These drug candidates excited researchers 10 years ago. What happened?

At yesterday’s First Disclosures session organized by the Division of Medicinal Chemistry at the American Chemical Society Fall 2026 meeting, one molecule’s debut was also its swan song. Medicinal chemist Gwenaella Rescourio of Pfizer presented a topical drug candidate intended to treat acne by disrupting production of new fats in skin cells. But the candidate will not be advanced further: Pfizer announced plans to discontinue its development in May.

Pfizer’s acne study began as part of a broader investigation of oral acetyl CoA carboxylase (ACC) inhibitors, aimed at fatty liver disease. Among participants in early-stage trials of those inhibitors, blocking the enzyme reduced the overall production of skin oils. (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aau8465).

So medicinal chemists developed an ACC inhibitor for use in a topical formulation. Re-engineering the oral compound, Rescourio said during the talk, “was not as easy as we thought.” But eventually, by combining structure-activity relationship data and experiments on skin penetration, the team obtained a new molecule to take forward. Pfizer tested the candidate against acne in a clinical trial that began in 2024. The results of that completed study are not yet public, but Pfizer removed the drug from its active pipeline earlier this year.

It’s just the latest in a series of killed programs to inhibit the enzyme ACC, which is involved in generating new fat. The enzyme has also lost traction as a target for fatty liver disease. What makes it so hard to drug?

ACC inhibition for fatty liver disease

As their name suggests, ACCs (ACC1 and ACC2) work on the central metabolic intermediate, acetyl CoA. Acetyl CoA is a versatile substrate that participates in many metabolic pathways, but when ACC carboxylates the molecule, it is routed toward incorporation into a fatty acid.

According to Jay Horton, a lipid biologist at the University of Texas Southwestern Medical Center, the role of ACCs in fatty acid synthesis made inhibiting the enzymes an interesting prospect for any disease that involves making new fats, including fatty liver disease. Fatty liver disease, also called metabolism-associated steatohepatitis (MASH), occurs when cells in the liver store excess fat, often as a result of diabetes or another energy imbalance. Runaway fat accumulation can cause inflammation, which eventually stiffens and scars the liver.

On the strength of promising preclinical results, and amid a broader liver-disease frenzy in biotech, at least three large pharmaceutical companies—Gilead Sciences, Pfizer, and Merck & Co.—brought ACC inhibitors into clinical trials for MASH.

“The rationale was reasonable,” says Scott L. Friedman, a physician-scientist at Icahn School of Medicine at Mount Sinai. “The disease is dependent on the generation of fat, and in some patients, that fat becomes more toxic, and patients develop inflammation and fibrosis.”

Merck conducted early trials in people who had fatty liver disease, instead of the more typical healthy volunteers. According to Horton, who consulted on Merck’s Phase 1 study of its ACC inhibitor, the trial team found that while participants produced less liver fat, they also had dramatic increases in circulating triglycerides—enough to raise concerns about heart attacks and strokes.

“That was completely unexpected,” Horton recalls. The result was counterintuitive, because triglycerides are made by conjoining fatty acids.

In effect, Friedman says, “you could defat the liver by blocking ACC1 and 2, but the liver tried to get around it by making more triglycerides and [very low-density lipoprotein].”

A second shot on the ACC goal

Merck chose not to move forward with its ACC inhibitor for MASH. But Horton, a basic scientist, dug in to understand better why blocking fatty acid synthesis could increase circulating triglycerides. His lab found that in addition to being a backbone for new fatty acids, the metabolite that ACC produced had another role. It was also indirectly involved in the expression of triglyceride-producing enzymes (Cell Metab. 2017, DOI: 10.1016/j.cmet.2017.07.009).

With ACC blocked, although liver cells could not generate new fatty acids, more triglyceride-building enzymes were expressed. Some of those enzymes could still source fatty acids from the periphery and build them into triglycerides that were secreted from the liver.

This kind of vexing feedback loop is common in metabolism. “By identifying the mechanism, though, it did open the opportunity to continue the development of the [ACC] drugs,” Horton says.

The mechanism suggested workarounds that companies hoped could block the dangerous side effect. Pfizer and Gilead, both of which had already begun testing ACC inhibitors in the clinic, introduced additional molecules they hoped would quash the triglyceride production.

For a time, those workarounds seemed promising. Pfizer’s combination of an ACC inhibitor with a compound that blocks a second lipogenic enzyme, DGAT2, received the US Food and Drug Administration fast-track designation in 2022. Meanwhile Gilead tested its ACC inhibitor in combination with fenofibrate, a drug whose numerous effects on lipid metabolism include increasing fatty acid oxidation, and also teamed up with Novo Nordisk to try it in combination with semaglutide.

Neither strategy was a runaway success. Gilead’s combination did not help to resolve MASH. In a trial concluded in 2023, Pfizer found that although its combination appeared effective, participants developed a “likely undesirable fasting lipid and apolipoprotein profile.”

A changing clinical landscape for MASH treatment

Meanwhile, other efforts to treat MASH proved to be more effective. In 2024 the FDA approved the first MASH treatment, Madrigal Therapeutics’ resmetirom, which targets a liver hormone receptor. The drug did about $958 million in sales last year. And in 2025, the agency greenlit semaglutide—which was already a blockbuster—to treat early stages of MASH.

Both Gilead and Pfizer terminated their MASH programs last year, though Pfizer licensed its DGAT2 inhibitor to Madrigal, which is investigating it in combination with resmetirom.

According to Horton, there’s no longer a need for new drugs to reduce fat production in the liver. The introduction of weight-loss drugs has been transformative for the industry and the people who take them, and “weight loss accomplishes many of the same things that ACC did.”

So what makes ACC so hard to drug? The answer seems to be a combination of unexpected, risky side effects that proved difficult to overcome, and the arrival of better options to address liver disease.

The enzyme still captures some researchers’ attention. Massimo Loda, a physician-scientist at Weill Cornell Medicine, says he has tried repeatedly to persuade pharmaceutical companies to test their ACC inhibitors in certain cancers.

And University of California, Berkeley, researcher Anders Näär recently cofounded a start-up to revive an ACC-blocking molecule that researchers expect will avoid the triglyceride pitfall.

But no major pharmaceutical company currently has a public ACC program. Friedman says people with later-stage MASH still need better therapies, but he thinks new development should focus on fibrosis.

Looking back, Horton says, the rise and fall of ACC inhibitors for liver disease shows the wisdom of testing first in people with the condition being studied. “Going into the disease population very early . . . could reveal a side effect that was unexpected,” he says. “This was, I think, an incredibly valuable study in very, very few patients, that had a lot of important implications.”

Bethany Halford contributed reporting.

Laurel Oldach is a senior editor and life sciences reporter at C&EN.