Is the next wave of obesity drugs moving beyond GLP-1? What Palatin, Rhythm, and Zealand are betting on

As glucagon-like peptide-1 (GLP-1) receptor agonists continue to dominate the weight loss treatment market, a new wave of biopharmaceutical innovation is quietly taking shape. Several companies are moving away from the now-crowded GLP-1 segment, focusing instead on alternative mechanisms such as melanocortin-4 receptor (MC4R) agonism and amylin analogues. Leading this shift are Palatin Technologies, Rhythm Pharmaceuticals, and Zealand Pharma, each pursuing differentiated approaches to modulate appetite, satiety, and energy expenditure in ways that extend beyond the incretin class.

This transition is not just about scientific curiosity. It reflects strategic decisions to create more targeted therapies, address rare and underserved obesity syndromes, reduce common side effects associated with GLP-1 therapies, and position for future combination treatments that offer additive or synergistic benefits. For institutional investors and clinicians alike, the focus on MC4R and amylin may represent the beginning of a multipronged obesity drug era.

Why are obesity drug developers looking beyond GLP-1 mechanisms?

While GLP-1 receptor agonists have transformed the market for obesity and type 2 diabetes treatment, generating blockbuster revenues for companies like Novo Nordisk and Eli Lilly and Company, they are not without limitations. Common side effects such as nausea, vomiting, and gastrointestinal discomfort, as well as challenges around long-term adherence, have triggered demand for new classes of drugs. Moreover, the growing number of GLP-1 competitors in clinical and commercial stages has led to concerns about market saturation, prompting investors and drug developers to scout for mechanisms that go deeper than pancreatic insulin modulation.

The melanocortin-4 receptor (MC4R) pathway is emerging as a compelling target due to its central role in regulating hunger and energy balance in the hypothalamus. Similarly, the satiety hormone amylin is gaining attention for its complementary effects on meal size reduction, slower gastric emptying, and insulin modulation. These alternative pathways are not only scientifically distinct from GLP-1 signaling but also offer avenues for treating rare genetic forms of obesity that GLP-1 therapies do not adequately address.

How is Palatin Technologies using MC4R biology to target obesity?

Palatin Technologies is developing PL7737, a selective oral MC4R agonist aimed at both general obesity and rare forms of the disease. Unlike GLP-1 therapies, which primarily affect peripheral insulin response, PL7737 acts on neurons in the hypothalamus that directly regulate hunger and energy expenditure. This central action gives it a unique pharmacological profile and opens the door for targeting obesity subtypes that originate from neuroendocrine dysfunction.

In preclinical studies using diet-induced obese rodent models, PL7737 demonstrated statistically significant weight loss within just four days of treatment. The drug also showed additive effects when combined with tirzepatide, a GLP-1 and GIP dual agonist. In high-dose combination cohorts, total weight loss reached up to 15 percent, outperforming either monotherapy. This data not only validates the standalone efficacy of PL7737 but also supports its potential use as part of a combination regimen with existing incretin drugs.

Palatin Technologies has received orphan drug designation from the United States Food and Drug Administration for the use of PL7737 in leptin receptor deficiency-related obesity. This rare genetic condition disrupts MC4R signaling due to mutations in the LEPR gene and leads to severe early-onset obesity characterized by insatiable hunger. By restoring this disrupted signaling pathway, PL7737 aims to treat a patient population with few or no pharmacologic options today.

The company has indicated that an Investigational New Drug application for PL7737 will be submitted by the end of 2025, with first-in-human data expected in the first half of 2026. Palatin Technologies is also developing a long-acting peptide-based MC4R agonist for weekly injection, aimed at providing flexible treatment options for different patient subgroups.

What is Rhythm Pharmaceuticals doing to advance MC4R agonists in rare genetic obesity?

Rhythm Pharmaceuticals is further along in its commercialization of MC4R agonist therapies, having already secured United States Food and Drug Administration approval for its injectable drug setmelanotide, branded as IMCIVREE. The drug is indicated for obesity caused by genetic deficiencies in POMC, PCSK1, and LEPR, and has shown strong efficacy in reducing hyperphagia and body weight in patients with rare monogenic obesity syndromes.

The company recently announced positive top-line results from the Phase 3 TRANSCEND trial, which evaluated setmelanotide in patients with acquired hypothalamic obesity. The placebo-adjusted reduction in body mass index approached 20 percent, signaling that the drug may have broader applications beyond its current rare-disease labels. Rhythm Pharmaceuticals is now positioning setmelanotide as a foundation for expanded indications in severe obesity subtypes with disrupted hypothalamic signaling.

