Sales of Eli Lilly and Novo Nordisk’s injectable GLP-1 drugs have soared in weight-loss indications, with Lilly’s Zepbound overtaking Novo’s Wegovy in new U.S. prescriptions for the first time last month. Obesity is a major global health crisis, and the allure of a market that could exceed $100 billion has companies throwing their R&D dollars into treating it. The next big move for the space—an easy-to-pop pill—is already well underway.
Along with Novo and Lilly, Pfizer, Roche and a handful of smaller biotechs are racing to create an oral GLP-1 option with efficacy rivaling that of the currently approved injectable drugs. A pill could be the ticket to truly cracking open the massive market, Graig Suvannavejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas told BioSpace in an email.
“Oral [GLP-1s] hold huge potential in lowering prices and broadening access for patients,” he said, adding that it could potentially bring them to a more global population.
Lilly Leads a Crowded Pipeline
Now in Phase III with its small molecule orforglipron, Lilly is leading the oral GLP-1 race. The company is already ramping up manufacturing capacities as it advances the pill into late-stage development.
In June 2023, the company shared Phase II data that showed weight loss of between 9.4% and 14.7% after 36 weeks on the drug compared to 2.3% for the placebo group. Lilly expects Phase III results in 2025, according to a company spokesperson. The results were comparable to the Zepbound injection, which led to weight loss of up to 15.7% after 72 weeks of treatment in the SURMOUNT-2 trial versus 3.3% for those on placebo.
Not to be left behind, Novo last month touted data from its Phase I trial of amycretin, a next-generation co-agonist of both the GLP-1 and amylin receptors. After 12 weeks, patients taking the drug saw 13.1% weight loss.
In December 2023, Roche bought its way into the obesity game with the $2.7 billion acquisition of Carmot Therapeutics. The deal gave Roche access to the biotech’s two dual agonists targeting GLP-1 and GIP receptors (a similar mechanism to Zepbound), as well as a once-daily oral GLP-1 drug currently in Phase I. At the time, Levi Garraway, the company’s chief medical officer and head of global product development, said the portfolio offered “different routes of administration and opportunities to develop combination therapies.”
Pfizer is working on an oral formulation of its oral GLP-1 receptor agonist of danuglipron. Last year, the pharma company chose to focus on a once-daily formulation and drop the twice-daily version of danuglipron due to smaller weight reductions than the competition and high rates of side effects and patient dropouts, STAT News reported. The pill is currently in a Phase I trial comparing pharmacokinetics between immediate and modified-release formulations.
On the biotech side, Viking Therapeutics is working on both a subcutaneous and oral formulation of its dual GLP-1/GIP receptor agonist. Viking unveiled promising Phase I data in March demonstrating dose-dependent decreases in mean body weight. Participants treated with the highest dose level of the drug saw a 3.3% drop in mean body weight relative to placebo.
Meanwhile, San Francisco–based Structure Therapeutics believes the successful Phase II trial of its oral small molecule GLP-1 asset proves its best-in-class potential. Interim results at eight weeks showed a mean weight drop of 5.5%. The company expects to initiate a Phase IIb obesity study in the second half of 2024, according to the announcement.
“Safe and effective oral small molecule GLP-1 receptor agonists would be a significant advance in that they could expand access for many patients for whom this is not now possible,” Structure CEO Raymond Stevens said in a statement.
Improved Accessibility
Despite their exploding popularity, the current GLP-1 injections face accessibility issues due to cost and limited insurance coverage, challenges oral versions may be able to address to some extent.
Weight loss medications currently aren’t covered by Medicare for obesity, and Medicaid coverage varies by state.
Commercial insurers can cover the drugs if the employer opts in, but many plans require prior authorization, a restriction that wasn’t an issue before GLP-1’s use for weight loss became common, said Michael Glickman, an obesity medicine physician and CEO of Revolution Medicine. An October 2023 survey found that only about a quarter of corporate health insurance plans cover GLP-1 drugs for weight loss, though another 13% were considering adding it as of February 2024.
“The majority of Americans still don’t have access to GLP-1s,” Glickman told BioSpace.
He hopes the approval of oral drugs will alleviate some of the pricing burden, as more medications on the market will drive competition. Suvannavejh concurred, saying he believes the arrival of oral GLP-1 drugs on the market will drive the cost down for consumers and perhaps also lead to better coverage from insurers.
Glickman also pointed out that a small percentage of the population is needle averse enough to not want to inject themselves. Pfizer believes the factor plays a role why the current obesity injections are underutilized, a representative told BioSpace in an email. The spokesperson added that Pfizer expects a small molecule oral GLP-1 could be “well-reimbursed.”
A Lower Manufacturing Burden
Drug shortages of GLP-1s have been consistently frustrating for patients, Glickman said, adding that his practice receives multiple calls each week from patients having trouble refilling their obesity medications. In January, the World Health Organization issued a warning to patients regarding falsified versions of the drugs as shortages continue to limit GLP-1 drug access.
“It’s very challenging to keep patients on track when you can’t maintain medication consistency,” Glickman said.
Creating and packaging injectable peptides is a complex process. If successful, the arrival of oral formulations to the market should ease the current bottleneck, he added. “The complexity of producing an oral medication is going to be a lot simpler than producing a sterile subcutaneous product.” Additionally, having multiple options on the market would allow patients to pivot from one brand to another in the face of a supply chain issue, Glickman said.
With the current global focus on obesity, large companies with ample production capacity simply have to tap into the opportunity, while small companies are betting on “building a better mousetrap,” or formulation, in order to compete in the crowded space, Suvennevejh said. If these drugs do eventually make it to market, “there’s plenty of room to go around.”
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