‘Risk averse’ rheumatologists report declining JAK use, increased reliance on abatacept
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The safety signals for cardiovascular events and malignancy associated with Janus kinase inhibitors in rheumatoid arthritis have led to rheumatologists increasingly reaching for abatacept instead, according to data.
The market analysis firm Spherix Global Insights surveyed 102 rheumatologists through the first quarter of 2022 and found that rheumatologists are increasingly opting for abatacept (Orencia, Bristol Myers Squibb) over JAK inhibitors.
The analysists at Spherix attribute the shift to negative results of the ORAL Surveillance study, which was published in January 2021 and led the FDA to add a black-box warning for JAK inhibitors, including new and updated alerts for baricitinib (Olumiant, Eli Lilly & Co.) and upadacitinib (Rinvoq, AbbVie) due to an excess risk for serious heart-related events, cancer, blood clots and death. That was in addition to a previous alert for serious health-related problems and cancer linked to tofacitinib (Xeljanz, Pfizer), compared with TNF inhibitors among older patients.
“Spherix has been tracking physician perceptions of the market for years and I can tell you that early on, when the JAK class began raising eyebrows with signals of increased risk of [venous thromboembolism], rheumatologists expressed only slight concern about the potential safety issues,” Maxine Yarnall, franchise head of rheumatology at Spherix Global Insights, told Healio Rheumatology.
For example, in previous surveys, when asked about their comfort level in prescribing JAK inhibitors across patient types, respondents only expressed notably declined comfort in patients older than 65 years — which Yarnall suggested was in in response to ORAL Surveillance — and patients younger than 18.
“This latter point was not a surprise given that our sample does not include pediatric rheumatologists,” she said. “They are likely less comfortable treating that patient base in general.”
According to Spherix, upadacitinib recently experienced “a minor decline in physician-reported brand share” for the first time since it emerged on the market.
Meanwhile, tofacitinib’s share has “slowly trickled” throughout the last year as physicians awaited more details on the outcome of the FDA's revised label, the company added.
“With the FDA black-box warnings and restrictions on use of JAK inhibitors after TNF inhibitors, the findings [from Spherix] are not surprising,” Stanley Cohen, MD, clinical professor in the department of internal medicine at the University of Texas Southwestern Medical School, and medical codirector of the Metroplex Clinical Research Center, said in an interview. “They confirm what we would have expected.”
‘Clinicians are risk averse’
The Spherix survey asked physician respondents about the last five prescriptions they wrote. The results suggest that new prescription shares for tofacitinib and upadacitinib have “sharply declined” in the past year. Conversely, over that period, abatacept prescriptions doubled.
“The ORAL Surveillance results fueled negative perceptions of the JAK class, particularly Pfizer's Xeljanz,” Yarnall said. “Favoritism for Rinvoq over Xeljanz had already been building since its 2019 approval in RA, and these results seemingly gave physicians the extra push they needed to pull further away from Xeljanz, even despite the class-wide label update.”
Other data from the survey demonstrated what rheumatologists prescribe when looking for an alternative mechanism of action after a TNF inhibitor fails.
“Interestingly, preference for Bristol Myer Squibb’s Orencia post-TNF use has been increasing at nearly the same rate that preference for the JAKs has been decreasing,” read the Spherix press release. “In the most recent report, two-fifths of respondents selected Orencia as their preferred agent to prescribe when discontinuing a TNF agent.”
When survey respondents are queried about brand attributes that are the most important in making treatment decisions, efficacy was consistently rated as the most important, followed by long-term safety, according to Yarnall.
“When asked to rate RA brands on their performance on key metrics, surveyed rheumatologists rate Orencia very favorably on safety attributes, such as tolerability, long-term safety and no serious adverse events,” she said. “However, its overall efficacy is seen as average and the brand rates poorly on onset of action, particularly in comparison to the rest of the competitive set.”
According to Cohen, abatacept is an effective therapy with similar efficacy to JAK inhibitors.
“But there is no signal suggesting an increase in MACE or malignancy in high-risk patients,” he added.
Cohen acknowledged, however, that abatacept has not yet been tested in this high-risk group.
“But most observational studies have suggested a good safety profile with abatacept,” he said. “It is often used in patients with comorbidities.”
Yarnall added that JAK inhibitors do not perform well on safety metrics and are seen as on par with other RA agents for most key efficacy metrics.
Ultimately, there may be two simple reasons for the shifts in RA market share from the JAK class to abatacept, according to Cohen.
“Clinicians are risk averse,” he said. “And now we have ample treatment alternatives.”
‘Limited to TNF failures’
According to Spherix, when physicians were asked to select their preferred alternate mechanism of action after a TNF inhibitor, the preference for abatacept grew from 32% in the first quarter of 2021 to 42% in the first quarter of 2022.
“JAKs seem to be taking the brunt of this growth, declining from 44% to 31%, respectively,” Yarnall said. “Furthermore, physicians are anticipating increasing their use of Orencia over the next six months.”
TNF inhibition remains the “mainstay” of treatment in RA and will likely continue to be, even with new alternate mechanisms of action coming to market, Yarnall added.
“They are effective, trusted and physicians have longstanding experiences with them,” she said.
However, Yarnall acknowledged that there is a significant number of patients with RA who have failed on TNF inhibition, or for whom these drugs are contraindicated.
“There is an opportunity for manufacturers of legacy products such as Orencia to capitalize on safety perceptions associated with the JAK class, or even future pipeline products to showcase other effective treatments that are considered safe,” she said.
It remains unclear whether the market will, in fact, follow this pattern, or whether new data will emerge on JAK inhibitors or abatacept that will shift the landscape again.
Said Cohen: “For now, until we better understand the signal from ORAL Surveillance, JAK inhibitor use in immune-mediated diseases will be limited to TNF failures.”
References:
Spherix press release:
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Healio interviews.
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