At the weight-loss market's poker table, Eli Lilly and Novo Nordisk have already won most of the chips. Roche has only just sat down.

 

But the chips this Swiss pharmaceutical giant brings are unlike anyone else's.

 

At its 2025 earnings call, Roche once again emphasized that its goal is to become a top-three global player in obesity. To that end, after missing the first wave of GLP-1 blockbuster drugs, Roche is spending billions of dollars betting on next-generation obesity treatments.

 

Its playbook is completely different from existing players: shifting from the single-minded pursuit of maximum weight loss to a greater focus on precisely improving metabolic health; from single-drug competition to building a complete weight-loss matrix spanning injectable to oral, incretin to non-incretin, monotherapy to combination.

 

Recently, another key piece has landed on this map.

 

On October 13, Roche entered into a global exclusive licensing agreement with Rona Therapeutics, obtaining rights to its proprietary extrahepatic delivery platform to develop RNAi candidates targeting activin receptor-like kinase 7 (ALK7) for the treatment of obesity and metabolic diseases.

 

Under the terms of the agreement, Roche will pay up to $100 million in upfront and near-term milestone payments, as well as up to $1.06 billion in potential development, regulatory, and commercial milestone payments, plus tiered royalties on global net sales.

 

The deal size is not the largest in Roche's weight-loss portfolio, but what it fills is precisely the most distinctive piece of Roche's entire weight-loss puzzle — small nucleic acids.

 

Chapter 1: Doubling Down on Small Nucleic Acids

 

To understand the value of this deal, one must first see clearly the uniqueness of the ALK7 target.

 

ALK7 (encoded by the ACVR1C gene) is a member of the transforming growth factor-beta receptor superfamily, primarily expressed in adipocytes. The ALK7 signaling pathway regulates lipid storage, lipolysis, and energy homeostasis in fat cells. Human genetics studies have linked reduced ALK7 activity to favorable fat distribution and metabolic phenotypes.

 

Unlike current mainstream incretin-based therapies — which primarily influence appetite and energy intake through the central nervous system — ALK7 inhibition acts directly on adipose tissue biology. Its core potential lies in: selectively reducing visceral fat and other ectopic fat deposits while preserving lean body mass.

 

In June 2026, a study published in Diabetes presented preclinical data for ALK7 RNAi, with quite convincing results. In diet-induced obese (DIO) mouse models, fat-targeted ALK7 RNAi monotherapy achieved over 70% ALK7 knockdown (p<0.001), with 17.5% body weight reduction, without affecting food intake.

 

More differentiated value lies in the combination data. When ALK7 RNAi was combined with tirzepatide (TZP), weight loss reached 23% (tirzepatide monotherapy: 15%), fat mass reduction reached 47% (tirzepatide monotherapy: 26%), while completely preserving lean body mass. The regimen also upregulated the expression of lipolysis and energy expenditure genes, alleviated hepatic steatosis and fibrosis, and did not alter serum free fatty acid, ketone body, or liver enzyme levels.

 

This dataset directly addresses the core pain point of current GLP-1 drugs: 25% to 40% of weight loss during treatment comes from muscle loss.

 

The "fat-loss, muscle-preserving" characteristic of ALK7 RNAi gives it a natural logic for combination with existing incretin therapies: it does not pursue simple "weight loss," but precisely "fat loss," especially reducing visceral fat that poses the greatest health hazard.

 

But there is a prerequisite to solve here: ALK7 acts on adipocytes, while current mainstream GalNAc delivery technology naturally targets the liver, meaning RNAi drug applications have long been concentrated on liver-expressed targets — to develop ALK7 RNAi, one must first deliver RNAi precisely to adipose tissue.

 

Perhaps this is precisely the key to Roche's bet on Rona Therapeutics.

 

According to its official website, Rona Therapeutics has established three major platforms: the GAIA hepatic-targeted delivery platform, the APOLLO extrahepatic targeted delivery platform, and the Bi-Valent/Multi-Valent scalable drug discovery platform.

