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Opportunity remains despite regulatory and access obstacles.
In the complex world of immunology, where drivers behind disease aren’t fully understood, pharmaceutical companies race to discover blockbuster mechanisms of action that will be safe and efficacious for a broad range of indications. One of these mechanisms that has been quickly climbing to the surface in the past decade is the Janus kinase (JAK) inhibitor family, which shows promise in treating a variety of autoimmune conditions. However, with the development of any new molecule comes unexpected hurdles and the JAKs have experienced this firsthand with recently updated safety warnings by FDA this past year. This article explores the entry and rapid expansion of the JAK inhibitors in immunology, the rise of next-generation JAKs and novel JAK-adjacent-targeted kinase inhibitors, and what manufacturers can learn from the regulatory obstacles new molecules can face.
Tofacitinib became the first JAK approved in immunology in 2012, when it received FDA approval for moderate-to-severe rheumatoid arthritis. As the first pill form treatment option in a space dominated by injectable biologics, the breakthrough mechanism offered the potential for an improved patient experience and appeared set to become the first of many JAK inhibitor game-changers for the crowded antirheumatic marketplace. Within years, tofacitinib received approval for the treatment of psoriatic arthritis and ulcerative colitis. Additional oral JAKs baricitinib and ruxolitinib received FDA approval in 2018 for rheumatoid arthritis and 2019 for steroid-refractory acute graft-versus-host disease (GVHD), respectively.
The early generations of tofacitinib, baricitinib, and ruxolitinib were pan-JAKs, which means they targeted several family kinases, for example, Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2). This lack of specificity first became a concern when the tofacitinib clinical trials in rheumatoid arthritis showed signals of a series of side effects, including increased risk of opportunistic infections, lymphomas, and other cancers. This led FDA to require an ongoing safety clinical trial as part of post-marketing surveillance, and approve tofacitinib with a boxed warning and risk evaluation and mitigation strategy (REMS) requirement to warn patients of potential risks.1 As the results from the post-marketing trial began to be analyzed, FDA updated the boxed warning in 2019 to include risk of pulmonary embolism and increased mortality in the 10mg dose of tofacitinib, which is approved in ulcerative colitis.2
As a result of these safety concerns, the clinical community has been somewhat wary in its adoption of JAKs, and JAK inhibitors have largely failed to gain traction as a frontline agent against anti-TNF agents. Adding further complications for the JAKs, in September 2021, FDA updated the tofacitinib boxed warning for serious heart-related problems, blood clots, cancer, and death to include both the 10mg ulcerative colitis dose and lower 5mg dose in rheumatoid and psoriatic arthritis.3 What surprised both physicians and manufacturers worldwide was the agency’s decision to include the other approved arthritic JAKs, baricitinib and upadacitinib, in their warnings, due to their common mechanism of action (MOA) despite the lack of similar large-scale safety trials for these agents. Upadacitinib, a JAK1 selective inhibitor, is thought to have a better safety profile compared with the other two pan-JAKs, due to its more targeted approach. However, FDA recommended physicians reserve use of all of these JAKs for anti-TNF refractory patients, further discouraging use.
Similar to FDA’s decision, the European Medicines Agency (EMA) noted the risk of malignancy and blood clots in tofacitinib and upadacitinib, based on results from these individual agents’ clinical trials, and marked them with an additional monitoring requirement.4 However, they appear to be taking a different approach than FDA by not grouping baricitinib into this same category and not marking the agent’s label with a black inverted triangle (▼) while long-term safety investigations are still ongoing. It is still yet to be seen whether this agent-by-agent approach to safety warnings will remain as more JAK inhibitors come into the European market.
Meanwhile, as the JAK class coped with its emerging safety concerns, the immunology pipeline grew with successors. These next-gen JAKs take a more targeted approach by selectively inhibiting specific receptors or tailoring their delivery to a specific area associated with a condition in an attempt to minimize the adverse events and avoid regulatory warnings seen in their predecessors.
TYK2 inhibitors are one such mechanism that have been following this playbook. PF-06826647, brepocitinib, and deucravacitinib are all currently in development for a variety of autoimmune conditions, with the latter two TYK2 agents showing solid efficacy and safety in the treatment of plaque psoriasis.5,6 However, outlook for these agents across immunology more broadly is uncertain, as deucravacitinib, which despite reporting safety consistent with previously reported studies, did not meet the efficacy endpoints in one of its two ulcerative colitis trials.7 Thus, the question remains whether the targeted nature of next-gen selective JAKs may limit the efficacy effect of the agent and fail to outweigh any safety improvements across immunology indications.
