The treatment of obesity has been transformed by highly effective, injectable incretin-based pharmacotherapies. They have unleashed unprecedented consumer-led demand which continues to dramatically outstrip product supply, while the buzz surrounding novel weight loss treatments has firmly established those brands as household names [1].

Despite the runaway commercial success of injectables semaglutide and tirzepatide, and a projected global opportunity for obesity pharmacotherapies worth $131Bn by 2028 [2], a number of important issues must be addressed for anti-obesity medicines to fulfil their tremendous potential as public health interventions:

• Ensuring affordability by patients, in out-of-pocket markets, and by health systems to expand reimbursement of weight loss medicines to ensure equity of access and enable the broad adoption of therapies in eligible patient populations
• Securing adequate product supply that meets fast growing demand
• Maintaining weight loss and realising associated, long-term health benefits, e.g., improvements in cardio-metabolic risk factors and co-morbidities

Oral obesity treatments will play a critical role in overcoming these challenges, for example, as convenient, long-term maintenance therapy following time-limited induction therapy with injectables. Furthermore, those oral therapies that are based on small molecules have favourable manufacturing economics compared to peptide-based injectables, allowing faster supply scale-up and enabling sustainable pricing to help address affordability and budget impact challenges.

Innovation landscape for oral obesity therapies

The current obesity pipeline, from pre-clinical through phase 3, comprises 50 assets with an oral route of administration, which represent 33% of total assets in development for this indication. The oral obesity pipeline is dominated by GLP-1 receptor agonists which account for 28% of oral assets, followed by cannabinoid receptor 1 (CB1) blockers and GLP-1/GIP dual agonists, with a share of 10% and 8%, respectively (see Figure 1).

Unsurprisingly, many innovators follow the well-trodden path of exploring incretin mimetics and amylin analogues in their quest for oral obesity treatments, including both single and multi-acting agents. Assets targeting GLP-1, GIP, glucagon and amylin, individually or a combination of them, collectively account for 46% of the oral obesity pipeline.

However, we find a number of noteworthy mechanisms of action (MoAs) among oral assets in development that pursue different approaches, including several aimed at improving the quality of weight loss:

• CB1 receptor blockers, modulating appetite and energy homeostasis, with peripherally restricted CB1 inverse agonists garnering particular interest due to their cleaner psychiatric side effect profile vs. first generation agents;
• Apelin agonists, increasing energy expenditure, promoting muscle metabolism, lowering fat accumulation and preventing muscle atrophy;
• Mitochondrial uncouplers, steering metabolic pathways towards energy expenditure and fuel preference for fatty acids, leading to selective weight loss from fat while preserving muscle mass;
• Leptin sensitisers, reducing appetite while also blocking the brain’s typical response signal to reduce energy expenditure, to enhance weight loss, utilise fat stores and preserve muscle;
• Myostatin agonists, blocking the myostatin/activin ActRIIB signalling pathway, the dominant pathway regulating muscle homeostasis, to prevent and/or reverse muscle loss – a common, undesired and possibly harmful effect of GLP-1-based weight loss therapies.

These MoAs are independent from and complementary to the more mainstream MoAs of incretin mimetics and amylin analogues, thus offering the potential for combination approaches to address different aspects of weight management, potentially even delivering enhanced, synergistic efficacy.

Beyond their MoA, the modality of oral obesity assets, i.e., small molecules vs peptides, is a key differentiator determining their commercial prospects and the impact these therapies will have. Small molecules make up the majority of the oral obesity pipeline, with a share of 60%. Peptides represent 32% of oral obesity assets in development, while the modality was not specified for the remainder.

Innovators’ strong preference for exploring small molecule-based oral obesity therapies reflects their attractive profile which offers multiple benefits compared to peptides:

• Pharmacology: Small molecules typically have better bioavailability, and food compatibility without the need for fasting, than oral peptides. This allows for lower dosing which may translate into a more favourable tolerability profile. Furthermore, small molecule-based drugs better lend themselves to fixed dose combination approaches with other treatments, e.g., to simultaneously deliver weight loss and muscle preservation, or to address more complex patient needs beyond obesity involving multiple cardio-metabolic co-morbidities.
• Manufacturing: Small molecules are typically much simpler to manufacture than peptide-based therapies, allowing rapid scale-up of production to ensure adequate supply to meet growing demand. Scalable, chemical synthesis of polypeptides instead of recombinant approaches may become fully established in the future which could narrow this distinction, however, for the time being small molecules have a manufacturing advantage.
• Economics: Small molecules have significantly lower COGS vs. peptides, driven by less complex manufacturing requirements, while their better bioavailability means less active ingredient may be required per treatment. This leaner cost structure provides headroom for pricing flexibility to address affordability challenges for patients and health systems.

Notwithstanding these compelling advantages of small molecules over peptides, one crucial question remains: How does the weight loss delivered by small molecule-based oral therapies compare to peptide-based treatments, whether oral or injectable?

We will elaborate on this issue in the next section.

Latest developments in the oral obesity pipeline

Over the past 12 months we have seen considerable movement in the oral obesity pipeline, as several important clinical trials read out for prominent pipeline assets.

As a result, a competitive field of potential, future oral obesity therapies is emerging that have reported compelling clinical data, albeit with the caveat of making cross-trial comparisons here. Furthermore, those select assets are in different trial phases, and their respective, reported weight loss was achieved after different durations of treatment (see Figure 2).