A "mystery.” A therapeutic "marvel.” “Revolutionary.” What more can be said about glucagon-like peptide-1 receptor agonists (GLP-1s) and related incretins, which have turned the makers of Wegovy and Zepbound into among the most valuable pharmaceutical companies in the world? A lot, actually.

This is because pharma and biotech companies are lining up to contend for a slice of a projected $150 billion weight loss market, with more than 100 ongoing trials focused on Type 2 diabetes, obesity and a range of other diseases. But vying for a toehold in this crowded space comes with baked-in risks beyond those inherent to all clinical development. Emerging from such a packed field will depend on devising innovative ways to address unmet patient needs beyond simple weight loss. Would-be entrants who focus exclusively on cardiometabolic endpoints do so at their own peril. 

Most companies today are developing obesity therapies focused on a narrow set of clinical endpoints headlined by weight loss percentage (Figure 1). 

By focusing so heavily on weight manaement and obesity-related endpoints, manufacturers risk repeating the mistake of late entrants to the statins market of the 1990s and 2000s, when products with weaker benefit failed to gain traction. When market leaders Lipitor and Zocor (later Crestor) went generic, the focus on a single metric—lowering low-density lipoprotein (LDL) cholesterol—made it difficult for would-be innovators to make headway, causing prices to drop across the class. If lowering LDL is the only endpoint the market values, the logic went, then why pay for a more expensive PCSK9 (for example) when LDL can be lowered effectively with a combination of a generic statin and lifestyle modification?

The comparison with today’s obesity market is ominously on the nose. As one leading endocrinologist told us, “In the future, payers will dictate obesity therapies. And just like they do with statins, there’s going to be a cheap first line and later agents further up the chain.”

With so many companies studying competing molecules offering comparable weight loss, payers, patients and providers are likely to look for other ways to differentiate products—namely, by price and auxiliary benefits. While offering more affordable GLP-1 therapies would address a significant unmet need, excessive focus on weight loss and related metrics means neglecting other areas of unmet need. Manufacturers face a dilemma: While continuing to focus largely on weight loss metrics may represent a dead end, branching out to develop multi-indication drugs to compete against Novo Nordisk and Eli Lilly represents an expensive proposition. 

Yet, there is a vast clinical whitespace that remains, including for:

• Obesity-related complications beyond cardiometabolic-related diseases. Obesity is associated with some 200 complications, but incretins have not been studied for many of them. Says one healthcare provider (HCP) treating patients with obesity: “We are seeing with recent trials [like SURMOUNT -1] that a growing number of comorbidities can be addressed. If these can gain payer coverage, we can start to see a resolution."
• Tolerability. While incretins are effective for weight management, they often cause nausea, vomiting and other gastrointestinal issues, as well as other tolerability and safety concerns.
• Unexplored weight management metrics. Total weight loss is not the only metric by which to evaluate weight management efficacy. Source, speed and durability of results are all significant unexplored metrics.

To understand current unmet needs in weight management and anticipate clinical innovation’s likely future path, we spoke with several clinical experts in obesity for perspective.

Given well-documented concerns about weight regain after discontinuing GLP-1s, stakeholders are prioritizing solutions for long-term weight management—including by keeping patients on therapy for longer. One such option under investigation is for patients to kickstart their weight-loss journey with an injectable medicine before moving to an oral therapy for ongoing maintenance. While first-generation oral incretins have proven less effective than injectable versions, they still offer up to 10%-15% weight loss.

While using oral GLP-1s as a maintenance therapy might ease administration burden for some, improving adherence, the need for long-term oral medication may still dissuade patients from staying compliant.

As one endocrinologist told us, “This class of drugs is not a cure, it’s a tool. And we’re seeing about 50% of patients regain weight after stopping therapy and a disbelief among patients that this is something they can control.”

Insurance coverage (or lack thereof) may also present a challenge to sustaining weight loss results. With strict prior authorization criteria and narrowing formularies, it’s common for patients to lose insurance coverage when their body-mass index (BMI) drops below a certain threshold or when moving to a payer that doesn’t cover GLP-1s for obesity. Given current prices, many patients who lose coverage are likely to discontinue therapy, making weight regain likely.

