The Pythagorean cup* of GLP-1Rs 

As the pharmaceutical landscape buzzes with the acclaim of GLP-1Rs (Glucagon-Like Peptide-1 Receptor) as the revolutionary frontier in the fight against obesity, there’s a palpable surge in public and industry interest. Brands like Wegovy and Zepbound are quickly becoming household names, fuelling unprecedented enthusiasm for growth in the obesity market. As we step into 2024, the biotech sector shows signs of rejuvenation with increased deal-making activity, placing investors and pharmaceutical decision-makers at a crucial juncture. They are now navigating the fine line between seizing a promising opportunity in the obesity domain and succumbing to a risky investment frenzy. At this critical juncture, stakeholders in the obesity market must balance their enthusiasm for emerging technologies with a cautious evaluation of potential risks, guarding against hasty investment decisions driven by fear of missing out (FOMO) and the allure of breakthrough innovations.

Just as the flow from a Pythagorian cup cannot be reversed once it overflows, further investment in obesity therapies might similarly risk becoming resources poured into a bottomless pit. This raises a pivotal question: have we reached the cup’s tipping point?

*A Pythagorean cup is a cleverly designed drinking vessel that drains its contents if filled beyond a certain level, illustrating a practical use of the principles of fluid dynamics.


The surge in GLP-1R drug development 

Providing a current and detailed overview of the obesity landscape presents a challenge, given the growing variety of therapeutic approaches and the constant influx of news about new contenders and business deals. In fact, it’s worth noting that some figures cited here may well become outdated by the time this article is published! However, if we narrow one’s focus on the GLP-1R-associated approaches, we can get a sense of the challenge decision makers face in the early stages of development. The Mechanism of Action (MoA) of Novo Nordisk’s market leader Wegovy (GLP-1R agonist) is shared by eight Phase 2/3 projects, seven Ph1 projects and more than seventeen pre-clinical projects announced in the public domain [1]. Lilly’s Zepbound MoA targeting GIPR (Gastric Inhibitory Polypeptide Receptor)/GLP-1R is similarly popular with five Phase 2/3 projects, one Phase 1 and more than three pre-clinical projects hoping to be direct in-class competitors. On top of that, five Phase 2/3 and three Phase 1s are exploring alternative GLP-1-associated approaches [e.g., tri-agonists, GLP-1/amylin, GLP-1/GCGR (Glucagon Geceptor) agonists].

Yet, MoA is only one part of a more complex differentiation puzzle. Route of Administration (RoA) is another critical aspect, with several companies racing to be the first to offer an oral treatment option. Perhaps not surprisingly, oral formulations are also heavily featured in the GLP-1R obesity pipelines with six Phase 2/3 and six Phase 1 hopefuls [1].

The capabilities of companies targeting the obesity sector also warrant attention. Beyond the current juggernauts Lilly and Novo, whose pipelines are also heavily reliant on the GLP-1R MoA, Pfizer and Amgen are among the list of big pharma with significant bets on obesity. Roche also recently joined this list with its $2.7 billion acquisition of Carmot Therapeutics. In fact, seven out of the ten biggest pharma companies by market cap are currently developing or have expressed direct interest in GLP-1R projects targeting obesity. With the recent positive Ph2 data of Viking Therapeutics’ dual GIPR/ GLP-1R agonist, touted as potential “best-in-class”, the company is likely on the acquisition radar of another big player looking to secure obesity market share. Whether it’s R&D, manufacturing capability, commercial excellence, or the sheer weight of capital, the bar for competing with the biggest in pharma is high. While such fierce competition may spur innovation and ultimately benefit patients, the risk of lower return on investment is significant as the cost to participate is driven up.


The summit of success is not desolate but cannot accommodate a crowd 

Perhaps the most used disclaimer in investing is that past performance does not indicate future success. Yet, parallels from the past can offer solid data points to inform future analytics. In this context, examining the trajectories of past ‘blockbuster’ markets can shed light on potential outcomes and reveal underlying universal principles.

Let’s begin with the bullish case for more GLP-1R deals in 2024 – pharma markets are rarely “winner-takes-all”, and history offers examples of late entrants beating “first-to-market”. One of the most prominent examples is AbbVie’s Humira, the third Tumor necrosis factor-alpha inhibitor (TNFi) to enter the immunology space and later become the first drug to reach $20 billion in annual sales. Also, differential sales trajectories for drugs with “equal starts” are not uncommon among blockbusters. An example of that is the oncology success of Merck’s Keytruda vs BMS’ Opdivo. Despite a slower start, strong clinical and commercial execution have led Keytruda to capture more than 50% of a busy PD-1 space. On a side note, if you want to know how AbbVie and Merck achieved this commercial success, my CHR colleagues have produced a fascinating whitepaper on that topic, which can be enjoyed here.

While being late to market is not an unsurmountable obstacle to commercial success, a more significant trend should be on the radar of 2024 obesity deal makers. Even when multiple “in-class” competitors can get to the proverbial top, the number of winners is usually small. Going back to the example with AbbVie’s Humira: while Humira was able to achieve twice the revenue than the combined returns from its in-class predecessors Janssen’s Remicade and Amgen/Pfizer’s Enbrel, the fourth TNFi entrant, Janssen’s Simponi did not achieve similar success, nor was able to match the historical performance of Remicade & Enbrel [2]. While the reasons for this warrant a longer discussion, perhaps the strongest factor is that the immunology field, where Simponi was hoping to make strides almost a decade after the entry of Remicade and Enbrel, had moved on. This included the emergence of newer oral agents such as JAK inhibitors and the entry of the first TNFi biosimilars in Europe and the US. The parallels with the current situation in obesity are clear.