 

Among them, the APOLLO extrahepatic platform uses small molecule conjugation to achieve efficient receptor-mediated uptake within the central nervous system; it employs local administration (intrathecal injection) to minimize side effects associated with systemic exposure. The platform is expected to enable dosing every six months or longer and has achieved proof of concept in non-human primates.

 

Currently, leveraging this platform, multiple assets under Rona Therapeutics are entering clinical stages, with indications covering obesity, metabolic diseases, epilepsy, Alzheimer's disease, and more.

 

Rona Therapeutics' Extrahepatic Platform and Pipeline

 

With this deal, potentially totaling over $1 billion, Rona Therapeutics' differentiated extrahepatic RNA delivery technology has gained recognition from a multinational pharmaceutical company, further confirming extrahepatic delivery as a core competitive advantage for next-generation RNAi drugs.

 

Chapter 2: The Weight-Loss Drug Landscape

 

In recent years, Roche has consistently sent a clear signal to the outside world: in the metabolic field, it is no longer a bystander, but a heavyweight preparing to join the first tier of global obesity treatment.

 

Roche was once one of the earliest pharmaceutical companies to research glucagon-like peptide-1 (GLP-1) drugs, but on the eve of the latest GLP-1 boom, the company exited the field due to successive late-stage trial setbacks.

 

After missing the first wave of opportunity, Roche is now striving to catch the second wave.

 

The Basel-headquartered company is investing billions of dollars in R&D and collaborating with multiple small biotech companies to build a broader obesity drug portfolio, hoping to differentiate itself in an increasingly competitive market.

 

Where the money flows is the most honest declaration. Since 2025, Roche has completed more than 20 deals totaling over $20 billion, the vast majority concentrated in metabolism and autoimmune fields. This is also the first time in Roche's history that it has invested more in businesses outside oncology.

 

What kind of map do these deals piece together? Specifically, Roche's differentiated weight-loss pipeline includes:

 

Enicepatide (CT-388): GLP-1/GIP dual agonist, aiming for best-in-class efficacy

 

At the end of 2023, Roche acquired Carmot Therapeutics for $3.1 billion ($2.7 billion upfront + $400 million milestones), obtaining a series of GLP-1/GIP assets. Among them, CT-388 (now named Enicepatide) is the core asset.

 

Phase II data showed that the 24 mg dose group achieved 22.5% placebo-adjusted weight loss at 48 weeks, without reaching a weight-loss plateau. Notably, no "tolerability ceiling" was detected in the highest dose group either. In patients with concomitant type 2 diabetes, the same dose group achieved 15.5% weight loss at 48 weeks — a difference consistent with the general pattern of GLP-1 drugs, and also suggesting heterogeneity in treatment response across different patient populations.

 

Roche has initiated Phase III clinical trials for this drug, covering three major indications: obesity, type 2 diabetes, and cardiovascular outcomes. The obesity indication could potentially submit regulatory applications as early as 2028.

 

Petrelintide: Long-acting amylin analog,主打 tolerability

 

In March 2025, Roche reached a collaboration agreement worth up to $5.3 billion with Zealand Pharma to jointly develop and commercialize petrelintide.

 

Phase II ZUPREME-1 data showed up to 10.7% weight loss at 42 weeks (1.7% in the placebo group), significantly lower than tirzepatide's 20%+, but with an extremely prominent tolerability advantage — 98% of participants in the maximum effective dose group successfully completed dose escalation, with no vomiting cases and no treatment discontinuations due to gastrointestinal adverse events.

 

Roche has launched three global Phase III trials in one go (ZUPREME-3/4/5), enrolling approximately 7,000 people in total, covering obese populations without type 2 diabetes, patients with type 2 diabetes, and high-risk populations with cardiovascular disease.

