The current mainstay treatments for IBD include immunomodulators (methotrexate and thiopurines), biologics (TNF-α being the most commonly used) and other monoclonal antibodies such as the anti-integrins and anti-interleukins (IL-12/23). The leading assets in moderate-to-severe UC include Takeda’s Entyvio (α4β7) for 1L and AbbVie’s Rinvoq (JAK1) for 2L patients. In CD, AbbVie’s Skyrizi (anti-IL-23) has seen significant traction alongside Rinvoq, which has some of the best data in CD as it does in UC. The major recurring issue for IBD patients continues to be primary and secondary loss of response, with often ‘diminishing returns’ in terms of efficacy for the next line of therapies. Additionally, most clinical trials show a response rate of <60%, which only worsens with each failing drug. In the last few years, there has been an influx of new and emerging therapies that are showing promising efficacy results in patients who have previously failed to respond to multiple drugs.
One potential barrier to these up-and-coming therapies is the loyalty to the steadfast therapies, such as Humira, which is evidenced by the fact that its biosimilars have largely been unable to displace Humira even though some of the alternatives cost around 85% less. However, sometimes change is needed and new entrants into the IBD pipeline have been gaining traction, with specific interest seen in TL1A inhibitors from some key players. Over the past year, Merck acquired PRA023 from Prometheus Biosciences, Sanofi and Teva announced an exclusive collaboration for TEV’574, and Roche acquired RVT-3101 from Roivant and has an option to enter into a global collaboration with Pfizer for the next-generation p40/TL1A directed bispecific antibody that is currently in Ph1. The latest investment in this class has been by AbbVie, who announced a licensing agreement with FutureGen to develop FG-M701, a next-generation TL1A antibody that is currently in preclinical development. What do these companies know that we don’t to substantiate this surge in investment?
The current data highlights that this class may alleviate an unmet need by demonstrating efficacy in a more refractory patient population (bio-exposed). There is also data detailing the correlation between TL1A upregulation and disease severity to reinforce the MoA. However, opinions are divided on whether this class can actually disrupt the current 1L therapies or if they will only be considered as 1L pending positive biomarker testing, in which there have been mixed results. In my opinion, TL1A inhibitors will only displace the current blockbuster therapies if the efficacy demonstrated in biomarker-positive patients is significantly better. Yet, what does significantly better efficacy mean to HCPs and patients? Another factor to consider in relation to the therapeutic positioning of TL1A’s may be HCPs perceptions of biomarker testing, and the “want” or “ability” to carry out the specific tests. This can similarly be applied to the patient in that will additional testing increase the disease burden, especially if these patients have failed previous therapies and subsequently, this could present as a barrier to prescription. Of course, the next wave of data will inform on whether this class has the guts to disrupt the current leaders – hang tight!
Author: Heather Ging, Solici