‘Split’ decision: JAK inhibitors have delivered on only part of their promise
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Janus kinase inhibitors have delivered on some, but not all, of the promises that were expected of them upon approval in 2012, a speaker said at EULAR 2022 Congress.
“I am trying to bring to you arguments for why particular promises associated with JAK inhibition have been fulfilled and why others have not,” Hendrik Schulze-Koops, MD, of the Ludwig Maximilian University of Munich, said in his presentation.
He was careful to note that the talk was not about individual drugs, but about the class itself and whether it has lived up to expectations. Specifically, Schulze-Koops aimed to discuss the promise of JAK inhibitors in terms of efficacy, adherence, safety and mechanism of action.
Regarding efficacy of the drug class, Schulze-Koops zeroed in on rheumatoid arthritis. He presented a cross-section of data comparing JAK inhibitors with mainstays like methotrexate, TNF inhibitors and other biologic drugs.
“In efficacy, at least in RA, the drugs are at least at the level of biological DMARDs in terms of clinical and radiographic response,” he said.
He added that JAK inhibitors show these responses, in particular, in methotrexate or TNF non-responders.
“They also do this in the first-line,” he added.
That said, Schulze-Koops noted that there are other details pertaining to efficacy where JAK inhibitors have not met the promise. Those include induction of disease remission, inhibition of progression and a cure for RA.
“So, it is a split,” he said. “They can fill the gap of ACR20, -50, -70 response, but to fill the gap of ACR100, or 100% disease remission, is not fulfilled.”
Turning to adherence, Schulze-Koops discussed the drugs’ duration of action.
“In essence, JAK inhibitors have a longer half-life with a patient,” he said. “They are clinically efficacious for longer.”
Importantly, many patients continue to see efficacy with JAK inhibitors regardless of other drugs they may be taking.
“It is really not a problem with or without methotrexate with regard to the adherence of the patient [to a JAK inhibitor],” Schulze-Koops said.
It is for this reason that he believes that the promise of JAK inhibitors is “given” regarding drug adherence.
For safety, Schulze-Koops stressed that recent data have changed the equation for JAK inhibitors. He noted that since the approval of tofacitinib (Xeljanz, Pfizer) in 2012, more than 200,000 patients have been studied for safety outcomes in pre- and post-marketing studies.
“It appears that this an enormous amount of data to draw our safety statements from,” Schulze-Koops said.
Early signals in those trials showed a potential increase in herpes zoster reactivation risk but an “otherwise benign profile,” according to Schulze-Koops.
However, he noted that recent findings from the ORAL Surveillance trial raised questions about risks for not only infections, but also cardiovascular outcomes and malignancy associated with JAK inhibitors.
“So, all of a sudden, we have a situation where it appears that certain populations have a risk of MACE or malignancies,” Schulze-Koops said.
However, these findings are drug-specific, and further studies are necessary.
“We should wait until we have really the conclusive evidence of why this happens in order to close the book here,” he said
The final promise of JAK inhibitors Schulze-Koops addressed pertained to whether the drugs have a simple mechanism of action. He noted that there are 580 kinases in the human body and that trying to inhibit just one of them in any given patient is a challenge.
“We have to accept that it is never 100% specific and never 100% selective in any given live situation,” he said. “One or the other may be effected in kinase inhibition.”
With this in mind, Schulze-Koops concluded that JAK inhibitors do, in fact, have a simple mode of action.
“But the role of specificity and the role of selectivity and the role of pathogenesis is completely unknown,” he said. “So this promise is fulfilled in part but we need to learn much more in order to understand exactly how a JAK inhibitor works.”
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Schulze-Koops H. JAKi: Are all promises fulfilled? Presented at: EULAR 2022 Congress; June 1-4, 2022 (virtual meeting).
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