The FDA’s long-running review of the safety of Jak inhibitors was expected to result in some sort of curtailment of use, but the strength of yesterday’s action came as a surprise. The regulator effectively concluded that an increased risk of serious cardiac events is a class effect, and limited the use of these drugs in rheumatoid arthritis to patients who have already failed on a TNF blocker.
This likely reflects how these agents are typically sequenced already, but the clear safety warning from the regulator rules out Jaks moving into earlier treatment lines in the future. It will also shore up the anti-TNFs’ dominant position in RA; these agents are already projected to remain the biggest-selling RA mechanism until at least 2026, according to Evaluate Pharma. It was concerns about the FDA’s next steps that wiped $15bn off Abbvie’s market cap yesterday, however, while the market also sought out potential beneficiaries.
Abbvie has the most to lose from the FDA's hardening stance here. Rinvoq is the company’s biggest sales growth driver, according to the sellside, with the Jak1 inhibitor forecast to balloon into a $9bn-a-year product by 2026. RA was expected to account for around half of those sales, and although the FDA’s action only applies to the US this country was expected to be by far the most lucrative region, accounting for two thirds of total sales.
The fear is that the FDA will not stop at RA, in terms of imposing strict conditions of use or approving suboptimal dosages. Jaks are lining up to win approvals in other inflammatory conditions like psoriatic arthritis and atopic dermatitis, and other diseases that are considered less life-limiting, like alopecia. The risk that these applications will be turned down also cannot be ruled out.
Pfizer is another potential big loser here: the company has focused development of its new Jak inhibitor abrocitinib on atopic dermatitis, with an FDA decision delayed since April. The graph below shows that the sellside has pencilled in sales of almost $15bn across the Jak class by 2026, according to Evaluate Pharma, numbers that now look less likely to become reality.
It seems that the FDA has shrugged off the differences between these Jak inhibitors that developers have tried to play up over the years. Abbvie, for example, has long argued that Rinvoq’s selectivity for Jak1 makes it safer than molecules that also hit Jak2 and 3 kinases.
Developers of Tyk2 inhibitors will be shifting nervously – as Leerink analysts point out, Tyk2 is called “the fourth Jak” by sceptics and is different only in its name, rather than kinase functionality. Bristol Myers Squibb and Pfizer are the big Tyk2 players.
Thus the quandary for Abbvie is whether it should attempt to disprove any class effect by conducting a large cardiovascular outcomes study with Rinvoq. This seems unlikely to be worth the risk, given the chance of the move backfiring. The company might consider refocusing on its second major growth driver, Skyrizi, to be a better bet.
Skyrizi is an anti-IL-23 antibody, a class that has proven very effective in psoriasis with big potential also seen in inflammatory bowel conditions. Indeed, Leerink named this mechanism as one of the beneficiaries from the Jak safety fallout. Other IL-23 players include Johnson & Johnson with Tremfya and Lilly with mirikizumab.
Assuming that the FDA also pushes back on Jak use in atopic dermatitis, the competitive threat to Sanofi and Regeneron’s Dupixent will also dim. Meanwhile, the makers of anti-TNF agents can continue to count the money; the dominant product here is of course Abbvie’s Humira. These drugs have already held off biosimilars for an improbable amount of time, with Humira copycats not due in the US until 2023 and biosimilars of Amgen’s Enbrel possibly unable to enter until the end of the decade.
Developers working on novel mechanisms might also benefit from the blunting of strong competitors, and several smaller groups saw share price jumps yesterday. These included Aclaris, which has had early success with its MK2 inhibitor in RA, and Arena, which is hoping that its S1P modulator etrasimod will yield positive results in various inflammatory bowel diseases over the coming months.
Biopharma watchers will also be pondering the broader repercussions of the FDA's move here. Leerink analysts described the action as "extraordinary", saying the agency's stance was hard to justify considering the data available and the not inconsiderable risks carried by anti-TNFs. They pondered whether "this amounts to continuing politicisation of the FDA’s decision making".
Political or not, the situation does provide another example of a widening gulf between European and US regulators when it comes to risks versus benefits. This was also seen recently with roxadustat, the Fibrogen drug that was approved by the EMA but remains stalled at the FDA, also on cardiac safety concerns. The EMA, meanwhile, has shown no indication of restricting Jak usage.
The full picture of how the FDA will handle the upcoming Jak approval decisions has yet to emerge, but it seems that the regulator has once again adopted a very cautious stance. While there might well be some immediate beneficiaries from any Jak cap, those developing novel mechanisms in big disease settings should be asking whether the safety bars are rising in the US.