SAN DIEGO – The use of abatacept (Orencia) in individuals at risk of developing rheumatoid arthritis is feasible, results from a proof-of-concept, phase 2b study showed.
The findings are encouraging because data from at-risk cohorts have reported rates of progression to RA in excess of 50% over 24 months, Andrew Cope, MBBS, PhD, head of the Center for Rheumatic Diseases at King’s College London, said during an abstract session at the annual meeting of the American College of Rheumatology. “If we’re going to do interception trials, we need to make sure that the risk-benefit is about right, and we also need to have enough events in the placebo arm against which to compare any impact of a drug,” he said.
Dr. Andrew Cope
For the randomized, placebo-controlled study known as the Arthritis Prevention in the Pre-clinical Phase of RA with Abatacept (APIPPRA) trial, Dr. Cope and colleagues at 28 sites in the United Kingdom and 3 in the Netherlands set out to evaluate the feasibility, efficacy, and acceptability of abatacept therapy in subjects at high risk of developing RA and to characterize the effects of T-cell costimulation modulation on the evaluation of immune and inflammatory responses associated with anti–citrullinated protein antibody (ACPA) prior to, during, and after therapy. They enrolled male and female individuals aged 18 and older with arthralgia, considered to be inflammatory in nature, and who were either ACPA and rheumatoid factor (RF) positive, or had high-titer ACPA. The researchers excluded individuals with clinically apparent arthritis, or a history of inflammatory arthritis as assessed by a rheumatologist, as well as those with a history or current use of conventional or targeted synthetic or biologic disease-modifying antirheumatic drugs (DMARDs), or oral or parenteral use of corticosteroids. They also excluded people with comorbidities requiring treatment with immunosuppressive or immune-modulating therapy, those who had received a live vaccine in the prior 3 months, as well as those who were pregnant or breastfeeding.
Study participants were randomized 1:1 to receive 52 weekly subcutaneous injections of placebo or 125 mg abatacept and were followed for another 52 weeks. The primary endpoint was time to development of clinically apparent arthritis in at least three joints, or to fulfillment of the ACR/European Alliance of Associations for Rheumatology 2010 criteria for RA, whichever comes first, during 24 months of follow-up, with joint synovitis confirmed by ultrasound.
Dr. Cope reported results from 103 patients in the placebo arm and 110 patients in the abatacept arm. Their mean age was 49 years and 77% were female. At baseline, 73% of study participants had a power Doppler score of 0, which suggests minimal levels of active subclinical synovitis in a substantial proportion of this at-risk trial population. At 52 weeks, the researchers observed 30 events in the placebo arm (29%) and 7 in the abatacept arm (6%), while at 104 weeks, there were 38 events in the placebo arm (37%) and 27 in the abatacept arm (25%). This reflected a difference in mean arthritis-free survival time between arms of 99.2 days in favor of abatacept (P = .002).
Prespecified exploratory analysis showed that individuals with high levels of ACPA or who had an extended autoantibody profile at baseline were more likely to remain arthritis-free after abatacept therapy. “So, we’re seeing a hint here that there is an abatacept-sensitive population,” Dr. Cope said.
There were 7 serious adverse events in the abatacept group and 11 in the placebo group, including 2 deaths, 1 in each arm. None of the deaths were attributable to the study drug.
In other findings during the treatment phase, subjects in the abatacept arm, when compared to those in the placebo arm, had reduced levels of anxiety on the Hospital Anxiety Depression Scale; reduced fatigue, improved physical and emotional well-being, and improved functional well-being on the Functional Assessment of Chronic Illness Therapy-Fatigue measure; reduced sleep problems on the Symptoms in Persons at Risk of Rheumatoid Arthritis questionnaire; positive impact on work instability on the RA Work Instability Scale, and a positive impact on illness beliefs.
Dr. Jon T. Giles
Based on the study findings, Dr. Cope concluded that clinical trials of RA interception are feasible, and that the rates of progression to RA are consistent with cohorts in other studies. “Abatacept reduced rates of progression to RA,” he said. “We also have data to suggest that the drug reduced subclinical inflammation as defined by ultrasound.”
One of the session moderators, Jon T. Giles, MD, MPH, associate professor of medicine at Columbia University, New York, asked Dr. Cope how he and his colleagues assessed the acceptability of abatacept. “Drug adherence is quite a good way to assess that, and we set the adherence level stringently at about 90%,” Dr. Cope said. “The nonadherence was about 26%. Getting people who don’t have disease to inject [the drug] weekly is not a trivial thing.”
Bristol-Myers Squibb funded the study. Dr. Cope disclosed that he has received grant support, consulting, and/or speakers bureau fees from GlaxoSmithKline, AbbVie, Janssen, Bristol-Myers Squibb, UCB, Galapagos, and Lilly. Many coauthors of the APIPPRA trial had financial relationships with multiple pharmaceutical companies, including Bristol-Myers Squibb. Dr. Giles disclosed that he is a consultant for AbbVie, Gilead, Lilly, Novartis, and Pfizer.