Says one HCP treating patients living with obesity: “There’s a tension with moving patients off these drugs. Even with a greater knowledge of lifestyle modification, they still regain the weight. And coverage spottiness will impact the number of patients funneling to other options, like bariatric surgery, where weight regain is also possible.”

In addition to weight regain, there’s a growing body of real-world evidence showing that weight loss results in clinical trials don’t always translate to the real world. While this isn’t unique to GLP-1s, it does underscore the idea that today’s GLP-1s—and, by extension, those in development—don’t work for everyone. And even when they do work, some patients struggle with side effects, fragmented care pathways and a lack of a clear and sustainable long-term end game.

Imagine a future where obesity treatment resembles oncology—where genetic tests inform treatment plans overseen by specialized care teams, and multiple lines of therapy and combination therapies deliver real-world results on par with those in clinical trials. It’s a far cry from the current landscape and pipeline.

To move in this direction, we may need to develop new metrics to complement BMI, which is merely a proxy for the biomarkers that predict someone’s true health risk.

As one clinician who specializes in treating obesity told us, “BMI was not designed by physicians, it doesn’t reflect perfect health, and it doesn’t reflect a broad population.”

Good news on this front: There appears to be strong momentum for change, especially with the forthcoming report from the Lancet Commission offering a clear definition of obesity. But supplanting BMI won’t happen overnight, especially in light of recent FDA draft guidance that strongly endorses BMI thanks to its ease of measurement and well-validated correlation with other relevant endpoints.

In the meantime, clinicians who treat patients with obesity are already experimenting with ways to use clinical and nonclinical factors to personalize treatment pathways (Figure 2).

True personalized weight management care will require enhanced clinical guidelines, which take years to develop and gain adoption. Until then, pharma can drive toward more personalized approaches in three ways:

1. Investigate why some patients respond to current incretins while others do not. With the accumulation of trial and real-world data, these analyses are becoming increasingly feasible.
2. Address tolerability. It’s possible some patients who can’t tolerate GLP-1s might experience strong results, without disqualifying side effects, using existing incretins and related molecules. Understanding why patients do or do not experience side effects will allow treatment personalization that balances efficacy—however we choose to measure it—with tolerability.
3. Develop solutions that operate through novel pathways or different mechanisms of action (MOAs) than today’s incretin-based treatments. There is a growing body of research contributing to our understanding of obesity’s biochemical pathways, including feelings of satiety and hunger signals in the brain, metabolism of fatty acids and adipogenesis.

Said one internal medicine obesity specialist with whom we spoke: “There is progress in higher-risk comorbidity groups that gives me hope. But to make a difference, we need to drill into specific central nervous system pathways to understand which patient populations should be closely monitored for tolerability and efficacy versus which ones are more stable.”

Genetic makeup can be viewed as a series of regulators, meaning there’s no single gene that “causes” obesity. Rather, it develops due to the presence of a combination of genes, often coupled with social and environmental factors that contribute to suboptimal lifestyle choices. Understanding each biochemical pathway that contributes to obesity may hold the key to resolving why some tolerate GLP-1s and related incretins with strong results, while others don’t (Figure 3).

Will manufacturers over-index on weight loss at the expense of other clinical endpoints, leading to a race to the (price) bottom? Or will they expand the frame to include a broader range of unmet needs and biochemical pathways, creating instead a field defined by personalized treatment journeys? While the headlines focus on weight loss, it behooves biopharma to widen its aperture.

GLP-1s may one day become the best-selling drugs in history. Dozens of pharma and biotech companies are racing to get in on the action, but given the head start today’s frontrunners enjoy, following the same formula risks repeating the mistakes that befell the also-rans of yesterday’s statins competition.

The decisions clinical development organization make now are critical.

For manufacturers looking to enter weight management, producing a next-in-class product targeting the same general population comes with inherent risk and a checkered history of success. The more fruitful and rewarding path will be one that focuses on personalizing care to address the full range of burdens associated with this complex and multifaceted disease. In time, this mindset will reward both manufacturers and patients alike.