 

Pegozafermin: FGF21 analog, directly targeting the core comorbidity of MASH

 

In September 2025, through the acquisition of 89bio for a total transaction value of up to $3.5 billion, Roche obtained the fibroblast growth factor 21 (FGF21) analog pegozafermin, which has already demonstrated strong anti-fibrotic and anti-inflammatory potential in Phase IIb clinical trials for MASH.

 

The close association between obesity and metabolic dysfunction-associated steatohepatitis (MASH) provides Roche with another important strategic entry point.

 

The drug has received FDA Breakthrough Therapy Designation, EMA PRIME designation, and in May 2026 was proposed for inclusion in China's NMPA Breakthrough Therapy Drug Program. Phase III ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis studies are ongoing, with histological data expected between 2027 and 2028.

 

HM17321: UCN2 analog, a new track for "fat loss with muscle preservation"

 

In August 2026, Genentech, a Roche subsidiary, reached an agreement with South Korea's Hanmi Pharmaceutical, paying $190 million upfront and up to $2.3 billion in total to license HM17321 — a globally first-in-class UCN2 analog.

 

The drug's mechanism is completely independent of the incretin pathway, aiming to reduce fat while preserving muscle mass, directly addressing the clinical pain point of lean body mass loss caused by GLP-1 drugs.

 

Preclinical data show that HM17321 has excellent weight-loss efficacy as monotherapy, can achieve upgraded efficacy when combined with GLP-1 drugs, and has potential for developing fixed-dose combinations.

 

CT-996: Oral GLP-1, anchored for long-term maintenance

 

CT-996 (development code RO7795081/RG6652) is an oral small-molecule GLP-1 receptor agonist obtained by Roche through the Carmot acquisition.

 

Unlike endogenous GLP-1 hormone, CT-996 is specifically designed as a biased agonist — preferentially activating the cAMP signaling pathway while minimizing or eliminating beta-arrestin recruitment. This design aims to reduce receptor internalization and desensitization, potentially leading to more durable efficacy.

 

Phase I data showed 6.1% placebo-adjusted weight loss after 4 weeks of treatment (p<0.001), and dosing may not need to consider meal timing. The drug has been approved for clinical trials in China for long-term weight management in overweight or obese patients.

 

In December 2025, Roche also reached an agreement with Structure Therapeutics, paying $100 million upfront to obtain rights to use specific oral GLP-1 agonist patents, aiming to clear potential patent obstacles for CT-996.

 

Beyond the above individual drugs, Roche also emphasizes combination strategies in its pipeline.

 

Roche has clearly planned a Phase II multi-arm trial (ZYNERGY) for a fixed-dose combination of Petrelintide and Enicepatide, planned to initiate in mid-2026. The combination aims to combine the tolerability advantages of amylin analogs with the potent weight-loss capability of GLP-1/GIP dual agonists, avoiding the common gastrointestinal side effects of GLP-1 drugs.

 

With the extrahepatic delivery platform license and ALK7 RNAi candidates obtained through this deal with Rona Therapeutics, Roche's weight-loss pipeline now covers multiple pathways including incretin, amylin, non-incretin, and RNAi, forming a complete matrix from injectable to oral, from monotherapy to combination.

 

Of course, Roche's weight-loss布局 is not only about adding. At the end of September, due to a negative interim analysis from the Phase II GYMINDA trial, Roche terminated development of the muscle-building drug Emugrobart (a myostatin-targeting antibody) for obesity, returning the rights to Chugai Pharmaceutical.

 

Previously, Roche also terminated development of another Carmot asset, Acmopatide (CT-868), despite the drug meeting its primary endpoint in Phase II for type 1 diabetes, choosing instead to concentrate resources on Enicepatide as a core molecule "capable of covering multiple indications."

 

Additionally, Roche abandoned another preclinical Carmot asset, CT-173 (a long-acting PYY analog), citing "failure to meet developability and competitiveness standards."

 

These trade-off moves precisely demonstrate that Roche's weight-loss布局 is not blind expansion, but has clear priorities and resource concentration logic.

