Lilly brushes off liver tox concerns after Pfizer drops an obesity candidate

Pfizer’s decision to drop an obesity candidate on liver toxicity concerns in June raised a red flag for the analyst community. Could Eli Lilly’s thriving obesity portfolio have similar issues?

Pfizer let go of lotiglipron because of phase 1 and 2 data that showed elevated transaminases, a type of enzyme that can be an indicator of liver dysfunction. The New York-based Big Pharma had been hoping to raise up lotiglipron over more advanced candidate danuglipron because it allowed for once a day dosing—which could have been a bigger threat to Lilly and Novo Nordisk’s offerings. But the safety data took lotiglipron out of the running, leaving the twice-daily danuglipron, which requires a higher dose, as Pfizer’s lead horse heading toward the competitive obesity market.

Lilly, meanwhile, has posted weight loss results for orforglipron showing an astounding 14.7% weight loss at 36 weeks in a phase 2 study published in the New England Journal of Medicine in June. In a second quarter earnings call Tuesday, Lilly Chief Scientific and Medical Officer Dan Skovronsky, M.D., Ph.D., acknowledged a few cases of liver toxicity in the studies for orforglipron. The company had previously said that safety was comparable to other incretin-based therapies.

“There's been more attention on liver safety for orforglipron following the competitor announcement from Pfizer on one of their two oral GLP-1s, so we don't see any read through from that. But of course, we've looked very carefully at liver safety,” Skovronsky said.

Pointing to the data from the journal publication, Skovronsky, who also serves as president of Lilly Research Laboratories, said that there was actually an improvement in liver enzymes when looking at group average data.

“That's not surprising,” he said. “We know that this disease, obesity, is characterized in many patients by excess liver fat, which can cause inflammation and liver abnormalities and when you reverse that, you see an improvement in liver function.”

One of the big questions with the obesity drugs taking the clinic and market by storm is whether patients have to stay on them long term. Skovronsky said that if a patient were to come off orforglipron or any obesity treatment, they could see liver fat and therefore liver enzymes go up again.

Lilly did see a few instances of liver enzyme elevations across the phase 2 trial, but some were in the placebo group. One patient had higher elevations that returned to normal while taking orforglipron.

“That's generally not a pattern that we see in drugs that cause liver injury,” Skovronsky said.

Lilly is advancing orforglipron to phase 3 in obesity and diabetes. Another candidate, retatrutide, also slid into the queue for late-phase testing in the second quarter.

“In phase 3 we'll keep an eye open for all possible safety consequences. I think I've frequently cautioned investors on all of our molecules that phase 3 is really the place where you can get surprised by any new safety findings,” Skovronsky said. “So we'll be watching liver safety closely, but not with any particularly heightened concern versus other adverse events.”

He continued: “And we'll also be watching carefully—this is a new molecule. This is the first time that we're exposing large, large numbers of patients to it for many years, or many, many months, I should say, and we will be monitoring safety carefully.”