Other approaches have attempted to target delivery of JAK inhibitors in hopes of curbing systemic effects. For instance, companies have been studying JAK inhibitors designed to exclusively target the gastrointestinal tract for the treatment of Crohn’s disease or have formulated JAKs as a topical cream for use in dermatological conditions. However, this more targeted approach has so far failed to avert the JAK class’ safety baggage, with the topical formulation of ruxolitinib receiving a boxed warning for JAK class effects with its FDA approval for atopic dermatitis in September 20218 despite general belief from experts that systemic absorption from a topical formulation is unlikely.
A similar situation of mixed success has come from several classes of JAK-adjacent novel kinases in development, including Bruton’s tyrosine kinases (BTK), interleukin-1 receptor-associated kinases (IRAK), and salt-inducible kinases (SIK). These agents aim to target immune pathways with increased specificity to try and mitigate potential adverse safety events, while still achieving broad-reaching efficacy across a range of immunological conditions. However, in cases to date where efficacy endpoints have been met, safety signals such as a high rate of infections and dose-limiting toxicity have been drawbacks. This seemingly repetitive pattern begs the question of how FDA might approach regulatory decisions for future kinase inhibitors in immunology, and whether they will consider each agent’s data in isolation or assume a class effect as seen with the JAKs.
As recent decisions by FDA indicate, despite drug developers’ focus on improving safety via new entries within the JAK inhibitor class, stringent safety warnings are likely to be applied class-wide in the US. However, this regulatory scenario will not necessarily hold true globally. With the more individualized approach taken by the EMA thus far given baricitinib’s lack of an additional monitoring requirement, it remains to be seen whether European regulators will continue to take a more product-specific approach in applying warning labels for new selective JAK and JAK-adjacent agents. However, regulatory decisions can change quickly with the release of new clinical data and post-marketing surveillance, so the impact of the JAK reputation on this new generation is undetermined. And while many pharma manufacturers developing JAKs are acutely aware of these dynamics, the outstanding question remains whether kinase inhibitors acting on other similar immune pathways will ultimately contend with similar safety rulings from health authorities.
Looking toward the future of kinases in immunology, the path forward is anything but clear cut. As more next-gen JAK and JAK-adjacent therapies progress toward entering the market, there are a number of challenges that will be key factors in determining the success of these agents.
First is the question of whether these agents’ perceptions will be complicated by the safety concerns of the first-generation pan-JAKs. The extent to which next-gen JAKs and JAK-adjacent therapies will be able to distance and differentiate themselves clinically as well as reputationally remains to be seen, and will be a key factor affecting both regulatory decisions and physician treatment choices. Additionally to be determined is the extent to which alternative routes of administration (for example, topical JAK formulations for dermatology) can aid perceptions, helping agents overcome the JAK safety baggage and propel them to success.
However, on the other side of the spectrum, there is also uncertainty around whether agents will be able to hit the necessary efficacy endpoints. Particularly with the selective next-gen JAKs, whether these therapies have over-indexed on safety to the detriment of efficacy via these more targeted as mechanisms will be an important question as players look to build cross-immunology franchises.
Finally, the potentially bifurcated way in which health authorities in the US and EU may handle JAK safety concerns will have downstream implications in each market. Regulators’ differing approaches will impact line of therapy and require developers to tailor commercial strategies on a per-geography basis to account for differing competitive landscapes and subsequent clinical trial comparators as well as pricing and access strategy.
So where does this leave the JAK players in immunology? While there is significant interest and remaining need in these indications, uncertainty and headwinds from regulatory, access, and clinical vantage points loom large. However, opportunity remains, and those innovators who can channel and seize the opportunity via careful commercial development and planning are poised to potentially make big splashes with their kinase inhibitors.
Brian Kwak is a director, Karina Ikeda is a senior consultant, and Natalya Stone is a consultant; all within the life sciences practice at Guidehouse
We would like to acknowledge and thank John Etchberger for his expertise and direction in developing this piece. We would also like to thank Raghav Sridhar for his assistance with research into immunology assets in development.