 

Chapter 3: Winning Odds and Chips

 

Against the backdrop of Novo Nordisk and Eli Lilly dominating the market, can this Swiss pharmaceutical giant still find a foothold?

 

The answer must first be sought in the shortcomings of existing weight-loss therapies.

 

GLP-1 incretin drugs represented by semaglutide and tirzepatide have been fully validated in terms of weight-loss efficacy. But some studies have found that while promoting weight loss, these drugs can lead to 25% to 40% muscle loss. For the general population, this cost may be acceptable; but for the elderly, sarcopenia patients, or individuals at high risk of fractures, muscle loss could bring health consequences far more serious than obesity itself.

 

Additionally, weight rebound after discontinuation is also an issue that cannot be ignored — some studies show that one year after stopping treatment, participants regained on average about 60% of the weight lost during treatment.

 

These shortcomings are precisely the opportunities Roche sees.

 

Manu Chakravarthy, Roche's Global Head of Cardiovascular, Renal and Metabolic Product Development, has clearly stated: "We are not just focused on the number on the scale, but truly on patients' overall health. In the course of obesity and its complications lasting 20, 40, or even 60 years, not everyone needs the same treatment at every stage."

 

Based on this judgment, Roche has shifted from the single-minded pursuit of maximum weight loss to a greater focus on precisely improving metabolic health — tailoring treatment plans according to individual biological characteristics.

 

Roche also believes that the weight-loss market will segment as weight-loss drugs reach broader populations — patients have different needs for weight-loss magnitude, different payment capacities, and different comorbidities, and no one-size-fits-all solution applies. This provides latecomers with entry opportunities.

 

Moreover, the synergy between diagnostics and pharmaceuticals has become Roche's most unique chip.

 

Chakravarthy noted that Roche's accumulated expertise in obesity research and its diagnostic tools that help identify obesity risk factors give it certain advantages over competitors. In other words, Roche may identify patient subgroups through diagnostic tools and then match them with corresponding weight-loss regimens, forming a "diagnostics + treatment" closed loop.

 

Chakravarthy believes: "We are not too late, because we are not competing for a small slice of the existing pie. What we truly want to do is make the entire pie bigger. There are still far too many unmet needs in this market."

 

This logic is fully reflected in Roche's pipeline布局. Current market leaders mainly rely on single or dual incretin pathways, while Roche is building a "multi-organ, multi-pathway, all-dimensional" metabolic disease solution.

 

Enicepatide, Petrelintide, HM17321, Pegozafermin, CT-996, ALK7 RNAi... each asset targets a specific shortcoming of existing therapies, and there is room for combination and synergy among them.

 

As the market moves from "one-size-fits-all" to "precision stratification," Roche's diversified pipeline is expected to capture considerable market share during the market's maturation phase, particularly among patient populations that respond poorly to existing therapies, cannot tolerate them, or seek higher-quality weight-loss outcomes.

 

Additionally, patents for first-generation drugs such as semaglutide will expire successively in the mid-to-late part of this decade, and the evolution of global reimbursement policies will also create important market access windows for new-generation products with clear clinical differentiation.

 

Roche may not be the fastest runner, but what it is paving is a wider road.

 

References:

1. Rona Therapeutics, Rona Therapeutics enters into global license agreement with Roche for ALK7-targeting RNAi therapy for obesity and metabolic diseases

2. FierceBiotech, Roche inks $1.2B deal with China's Rona to enter emerging ALK7 obesity race

3. Rona Therapeutics Official Website

4. Tongxieyi, New Variable in Weight-Loss Drugs: Small Nucleic Acids "Flip the Table"

5. Pharma Times, Cutting One Pipeline, Launching Three Phase III Trials! Roche's Weight-Loss Pipeline Major Reshuffle

6. swissinfo, Can Swiss Pharmaceutical Giant Roche Reshape the Obesity Market?

7. Metabolic Line Report, Roche Appears at ADA2026 — Obesity Pipeline at Full Speed: Already Has a Ticket to the First Tier of Global Obesity Treatment