To further illustrate the point that blockbuster success is usually shared in small circles, we can look at some additional examples. Focusing on the PD-1 market mentioned previously, in 2022 Keytruda achieved about 54% of worldwide PD-1 sales, totalling approximately $21 billion [3]. Opdivo captured about 24%, with the remaining 22% (about $8.4 billion) shared by five other in-class competitors [3]. In the cardiometabolic space, the success of the Sodium Glucose co-Transporter 2 inhibitor (SGLT2i) paints a similar picture, with 90% of sales shared by leading brands Farxiga/Forxiga and Jardiance, while the three remaining SGLT2is capture the remainder [1]. The observed phenomenon can be largely attributed to diminishing expected returns on investment as markets for similar products mature, often nudging commercial decisions towards termination. However, what is more difficult to unpick are the lessons from the numerous initiatives halted after considerable financial commitments. This “project graveyard”, populated by the victims of yesterday’s hype, remains concealed from current investors’ view, becoming all too easy to overlook amidst the fervour of a hype cycle.


The tightrope of tomorrow cuts between the obvious and the overlooked 

While the past can provide sobering examples warranting caution, it’s equally important to anticipate future trends that can be reasonably predicted. In obesity, certain economic forces are bound to shape the landscape. For instance, in a scenario where multiple market entrants challenge Lilly and Novo’s positions, the high degree of competition catalysed by GLP-1R enthusiasm will likely result in squeezed margins for all. This competitive pressure might prove challenging to counter, considering the existing hurdles to obtaining market access for obesity treatments. These range from the substantial lobbying expenses required for securing coverage in the US to the more cautious reimbursement strategies at the national level in Europe.

One difficult aspect to predict and perhaps the basis on which many investors’ hopes are hinging is the emergence of the GLP-1R agonist (or GLP-1R variant/combination) with significantly higher efficacy eclipsing current competition. While this certainly may occur, I believe that success in obesity will be a lot more reliant on two other factors – supply and innovative marketing. The first, has been in the spotlight for most of 2023 with Lilly and Novo grappling with a demand for GLP-1R agonists that far surpassed their production capacities. As a result, substantial investments have been poured into manufacturing capabilities, including what some have considered “unprecedented” moves such as Novo’s acquisition of the contract manufacturing organisation (CMO) Catalent. On the other hand, Lilly has invested in constructing manufacturing sites “at risk” to potentially keep up with demand, should its oral GLP-1R agonist reach clinical success. These developments underscore that the two companies see establishing a robust supply chain as foundational to winning in obesity. However, manufacturing commitments of the scale undertaken by Lilly and Novo are unlikely to be replicated by prospective competitors eyeing GLP-1R opportunities.

As we enter 2024, the second aspect of innovative marketing is witnessing a significant uptick in activity, supercharged by heightened public discourse and awareness. Lilly, for instance, kicked off the year by unveiling its ‘LillyDirect‘ platform, an end-to-end digital healthcare solution catering to diabetes, migraine, and obesity – the last likely being the major driver behind the initiative. By acting as the “middleman”, Lilly is moving on multiple fronts. For one, it aims to be much closer to patients which could provide an opportunity to better shape patient experience and gather critical data to influence the market. Moreover, by associating its brand closely with Zepbound, Lilly aims to leverage the growing focus on obesity management to enhance the visibility and recognition of its product. The recent deal between Lilly and Amazon, selecting Amazon Pharmacy as a dispensing option for LillyDirect, is another indicator that obesity companies are thinking big when seeking advantage. On the other side of the competitive landscape, Novo Nordisk is also exploring new partnership models, such as providing Ozempic and Wegovy on the consumer-centric health service Weightwatchers. The collaboration integrates Novo’s GLP-1R therapies into subscription-based models, challenging traditional approaches with innovative blending of medical treatment with lifestyle and dietary guidance. While it’s too early to say whether initiatives like these successfully break the mould of traditional pharma marketing, assessing the prospects of commercial innovation and execution is a key and, perhaps overlooked, aspect of projecting future obesity markets.


Putting the cup down will help you see the brim 

One can easily argue that current developments in pharma are ripe with excitement, as many following the industry are witnessing the formation of a new and prolific market, which has drawn widespread attention without the shadow of an impending global crisis (looking at you, COVID pandemic). This enthusiasm, while invigorating, places immense pressure on pharmaceutical decision-makers, tasked with sifting through daily hype to make prudent investment decisions that will set the stage for future triumphs.

In conclusion, I aim to advocate for caution, not deterrence. The key to overcoming the “obesity FOMO” lies in its acknowledgement, followed by critical evaluation of commercial prospects through precise market forecasts. Despite the crowded GLP-1R pipeline, top competition, and challenging manufacturing hurdles, opportunities for disruption may still remain. For example, a hint of new headwinds may be seen in the increased discourse on combining GLP-1Rs with muscle preservation treatments, which some have hailed as the next frontier, as we await validation by later-stage data.

Regardless of the specific case, a rigorous analysis of future market dynamics, a solid evidence base, and resisting the distractions of the latest trend are essential to every decision. Adhering to these principles could unveil significant opportunities yet to be captured in obesity or illuminate hidden roadblocks in contrast to the widespread enthusiasm. Taking a step back might just stop you before the tipping point of the GLP-1R cup, providing clarity and confidence in your future direction.



[1] Solici research, Mar 2024

[2] Data from Evaluate, accessed Mar 2024

[3] Data from Evaluate, accessed Mar 2024; PD-1 competitors with at least 4 years time in the market


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