed a phase 1 drug in nonalcoholic steatohepatitis (NASH), or fatty liver disease. But the company's scientists remained interested in the drug's mechanism of action: It targets diacylglycerol acyltransferase 2 (DGAT2), a protein that catalyzes the formation of the fatty molecules triglycerides, especially in the liver.

Now, scientists at the New York pharma have detailed findings from mice and two small clinical studies showing how the drug, known as PF-06427878, reduces fat content in the liver.

Even though Pfizer has terminated development of PF-06427878, learnings from the studies have led to a follow-on candidate dubbed PF-06865571, a Pfizer spokesperson told FierceBiotechResearch. That improved therapy is now in phase 1 development and is covered by a Novartis partnership aimed at studying potential combo approaches for treating NASH.

Previous studies demonstrated that inhibiting DGAT2 directly affects triglyceride synthesis while also indirectly reducing fatty acid accumulation by suppressing genes that encode the proteins needed for lipid formation. 

In a mouse model of NASH, treatment with the older drug significantly improved fat levels in the liver and hepatocellular ballooning—a key hallmark of NASH. It also helped decrease liver inflammation, the Pfizer team found. What’s more, it reduced the expression of several lipid-related genes, including Srebp1c, Acc1, Fasn and Scd1. The results were published in Science Translational Medicine.

Based on the positive preclinical results, the scientists pushed the drug into two small phase 1 studies involving a total of 62 healthy adults. After 14 days of treatment, the drug didn’t cause any alarming adverse effects, they reported.

Even though the drug’s ability to lower blood triglycerides was not consistent across the trials, the Pfizer team did notice it improved markers of liver function at the highest dose. MRI scans showed that treatment with PF-06427878 pared down liver fat by an average 31.5% over placebo.

RELATED: A map of liver cells provides insights that could boost search for NASH drugs

NASH, a leading cause of liver disease in the Western world, can progress to cause deeper fibrosis and eventually liver cancer. Interest in the field remains high, as big companies continue to make major investments in the search for an effective therapy.

Novo Nordisk, which is already running clinical studies of its GLP-1 diabetes drug semaglutide in NASH patients, recently bagged UBE Industries’ UD-014, a preclinical candidate that inhibits SSAO/VAP-1. And it also just put down $225 million for Dicerna’s RNAi platform for drug discoveries in areas including NASH.

The burgeoning field of NASH R&D also saw Boehringer Ingelheim license a dual agonist against GLP-1 and the liver hormone FGF21 from South Korea’s Yuhan for up to $870 million. And Novartis shelled out $80 million upfront for Pliant Therapeutics’ NASH candidates. The pact includes PLN-1474, an inhibitor of the integrin αVβ1, which has been implicated in the scarring of the liver.

Despite generating promising data on the older DGAT2 inhibitor, Pfizer discontinued the development of it after noticing it “had chemical properties not fully optimized for chronic exposure” in NASH patients, the spokesperson said. But, as the current paper’s authors noted, their study validated the beneficial role for DGAT2 inhibition as a therapeutic target for NASH.

And now, the follow-on drug PF-06865571 has also been paired with Pfizer’s own acetyl-CoA carboxylase inhibitor PF-05221304 in a phase 2 trial.