DENVER – Treatment-resistant dermatomyositis improved significantly with the investigational TYK2/JAK1 inhibitor brepocitinib, according to a randomized trial.
Two higher doses of brepocitinib improved the total dermatomyositis score by approximately 50% at 1 year compared with placebo. The novel therapy demonstrated superiority over placebo on all nine secondary endpoints, including skin disease, glucocorticoid tapering, and functional disability. Noticeable improvement occurred within 4 weeks.
Adverse events (AEs) occurred in similar proportions of patients treated with brepocitinib or placebo, Ruth Ann Vlugels, MD, of Brigham and Women’s Hospital in Boston, reported at the annual meeting of the American Academy of Dermatology. Study was published simultaneously in New England Journal of Medicine.
“The 30 mg dose achieved statistical significance that was robust across all 10 primary ranked endpoints,” Vluegels said. “This is important because these ranked endpoints represent improvements not only in skin but also muscle, global disease activity, severity of onset, and our ability to reduce corticosteroids – extremely impressive data.”
“For those of us who study dermatomyositis, this is truly a landmark achievement,” he said. “Most importantly, this is a major step forward for our patients who, ideally, will be able to receive a targeted, effective therapy early in their disease in the near future and avoid the side effects of systemic corticosteroids and other traditional DMARDs (disease-modifying antirheumatic drugs).”
One drug vs. two, safety
During the post-presentation discussion, Hensin Tsao, MD, PhD, of the Mass General Research Institute in Boston, asked how the combination drug differs from giving the individual components separately.
“The TYK2 inhibitor currently on the market is an allosteric inhibitor, and there is evidence that (a non-allosteric inhibitor) would be better for this population,” Velugels said. “Also, with the combination, we think that by targeting interferon-1, interferon-2, and interleukins (IL), there will be greater benefits than the traditional JAK inhibitors that I have used for many years. With existing treatments, I could not get this drug. I just couldn’t put a few things together and take brepocitinib.”
Aaron Mark Drucker, MD, of the University of Wisconsin-Madison, asked about potential long-term side effects, particularly lethality. “What should we pay attention to?”
“On the open-label extension study, I think the safety data will be exactly the same as what we’re seeing here,” Velugales said. “I think the goal of brepocitinib, over time, is to use it early rather than putting patients on steroids and methotrexate and mycophenolate mofetil and then putting brepocitinib on top, which is necessary in a phase III study like this. So I would argue that using only brepocitinib and that before that would really reduce[AEs].”
“In terms of the risk of malignancy and clots, I have no concerns from the long-term safety data,” Vluegels said. I have been using JAK inhibitors off label for many years for many diseases. …I also want to highlight that my colleagues in oncology actually use JAK inhibitors in patients who are on immunotherapy. Patients respond to immunotherapy, the immunotherapy stops working, and they now give those patients JAK inhibitors to reactivate the immune system and allow them to respond better to immunotherapy moving forward.”
Background, main results
One autoimmune diseaseDermatomyositis is characterized by inflammation and progressive damage to the muscles, skin, lungs, joints, heart, and gastrointestinal tract. Situation often follows A chronic, unpredictable and long-lasting disease, causing substantial morbidity, disability and poor quality of life (QoL). current treatment Provide incomplete efficacy and are associated with treatment-related toxicity.
“We know that patients with skin disease cycle through any number of treatments and despite being on five, six, or seven prior treatments, our best data indicates that only 14% achieve clinical disease remission,” Vlugels said. “So, this is an area where we really need targeted quick-acting, effective treatments.”
Brepocitinib is a first-in-classSelective inhibitor of TYK2/JAK1 that suppresses key cytokines involved in dermatomyositis pathogenesis, including type I and II interferons, IL-6, IL-10, IL12, and IL-23. one in proof of concept study In patients with severe, skin-predominant dermatomyositis, brepocitinib induced rapid suppression of type I and II interferon signaling, which is associated with early clinical improvement.
Vlugels reports preliminary results from Phase III Valor Randomized trial comparing two doses of brepocitinib and placebo in patients with treatment-refractory dermatomyositis. Patients received 15 or 30 mg brepocitinib or daily placebo (in addition to existing therapy) for up to 52 weeks. The primary endpoint was total improvement scoreWhich ranges from 0 (worst) to 100 (best).
Data analysis included 241 randomized patients whose mean age was 50 years. Treatment history included prior DMARD therapy in approximately 70%, and approximately 80% of patients had received at least two prior dermatomyositis-directed therapies.
Data after 52 weeks showed that the placebo group had a mean total improvement score of 31.2, compared with 37.5 for the 15-mg dose of brepocitinib and 46.5 for the 30-mg dose (P<0.001 vs placebo). The between-group difference in favor of brepocitinib 30 mg was evident as early as 4 weeks.
The difference between the lower brepocitinib dose and placebo and between the higher and lower brepocitinib doses did not reach statistical significance. Among patients taking systemic corticosteroids at baseline, 62% of the high-dose brepocitinib arm were tapered to ≤2.5 mg/day, and 42% were tapered to 0, compared with 3% and 23% of patients taking 15 mg brepocitinib and placebo, respectively.
For all nine key secondary endpoints, the higher dose of brepocitinib led to significantly better outcomes than placebo (P=0.04 to P<0.001). Improvements covered all aspects of skin disease, including disease activity, pruritus, and skin-related QOL.
The incidence of all AEs was similar across treatment groups (86–91%). The most common any grade AEs (≥5%) in either group were upper respiratory tract infection, COVID, urinary tract infection, nausea, diarrhea, and headache. Serious infections occurred more frequently with brepocitinib 30 mg (10% versus 2% for brepocitinib 15 mg and 1% for placebo), but all infections resolved with treatment, and most patients completed treatment.
