Specialized expertise and customized solutions across 14 therapeutic centers of excellence, including oncology, GI/NASH, pediatrics, neurology and rare diseases.
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:
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.
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:
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:
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.
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).
This snapshot of the emerging competitive landscape for oral obesity therapies allows some intriguing observations:
It is important to note that several of these observations are directional only at this time, because they are based on limited phase 1 data. Efficacy, safety and tolerability of early-stage oral obesity assets will need to be confirmed in larger trials and with longer treatment durations.
Oral anti-obesity pharmacotherapies offer many compelling advantages over injectables, which positions them to play a critical role in tackling the obesity global health crisis. However, several uncertainties remain that will determine whether oral obesity therapies will fulfil their promise, in particular as maintenance therapies that help realise long-term health benefits:
As novel obesity assets continue to accumulate clinical data, progress through the pipeline and eventually enter the market, we should expect to get answers to these questions in the coming years, and with it clarity about the future role that oral obesity therapies will play.
We are likely to see the first oral obesity treatments entering the market around the 2026/27 timeframe, with Lilly’s orforglipron and Novo Nordisk’s oral semaglutide, both in phase 3, as the current front runners. However, timelines for the current early- and mid-stage pipeline are more fluid. As illustrated by several announcements made during recent Q2/2024 earnings calls, innovators who firmly believe in their assets are not shy about doubling down to accelerate their development programmes in obesity.
Without a doubt, the rapidly evolving obesity market will continue to be a fascinating place to observe.
Specialized expertise and customized solutions across 14 therapeutic centers of excellence, including oncology, GI/NASH, pediatrics, neurology and rare diseases.
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