Amid safety concerns, FDA grants two new JAK approvals — but with added warnings and a key label change
After a post-marketing trial for Pfizer’s Xeljanz turned up concerning safety results at the beginning of the year, thwarting the whole JAK class, the FDA is finally rolling out some new approvals — but with added warnings and a key label change.
Both Xeljanz and AbbVie’s Rinvoq got cleared for new indications on Tuesday, but on one condition: They can only be taken after a patient has failed on one or more tumor necrosis factor (TNF) blockers, like Humira or Enbrel.
Earlier this month, the FDA slapped boxed warnings on the labels of Xeljanz, Rinvoq and Eli Lilly’s Olumiant, flagging the risk of cardiovascular events such as heart attack or stroke in high-risk patients who are 50 years and older, especially those with other risk factors such as current or past smokers.
Xeljanz is now approved for adults with active ankylosing spondylitis, a rare type of arthritis that causes pain and stiffness in the spine. And Rinvoq pulled a win in adults with active psoriatic arthritis, a type of inflammatory arthritis that causes joint pain, stiffness and swelling.
The latest fallout over JAK safety began back in January, when Xeljanz failed a six-year post-marketing safety study across 4,362 rheumatoid arthritis patients. Researchers found that those who received either a low or high dose of Xeljanz experienced more major cardiovascular events — such as stroke and heart attack — than those on Humira or Enbrel. They also had higher rates of cancer, with Pfizer failing to hit non-inferiority on both primary endpoints.
The study renewed some difficult questions for JAK inhibitors more broadly, a class that generated significant efficacy in autoimmune conditions but faced repeated safety concerns.
In the first week of December, the FDA concluded that there’s an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots and death associated with Xeljanz, and put updated warnings on that drug and two others. Although Olumiant and Rinvoq hadn’t been studied in large safety trials, regulators decided that they may pose similar risks, as they share the same mechanism of action.
The Xeljanz approval is based on data from a Phase III trial, showing that twice-daily 5 mg doses of the blockbuster drug helped 56.4% of patients achieve an improvement of at least 20% on the Assessment in SpondyloArthritis international Society scale (ASAS20), compared to just 29.4% of placebo patients (p<0.0001).
Just over 40% of patients on Xeljanz achieved an ASAS40 response, compared to 12.5% on placebo, according to Pfizer. The safety profile was similar to that in approved indications of rheumatoid arthritis and psoriatic arthritis, the company said.
Meanwhile, Rinvoq helped psoriatic arthritis patients treated with 15 mg doses achieve higher ACR50 responses (an improvement of at least 50% on the American College of Rheumatology scale) compared to placebo in two Phase III trials. In the trials, 38% and 32% of patients on Rinvoq achieved ACR50, compared to 13% and 5% on placebo, respectively.
The Rinvoq arms also boasted 16% and 9% ACR70 responses, compared to 2% and 1% in the placebo arms, respectively. And the drug was seen to significantly inhibit the progression of structural joint damage compared to placebo, according to AbbVie. The company said Rinvoq’s safety profile was consistent with that in patients with rheumatoid arthritis.
Now, we’ll wait to see if the added warnings affect the drugs’ performances. Xeljanz pulled in $2.4 billion in 2020, and Rinvoq was a bit behind it with $731 million in net sales.