Noteworthy Focus Points That Help Differentiate Anti-Obesity Drug Development Strategies in a Rapidly Evolving and Expanding R&D Landscape

The anti-obesity drug development landscape is undergoing a rapid transformation driven by the emergence of highly effective therapies and shifting patient needs. As clinical trial sponsors seek to optimize development strategies to meet patient needs, they are embracing novel trial designs, addressing weight maintenance challenges and adapting to new safety concerns, all while navigating a complex regulatory environment.

Below, we explore several dominating themes that are shaping the near and long-term future of obesity research and development.

Considering cross-therapeutic potential

Obesity is increasingly being recognized as a standalone, chronic condition by leading public health and medical organizations and regulatory authorities. With its most recent draft guidance on obesity clinical trials in January 2025, the FDA helped signal a historical shift in industry thinking by redefining obesity as a chronic disease rather than a chronic, relapsing health risk, per previous guidance. However, it is also well established that the excess adiposity of obesity is associated with an increased risk of death and multiple comorbidities, including type 2 diabetes, cardiovascular disease, osteoarthritis, and mental health disorders.

As more effective weight reduction therapies emerge, sponsors are exploring novel designs, such as basket trials and master protocols, that allow a single study to support multiple indications in parallel.

For example, the TRIUMPH-1 Phase III study is currently evaluating retatrutide, a triple hormone agonist (targeting glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors), across multiple patient subpopulations diagnosed as overweight or obese who also have weight-related comorbidities. The global pharmaceutical sponsor has designed a basket trial using a single master protocol to evaluate safety and efficacy of the therapy across several sub-studies, targeting both long-term weight reduction and improvements in obesity-related conditions, including knee osteoarthritis and obstructive sleep apnea. This basket trial framework allows data collection across different disease states in parallel while maintaining consistency in methodology and endpoints. Having a broader understanding of how retatrutide performs across various obesity-related health issues may improve clinical relevance and allow for a more efficient development program.

Because they address cross-indication therapeutic impact, master protocols and basket trials are increasingly recognized as a valuable tool in this changing landscape of obesity drug development. These sophisticated yet streamlined designs for evaluating therapeutic effects across multiple patient subgroups also align with the FDA-endorsed guidance for efficient drug development in chronic conditions.

Considering weight loss maintenance—designing for long-term success

With the widespread adoption of incretin-based treatments and other weight loss medications, trial sponsors face a new challenge: how to help patients maintain weight loss over time with continued use of therapy. Obesity drug development must account for the dynamic nature of weight change along with reasons why patients may discontinue therapies, including potential gastrointestinal side effects and lack of insurance coverage or higher out-of-pocket costs. Also, in some cases, patients may have an unrealistic expectation of weight loss or health improvements that lead to early discontinuation. On the other hand, after achieving weight loss, some patients may discontinue treatment, assuming it is not needed any longer, which may lead to weight regain.

The FDA’s current guidance emphasizes the need for trials to be designed to support long-term weight reduction. In response to patient and clinician demand, sponsors are exploring flexible dosing regimens to further inform optimal dosing after initial weight loss, including continuing the same dose indefinitely, transitioning to a lower dose or reducing dosing frequency.

In October 2025, a Phase I randomized, double-blind, placebo-controlled study was initiated to explore various maintenance dosing regimens for VK2735, a dual GLP-1/GIP receptor agonist. After an initial 19-week period of weekly subcutaneous dosing, participants are to transition to monthly subcutaneous, weekly oral or daily oral dosing. The study aims to evaluate safety, tolerability and pharmacokinetics, with exploratory endpoints that include weight maintenance and treatment adherence, indicating the potential viability of flexible dosing to offer similar improvements in long-term outcomes as higher, initial-use doses, while also improving adherence.

Another promising approach is the randomized withdrawal design, in which patients initially receive treatment and are later re-randomized to continue at the same dosing or adjust to a different dosing regimen, to gauge whether patients can achieve similar outcomes. The potential timing of dose transition among study participants may depend on the goals for the therapy. As such, sponsors will need to ask what is optimal, such as making changes when:

• Weight loss plateau occurs?​
• BMI is categorized as normal?​
• A certain threshold of weight loss is achieved (e.g., at least 5%, at least 10%, etc.)?

