“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.
To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.
Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.
All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.
Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.
Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.
Time to push forward with additional studies on abatacept
The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.
Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.
Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.
The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.
The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.
SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.