Abatacept Shows Promise for Some Myositis Patients

An isolated T cell. Abatacept is a selective T cell costimulation modulator.

Injected abatacept may be a worthwhile treatment for certain patients with idiopathic inflammatory myositis (IIM), according to recent research.¹ Patients with the rare autoimmune conditions involving inflammation of muscle (myositis) and other organ systems suffer widespread organ dysfunction, increased morbidity, physical disabilities and early death. Symptoms vary by subtype. For example, dermatomyositis (DM) involves muscle weakness and skin rash on the face and joints; polymyositis (PM) does not. Immune-mediated necrotizing myopathy (IMNM) is a severe form of the disease marked by rapid muscle breakdown. Standard treatment for IIM is often the glucocorticoid prednisone, which has many side effects because it is given at high doses for long periods. Other common treatments include methotrexate or azathioprine, and gammaglobulin.

The phase 3 clinical trial of abatacept, commonly used to treat rheumatoid arthritis, in the treatment of patients with IIM shows the drug may present an alternative for some patients. Patients with PM and IMNM experienced benefit from injected abatacept that was sustained for a year, when added to standard therapy, with no new safety concerns.

But abatacept is not a first-line treatment. “I do advise that if you have a [patient with] necrotizing myopathy [for whom traditional first-or second-line immunosuppressive therapies [have failed to work] then it is reasonable to consider abatacept,” says Rohit Aggarwal, MD, professor of medicine at the University of Pittsburgh, associate director of the University of Pittsburgh Myositis Center, program director of the UPMC Myositis Fellowship Program and the paper’s first author.

Why Study Abatacept?

The U.S. Food & Drug Administration (FDA) has approved no drugs for IIM tested in phase 3, randomized trials. The FDA approved prednisone and adrenocorticotropic hormone in the 1950s, but to this day little data exist to suggest it is effective and safe for patients with myositis, Dr. Aggarwal notes.

He studied abatacept because “it had strong biological plausibility and rheumatologists have safety experience with it.” Abatacept blocks B and T cell interaction and prevents T cell activation. In myopathies, certain T cells infiltrate muscle tissue and damage it, and B cells produce autoantibodies that exacerbate the immune response, leading to destroyed muscle tissue. Meanwhile, a small phase 2 trial found that treatment with abatacept was associated with significant improvement of disease activity in almost half of adult patients with DM and PM, with an acceptable safety profile.²

The Study

The randomized, double-blind, placebo-controlled, phase 3 trial included 149 adult patients with IIM who had not previously responded to treatment. They received 125 mg of abatacept injected weekly plus standard treatment with prednisone (abatacept group) or a placebo plus prednisone (placebo group) weekly. Patients had IIM including DM, PM, IMNM or overlapping myositis. The study involved 58 clinical sites in 11 countries.

After a 24-week, double-blind period, a 28-week open-label period determined outcomes from continued therapy with abatacept in a group of placebo patients who switched to treatment with 125 mg of abatacept and usual treatment weekly.

The study’s primary end point was International Myositis Assessment and Clinical Studies (IMACS) definition of improvement at week 24. Secondary end points were efficacy and safety.

Results

In the double-blind period, 56% of the abatacept group and 42.5% of the placebo group met the IMACS definition of improvement. Analysis by IIM subtype, however, showed that observed differences between the abatacept and placebo arms were due to the improvements in PM and IMNM patients. DM patient outcomes did not differ significantly between treatment groups. Among PM and IMNM patients in the abatacept group, the response rate was 57.1% vs. 32.3% for patients in the placebo group.

Patients continuing to the open-label period demonstrated continued benefit up to week 52, regardless of original treatment group or IIM subtype. Among them, 69.8% of patients who continued abatacept and 69.0% of those who switched to abatacept from placebo improved. This result suggests a sustained benefit with abatacept up to one year.

The study failed to meet its primary objective, increasing the overall proportion of patients who met the IMACS improvement criteria (IMACS DOI) in the abatacept group, compared with the placebo group. The treatment arm’s response rate of 56% was very close to the rate expected based on prior data. But the response rate for the placebo group (42.5%) was higher than expected, leading to negative results. However, in subgroup analysis, PM/IMNM showed statistically significant improvement compared with placebo, Dr. Aggarwal notes.

Overall, these results suggest that patients with PM and IMNM subtypes may be more responsive to treatment with abatacept than DM subtypes.

Dr. Aggarwal, whose own IIM patients have benefited from abatacept, was surprised that it did not help a higher proportion of study patients. He is more pleasantly surprised with the good results in non-DM patients, especially those with IMNM, which typically is very resistant to standard of care treatment.

Safety

Abatacept’s known side effects include respiratory infections that are occasionally serious, allergic reactions and, very rarely, malignancies. Researchers identified no new safety concerns and found that adding abatacept to standard treatment was safe and generally well tolerated by trial patients.

During the double-blind period, the abatacept and placebo groups had similar rates of adverse events, including serious ones and events leading to discontinuation. Each group had four patients with serious adverse events. Infections occurred in 25.3% of abatacept patients and 42.5% of placebo patients. Serious infections occurred in 14.5% of abatacept patients and 6.3% of the switch group. No malignancies occurred in either group. One death in the placebo arm was due to an unexplained acute respiratory event.

During the open-label period, the observed safety profile was similar, the researchers report.

What’s Next

Despite promising results, the trial sponsor has decided to forgo regulatory approval for abatacept for non-DM patients, Dr. Aggarwal says.

Despite this decision, findings from the trial have advanced the field, Dr. Aggarwal maintains. “We have proved that targeting an interaction between B and T cells and preventing activation of the T cells gets efficacy in myositis and is safe,” he explains. “That means future novel therapies that target T cells or the interaction between B and T cells could be very lucrative in myositis.” This knowledge could be used to find other novel therapeutic targets.

In the meantime, as rheumatologists in both academic centers and general practices continue to see some patients with IIM, abatacept might help a portion of them. “Based on this trial, abatacept is a reasonable option for patients with myositis, especially necrotizing myopathy, once they are failing their initial lines of treatment,” Dr. Aggarwal notes.

Deborah Levenson is a writer and editor based in College Park, Md.

References

1. Aggarwal R, Lundberg IE, Song YW, et al. Efficacy and safety of subcutaneous abatacept plus standard treatment for active idiopathic inflammatory myopathy: Phase III randomized, controlled trial. Arthritis Rheumatol, 2024 Nov 28, Online ahead of print.
2. Tjärnlund A, Tang Q, Wick C, et al. Abatacept in the treatment of adult dermatomyositis and polymyositis: A randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis. 2018 Jan;77(1):55-62.

Disclosures

Dr. Aggarwal has received grants or contracts from Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono and Q32. He has received consulting fees from Actigraph, Alexion, ANI Pharmaceutical, Argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta Bio, Capella, Corbus, CSL Behring, EMD Serono, Galapagos, Horizontal Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Octapharma, Pfizer, Roivant, Sanofi and Teva.