For many GLP-1 patients, reaching a weight loss goal is only part of the challenge. The longer-term hurdle is often keeping those pounds off.
“For centuries, our bodies have been trained by famine to imagine that the obese weight is your baseline weight,” Raj Kannan, CEO of Alveus Therapeutics, said, referring to biological adaptations that push the body to regain weight after shedding pounds. One study found that patients regained an average of 60% of the weight they lost on GLP-1 medications within a year of stopping treatment.
While many companies are still competing to develop the best assets for losing the highest amount of weight, Alveus is aiming to solve the riddle of how to prevent it from returning.
The clinical-stage biotech counts two former Novo Nordisk executives among its leaders including Jacob Jeppesen, Alveus’ chief scientific officer, and Patrick Garibay, the chief development officer. Both bring experience on the weight-loss side of the equation.
Alveus’ lead asset, a phase 2 drug ALV-100, is a fusion molecule that marries a GIPR antagonist and a GLP-1R agonist, a similar strategy to Amgen’s investigational drug MariTide.
“It’s designed for maintenance versus weight loss,” Kannan said.
The company is running a phase 2 trial testing ALV-100’s ability to sustain weight loss and a phase 1b study evaluating different dose-escalation strategies, safety and tolerability — ongoing challenges in the obesity drug R&D space. In fact, side effects and cost are among the most common reasons patients discontinue GLP-1 drugs, according to one study.
“At the end of one year, you lose about 60% or 65% of patients, depending on which source of data you look at. Roughly about 85% drop of therapy by the end of year two,” Kannan said. “We're working on making it as tolerable as possible compared to incretins or potentially even comparable to placebo.”
Alveus expects readouts from both trials next year.
A patient-friendly dosing regimen is also a top priority. The drug’s long extended half-life could help in that regard, potentially enabling quarterly, or even less frequent dosing to support weight maintenance, he said.
And the company has three preclinical programs focused on oral and injectable treatments linked to the major metabolic hormone amylin, which is another “very highly validated target,” Kannan said. Amylin has become a particularly popular target among other drug developers for its potential to produce superior weight loss with fewer side effects than GLP-1s. Large pharmas like AbbVie, Pfizer and AstraZeneca are also exploring amylin drugs.
But Alveus is trying a differentiated approach that uses more precise targeting. Its ALV-200 program, for example, targets the AMYR3 receptor with the aim of promoting better body composition and less fat while preserving muscle.
The race to demonstrate durability
Other companies like Eli Lilly are also exploring weight maintenance strategies, such as switching people from an injectable GLP-1 to a pill to keep weight off. One phase 3 study found that switching patients to Lilly’s now-approved weight-loss pill, Foundayo, helped maintain most of their weight loss.
Viking Therapeutics also recently announced topline results from a maintenance study showing that after once-weekly dosing of its investigational GLP-1/GIP agonist VK2735 for 21 weeks, participants in one every-other-week dosing group maintained 97% of the mean weight loss achieved during weekly dosing.
Amgen too has tested this approach, finding that lower or less frequent doses of its combination GLP-1 receptor agonist and GIPR antagonist drug MariTide helped participants maintain their weight in a recent phase 2 extension study.
Over the next 18 months, clinical milestones from Alveus will provide more information about ALV-100 and hopefully move two of its amylin strategies into the clinic, Kannan said. If successful, Alveus won’t be competing with any of the established players, but looking to carve out a complementary niche in the existing ecosystem, according to Kannan.
“The question is not whether ALV-100 can win in a weight loss race or not, but whether it can preserve weight loss with durability of outcomes, tolerability and convenience,” he said.
