In the past few months, significant interest within the inflammatory bowel disease (IBD) space has been directed towards the therapeutic target, tumour necrosis factor-like cytokine 1A (TL1A). The buzz surrounding this developing drug class began in April 2023 with Merck (MSD) announcing that it has offered to acquire the biotech company Prometheus Biosciences for approximately $10.8bn, and its developing anti-TL1A pipeline agent, PRA023 (now known as MK-7240), along with a clinical diagnostic test (CDx) concurrently being developed. At the time of MSDā€™s announcement, MK-7240 was still relatively early in its development, having just reported preliminary data from the Phase IIa (APOLLO-CD) and II (ARTEMIS-UC) trials at the European Crohnā€™s and Colitis Organization (ECCO) the prior month.

Following the acquisition of Prometheus by MSD, action within the space continued with the announcement on 4 Oct of the collaboration between Sanofi and Teva to co-develop and co-commercialise Tevaā€™s anti-TL1A asset, TEV-ā€˜574. Under the agreement, Teva received an initial payment of $500m, with the potential of additional compensation totalling $1bn with development and launch milestones. The two companies will equally share the development costs globally and net profits and losses in major markets, with other markets subject to a royalty arrangement. Finally, the most recent and major deal within this class was the proposed acquisition of Roivantā€™s anti-TL1A, RVT-3101, by Roche for $7.1bn this past October.

The promise of TL1A as a therapeutic target with IBD is partially due to the involvement of the cytokine in multiple immune signalling factors (Xu et al., 2022). The downstream effects of TL1A binding to its corresponding receptor, death domain receptor 3 (DRE), involves several important proinflammatory cytokines such as tumour necrosis factor (TNF) alpha and interleukin (IL)-6 and -17 (Meylan et al., 2014). Treating IBD by targeting multiple signal pathways is a necessary approach touted by physicians and other thought leaders, as opposed to current treatments, which target individual pathways. Additionally, it has been shown that TL1A has been upregulated in IBD patients (Wallace et al., 2014).

As with all pipeline agents, the future of any drug class is speculative. After identifying the buzz around TL1A, one must acknowledge the challenges these agents will face as they attempt to enter a growing and dynamic landscape. In many ways, TL1A drugs will have to overcome multiple challenges to achieve the IBD market share required to justify the excitement and investment. This is of particular note as IBD is currently entering an inflection point, where newly approved therapies, such as the anti-IL-23s, AbbVieā€™s Skyrizi and Lillyā€™s Omvoh, are establishing themselves as next-generation treatments over the older anti-TNFs and anti-IL-12/23s.

The shifting of therapies is a critical point, as anti-TL1As will need to show significant superiority over current treatments to justify the anticipated higher costs of these drugs. It should be noted that the cost discrepancy will be compounded with the presence of biosimilars in the market, with the Humira (adalimumab) biosimilar being well-established in the US, and the biosimilar of Janssenā€™s Stelara launching well before any TL1A is expected to be approved. It should also be stated that MSDā€™s entry into TL1As came with the acquisition of Prometheusā€™s CDx (in addition to its library of biomarkers). This will allow MSD to position MK-7240 strategically as the best treatment option along with the CDx for new patients, an obvious advantage not shared by Sanofi/Tevaā€™s TEVā€˜574 or Roivantā€™s RVT-3101. This will ultimately strengthen MSDā€™s position in the space if all three assets make it to market.

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