Retatrutide leads in obesity treatment and CMC innovation

“Obesity affects approximately one billion people in the world,” Eli Lilly’s Michael Kopach told audiences at TIDES USA in Boston, Massachusetts. “It’s the leading risk factor for type II diabetes, contributing to over four million premature deaths every year.”

He added that high numbers among adolescents (340 million) and children (39 million) suggest that there is still “a great need to have better solutions.”

Kopach is an associate vice president overseeing synthetic molecule design and development at Lilly. Previously, he worked at Roche developing the antiviral peptide enfuvirtide (Fuzeon) against HIV. His work around enfuvirtide helped pave the way for some of the CMC approaches Lilly now relies on for its top glucagon-like peptide-1 (GLP-1) drugs.

Now, his focus is on retatrutide, a multifaceted peptide Lilly hopes will be the next big thing in diabetes and obesity management.

Three-for-one

Lilly shifted the market when it released its last blockbuster weight loss medication, tirzepatide (Zepbound/Mounjaro). That peptide was a dual agonist, meaning it was able to hit both GLP-1 and gastric inhibitory polypeptide (GIP) to achieve the current industry benchmark for weight loss.

Related:GLP-1s forced industry’s hand on sustainable peptide synthesis, says expert

Retatrutide is a triple agonist, or “triagonist.” That means that the 41-amino acid molecule modulates three different receptors: GLP-1, GIP, and glucagon.

“There's a synergy between how these hormones all operate,” he said. “They regulate specific physiological pathways related to appetite, insulin secretion, gastric emptying, and energy expenditure.”

He said his team’s hope is that adding glucagon agonism to the mix will promote “further fat burning, higher energy levels, and improved liver metabolism.” 

The data seems to bear out the weight loss aims. Lilly reports that retatrutide demonstrated high efficacy in clinical trials, achieving an astounding 28.7% weight loss in patients following weekly subcutaneous administration, compared with 15% for semaglutide (Ozempic/Wegovy) and 21% for tirzepatide. They also observed significant reductions (75–80%) in liver fat and knee pain (75.8%), as well as cholesterol and blood pressure.

The team published their Phase II (NCT04867785, NCT04881760) clinical results across the New England Journal of Medicine, Nature Medicine, and The Lancet. The team’s Phase III TRIUMPH-4 (NCT05931367) results are incoming and have not yet been peer-reviewed.

“For retatrutide, we’re getting, I think, maximum benefit for a single asset.”

Kopach anticipates sharing the results of seven Phase III studies by the end of 2026. 

Related:DIY dosing: Experimental injectable peptides craze takes US by storm

Not all weight loss is created equal, however. Some researchers have begun shifting away from gross totals to more focused approaches that remove harmful fatty tissue while leaving healthy lean mass – muscles, for example – intact. Along these same lines, some experts have expressed concern that patients losing nearly 30% of their body weight could be dangerous.

Kopach acknowledged that a triple agonist isn’t necessarily best for everyone, hinting at opportunities to mix and match different kinds of single or dual agonists for therapeutic benefit.

“We may see different combinations in the future,” he conceded. “I think Lilly's assessing that. Others are as well.”

Hybrid approach

One of the hardest steps for any drug is taking a powerful therapeutic molecule and preparing it for mass production. Manufacturing at scale brings with it a host of concerns, such as sustainability, cost, and efficiency.

“At Lilly, our philosophy is that we don’t restrict discovery,” Kopach said. “We say come up with the absolute best asset, and it’s our job in CMC to commercialize it.”

Kopach said novel CMC innovations have transformed how the company handles peptide production. The team will use what he called a “hybrid solid-phase, liquid-phase” continuous manufacturing approach to produce retatrutide. The company has already had success applying these protocols to tirzepatide.

Related:‘Quieting craving itself’: GLP-1s reduce risk of substance addiction in US veterans

“Hybrid liquid-phase/solid-phase work was really pioneered early on at Roche with Fuzeon,” he said. “Now getting a lot more traction, the fact that we've developed processes for Mounjaro, Zepbound, and retatrutide that are using analogous technology.” 

Hybrid synthesis, inspired by insulin production methods, takes a 40-step process for typical batch linear synthesis and simplifies it to just ten, according to Kopach. That’s in part because steps can be done simultaneously rather than one at a time with linear production.

“Doing all those [steps] consecutively, if one thing goes off in your synthesis, you may have a non-recoverable situation,” he said. “There's been studies done articulating as high as 20% failure for linear builds, unfortunately.”

Waste not

Kopach was quick to emphasize the environmental benefits of a hybrid peptide CMC process. It can take up to 14 metric tons of solvent to produce just 1 kg of peptide versus 1 metric ton for a small molecule drug – a fact that weighs on the industry as a whole.

BioXconomy has reported on the sustainability issues in peptide manufacturing and how the immense scale of GLP-1 demand has forced the industry to consider alternatives to “forever chemicals.”

“Right now, I think we had a little bit of a bad rap on the PMI [process mass intensity],” Kopach said, referring to one of the primary metrics for evaluating total raw material usage in drug production. Yet he thinks that comparisons to other therapeutic modalities should take into consideration relative therapeutic dose, which helps put peptide manufacturing in perspective.

He shared data suggesting that oligos produce an average of 0.1 kg of waste per patient per month versus 0.6 kg for biologics. Peptides, meanwhile, hit 0.8 kg while small molecules sit at the top with 1 kg of waste. That puts peptides in the top two most wasteful options in therapeutic development but also reframes small molecules as one of the less sustainable options on the market.

Kopach highlighted that their hybrid approach was able to further reduce waste per patient per month by 60–75%, making peptide synthesis a more viable option.

“We measure the PMI, your total material usage, that allows you to focus on reducing the most important items,” he said. “We’ve reduced DMF [dimethylformamide] for retatrutide by about 80%.” He said that they’re largely replacing DMF washes with the more sustainable isopropyl acetate.

Kopach added that DCM (dichloromethane) and piperidine are now “eliminated” in retatrutide production – and the team is still getting “purity up to 98–99%.”

He emphasized that Lilly is all in on its hybrid continuous manufacturing process for retatrutide.

“We've really doubled down on the commercial process,” he concluded. “For tirzepatide, we went to the market with two different processes, hybrid and linear. For [retatrutide], we converted to a hybrid process right out of the gate.”

The team has an eye toward further optimizations in the years to come. He hopes the team can convert additional parts of its pipeline from solid-phase to liquid-phase to further streamline production and reduce waste.

“As a post-approval effort, we can potentially put in liquid-phase alternatives,” he said. “One of the real strengths of hybrid is it allows you to have more innovations brought in even at a later time.”

Ultimately, Kopach and his team are hoping retatrutide can help patients tackle high levels of obesity in a way that single and dual agonists can’t.

“Retatrutide is the first triagonist that we're heading to the market with, which we’re hoping sets a new standard in weight loss and patient benefit.”