While Pfizer has witnessed a positive experience regarding the development of its Janus kinase (JAK) inhibitors, there is the distinct possibility that having so much of its portfolio dependent on JAK inhibitors may cost the company in the long run. A combination of drug class safety concerns, impending patent expiration and the looming threat of direct competition in various indications threatens the potential benefits Pfizer is currently seeing in the development of its JAK inhibitor portfolio, says GlobalData, a leading data and analytics company.

Antoine Grey, Senior Immunology Analyst at GlobalData, comments: “Despite positive news in ankylosing spondylitis (AS), Xeljanz (tofacitinib) already has a troubled past – having had a boxed warning added to its label due to the increased risk of pulmonary embolism associated with the higher 10mg dose. The drug’s appeal is also marred by the fact that the 5mg and 10mg doses of Xeljanz need to be administered twice daily, rather than once daily as most JAK inhibitors are.

“To add insult to injury, Xeljanz will only have a couple of years on the AS market before suffering the influx of tofacitinib generics when its constraining patent expires in 2025 in the US. October 2020 saw the first tentative market approval for generic tofacitinib, manufactured by Zydus Cadila, suggesting patients will have access to the generic version as soon as Xeljanz’s patent expires. As a result, GlobalData forecasts 2028 sales of $18.2m for Xeljanz in the seven major markets (7MM*), which is a significant dip from expected peak sales of $88.7m in 2025.”

The future looks brighter for abrocitinib in atopic dermatitis. Having received Priority Review designation from the Food and Drug Administration (FDA) in October 2020, the drug has been fast-tracked to receive approval in April 2021, and has had its development sped up by being granted Breakthrough Therapy designation. Whereas Xeljanz is taken twice daily, abrocitinib is administered once daily and targets JAK1 specifically, rather than JAK1 and 3 in the manner of Xeljanz. All this combined led GlobalData to forecast 2027 abrocitinib sales of $1.5bn, beating out Rinvoq, which is also attempting to gain approval in AD.

Grey continues: “There are still concerns over abrocitinib’s potential performance. Firstly, it is still unclear whether JAK specificity in its mechanism of action contributes to efficacy or safety. Secondly, the latest results from JADE REGIMEN suggest abrocitinib also has a distinct side effect profile due to the incidence of adverse events being much higher in the 200mg and 100mg cohorts compared to the placebo group. Furthermore, serious adverse events were seen more frequently in the treatment groups, leading to a significantly higher study dropout rate in the 200mg cohort than either the 100mg or placebo arms.”

Even if abrocitinib’s side effect profile is deemed acceptable and it becomes the first systemic JAK inhibitor in atopic dermatitis, it will still have to contend with, Regeneron and Sanofi’s blockbuster, Dupixent (dupilumab), that is currently the gold standard of treatment in moderate-to-severe atopic dermatitis patients. Having been on the market since 2017, dermatologists are very comfortable with its mild side effect profile and may prefer it to JAK inhibitors.

Grey adds: “It is safe to say JAK inhibitors have a place in the treatment of various diseases and Pfizer has other candidates in development such as ritlecitinib and brepocitinib tosylate for various indications in rheumatology, gastroenterology and dermatology. However, the magnitude of the success of JAK inhibitors as a class is dependent on Pfizer and other pharmaceutical companies conducting post-marketing studies and collecting real-world data to ease concerns over their safety profile, as well as protecting branded JAK inhibitors from inevitable patient share erosion from generics.”

*7MM: US, France, Germany, Italy, Spain, the UK, and Japan