Rhythm Pharmaceuticals is also developing an oral MC4R agonist called bivamelagon. Phase 2 data demonstrated statistically significant weight loss in patients with hypothalamic obesity, providing a promising oral alternative to its injectable formulation. This oral pipeline candidate could broaden access and adherence while maintaining the receptor-specific targeting that defines the company’s clinical approach.

Institutional sentiment toward Rhythm Pharmaceuticals reflects cautious optimism. While the company operates in a niche segment of the obesity market, it enjoys high regulatory credibility and has secured rare disease exclusivities that enhance its commercial prospects. Analysts have noted that the shift toward oral MC4R agonists may be critical for scaling the business and reaching larger patient populations with similar central neuroendocrine disorders.

How is Zealand Pharma expanding obesity drug development with amylin-based combinations?

Zealand Pharma is approaching the post-GLP-1 landscape through a different biological axis. The Danish biopharmaceutical firm is advancing multiple peptide-based candidates, including petrelintide, a long-acting amylin analogue. Amylin is a hormone secreted alongside insulin and plays a role in meal-induced satiety and glycemic regulation. Its pharmacological profile complements GLP-1 agonists, offering a differentiated yet synergistic effect.

In a major milestone for the company, Zealand Pharma entered into a co-development and co-commercialization agreement with Roche for petrelintide. The partnership includes development of both standalone formulations and a fixed-dose combination with Roche’s CT-388, which contains a long-acting GLP-1/GIP receptor dual agonist. The total deal value exceeds USD 5.3 billion, with substantial near-term payments and global rights-sharing provisions.

The company is also progressing other assets, such as dapiglutide, a GLP-1 and GLP-2 dual agonist, which in early trials showed over 11 percent body weight reduction within 28 weeks. Zealand Pharma’s strategy of using peptides to enhance tolerability, target gut and brain co-signaling, and improve body composition may appeal to patients who are unable to tolerate traditional GLP-1 therapies.

Analysts view Zealand Pharma as a strategically important player in next-generation obesity drug development. Its partnership with Roche provides not only financial strength but also validation of its amylin platform. The company’s progress has drawn interest from institutional investors seeking exposure to obesity therapeutics outside the GLP-1 class, especially those with modular or combination-friendly pharmacology.

What are the broader implications of this shift away from GLP-1 dominance?

The movement toward MC4R agonists and amylin analogues is not just about scientific diversification. It reflects a larger realignment of clinical strategy, patient targeting, and regulatory opportunity. Developers are increasingly interested in pursuing rare disease designations to secure market exclusivity, building combination regimens to improve outcomes, and offering alternative delivery formats such as oral tablets and long-acting injectables to address adherence challenges.

For Palatin Technologies, Rhythm Pharmaceuticals, and Zealand Pharma, the ability to demonstrate efficacy, safety, and tolerability in central pathways like MC4R or hormonal modulators like amylin could unlock competitive positioning not only in niche markets but also in general obesity management. Investors are paying attention to timelines, trial outcomes, and strategic partnerships as indicators of whether these alternative approaches can scale.

The obesity treatment market, once dominated by a handful of incretin-based drugs, is evolving into a multi-pathway arena where mechanisms, formulation, and patient subtypes are all driving value. GLP-1 will remain a foundation for years to come, but its limitations have created opportunities for smaller biotechs and strategic pharma collaborations to break new ground. As the market continues to mature, the companies that can offer novel biology with scalable platforms may emerge as the new leaders in chronic weight management.

What are the key takeaways from the shift beyond GLP-1 therapies in obesity drug development?

Palatin Technologies is developing PL7737, an oral MC4R agonist, and expects to file an Investigational New Drug application by the end of 2025. Preclinical data shows additive weight-loss effects with tirzepatide, and the drug has orphan drug designation for leptin receptor deficiency-related obesity.

Rhythm Pharmaceuticals has commercialized the injectable MC4R agonist setmelanotide and is expanding into broader obesity subtypes, including hypothalamic obesity. Its oral candidate bivamelagon has also shown positive Phase 2 results.

Zealand Pharma is targeting satiety modulation through peptide science. Its long-acting amylin analogue petrelintide is being co-developed with Roche as a standalone therapy and in fixed-dose combinations with GLP-1 agonists.

Investor sentiment is shifting toward differentiated mechanisms with regulatory exclusivity, improved tolerability, and combination potential. Analysts are watching for Phase 1 and Phase 2 readouts, IND filings, and partnership progress to validate the clinical and commercial viability of these approaches.