Considering adjustments for lean mass loss and potential malnutrition

Because rapid or substantial weight loss can sometimes lead to unintended loss of lean muscle mass, sponsors are advised to monitor for lean muscle mass loss and nutritional deficiencies in obesity trials. With the growing body of drug mechanisms becoming more targeted and effective, a more nuanced understanding of treatment effects can help ensure that clinical research continues to place importance on preserving health and functionality alongside weight loss with quality. This may help to fine-tune pairing the right treatment to the appropriate patients as more options become available.

In response to the concerns raised about lean mass loss, clinical trial sponsors are expanding supplementary support for trial participants, such as:

• Incorporating resistance training and/or protein supplementation into trial protocols.
• Monitoring vitamin and mineral levels to detect malnutrition.
• Using physical function endpoints to assess any negative impact of lean mass changes.

In addition to dual-energy x-ray absorptiometry and MRI imaging for lean mass safety-related changes,there is also interest in evaluating lean mass preservation as an efficacy endpoint to support a labelling claim. The FDA guidance recommends physical function measures and analysis at the subgroup level for vulnerable populations.

These adjustments reflect a broader shift in how obesity trials are conducted, with sponsors taking more proactive steps to address emerging concerns about further anti-obesity drug development.

Considering evolving role and expectations of regulators

The FDA and other regional regulators play a pivotal role in shaping the anti-obesity R&D global landscape. Aiming to keep pace with drug development, changes are also being made to regulatory guidance documents and review processes to reflect the complexity of obesity as a chronic, multifactorial condition. Clinical trial sponsors will need to closely monitor updates in regulatory guidance and expectations.

For example, the FDA issued draft guidance in January 2025 outlining the agency’s key expectations for weight reduction clinical trials:

• Substantial evidence of effectiveness: This remains the gold standard for regulatory approval and should include at least two well-controlled trials with clinically meaningful endpoints that reflect how a patient feels, functions, and survives.
• Expanding patient populations: Sponsors should ensure trials reflect US demographics and disease prevalence, with increased enrollment of male and Black/African-American participants. Companies should ask, “Does the trial population align with the indicated population who are impacted most?”
• Maintenance indications: FDA has always required that trials be designed to support long-term use claims and is now providing added guidance on potential design strategies to consider for flexible dosing.
• Placebo ethics. While placebo-controlled trials remain standard, the FDA may be open to evolving designs, as the treatment landscape continues to evolve. For example, a Phase III program that uses placebo comparator in trials of low-risk patients while trials of high-risk patients receive active comparators may be a viable future pathway. This nuanced approach balances methodological rigor with ethical considerations.
• Safety monitoring. Trials must assess cardiovascular, gastrointestinal and psychological risks, as well as malnutrition and lean muscle mass changes.

Along with safety monitoring, the guidance also clarifies that body mass index remains a valid endpoint for population-level studies while risk stratification though diagnosing obesity in individuals may require supplementary anthropometric measures, which aligns with recommendations from the Lancet Commission on Clinical Obesity. In rethinking what obesity means, the Commission advocates for clinical definitions to be based on measurable health impairments, such as metabolic dysfunction or organ damage, instead of relying solely on BMI thresholds. For example, at Obesity Week 2025, results from the STEP UP Phase IIIb study showed that in addition to losing body weight, participants taking semaglutide at either 2.4 mg or 7.2 mg doses achieved BMI of less than 27 and waist-to-height ratio of less than 0.53 compared to those taking placebo. These participants’ blood pressure, cholesterol, and blood sugar levels returned to the healthy range associated with low risk of cardiovascular disease.

In looking beyond BMI, this approach aims to improve diagnostic accuracy and treatment relevance, potentially influencing future endpoint selection and related trial design.

A landscape in motion: What’s next to think through?

As new therapies emerge and patient needs evolve, industry stakeholders will need to remain agile in a dynamic and multifaceted landscape where differentiation of therapeutic benefits will be essential. The future of weight reduction R&D not only lies in long-term weight loss but also in holistic and long-term health improvement, supporting health outcomes in terms of cardiovascular function, inflammation, quality of life and cognitive health. Also, as discussed at Obesity Week 2025, there is a move toward more personalized treatment based on patient subtypes, considering factors such as age, sex, and hormonal status.

This means staying ready to adapt patient-centric trial design and engage a wider range of populations to deliver more meaningful outcomes while staying compliant with regulatory expectations as they evolve.

Guilherme Andretta, PharmD, MBA, Director, Therapeutic Strategy Clinical Scientist; and Laura Higginbotham, MD, MPH, Vice President Therapeutic & Regulatory Strategy; both with IQVIA