Abatacept Ineffective in Prevention of Psoriasis Relapse

Kristina M. Harris, PhD

Recent data from the Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE) clinical trial suggested that the costimulatory-blocking fusion protein abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal.

Investigators noted that abatacept did not completely block the pathogenic psoriasis molecular pathways that led to a relapse in participants.

The function of abatacept has been to compete for CD80/CD86 binding to CD28 on T cells, inhibiting T-cell activation and function. Early phase psoriasis trials had shown that abatavept was an effective treatment, which led to the hypothesis that costimulatory blockade with the protein could induce tolerance in pathogenic T-cells encountering antigen in resolving psoriasis lesions leading to long-term remission.

As such, a team of investigators led by Kristina M. Harris, PhD, Biomarker and Discovery Research, Immune Tolerance Network, University of California, conducted the PAUSE trial to determine whether blockade of costimulatory signaling with abatacept could prevent psoriasis relapse after ustekinumab withdrawal.

The Methods

The multicenter parallel-design, double-blind, placebo-controlled randomized clinical trial was conducted at 10 investigational sites in the United States and Canada, with enrollment opening on March 19, 2014, and concluding on April 11, 2016.

The trial consisted of a lead-in phase (weeks 0 to 12), a randomized treatment phase (weeks 12 to 40), and an observation phase.

A total of 108 participants were enrolled and treated with open-label ustekinumab, with 91 being randomized for blind treatment. Each participant in the ustekinumab group had moderate to severe psoriasis vulgaris.

Participants who weighed 100 kg or less received 45 mg per dose, and participants who weighed more than 100 kg received 90 mg per dose. By week 12, participants’ response to ustekinumab was assessed using the Psoriasis Area and Severity Index (PASI), and participants were eligible for randomization if they achieved 75% or greater improvement from baseline.

The abatacept group received subcutaneous abatacept, 125 mg, which was administered weekly from weeks 12 to 39, and ustekinumab placebo at weeks 16 and 28. The ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39.

Additionally, statistical analyses were performed in the intention-to-treat (ITT) sample.

The Findings

Investigators reported that more participants experienced psoriasis relapse in the abatacept group before week 88 compared to participants in the ustekinumab group (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41).

Additionally, the psoriasis relapse had not decreased in the abatacept group compared with the ustekinumab group, and the primary end point of psoriasis relapse between weeks 12 and 88 was not met.

The median time to relapse from enrollment for the abatacept group was 40 weeks (95% CI, 40-52 weeks) and 60 weeks (95% CI, 56-68 weeks) in the ustekinumab group.

Harris and colleagues also collected data from the skin transcriptomic analysis featured in the study that revealed key molecular targets of abatacept were down-modulated in resolving lesions following successful ustekinumab treatment. As such, they recorded that theu were not surprised that abatacept did not delay relapse or maintain suppression of the IL-23–mediated psoriasis molecular signature after ustekinumab withdrawal.

The investigators suggested future studies focus on targeting alternative costumulatory molecules as a potential treatment option for the prevention of psoriasis relapse.

Understanding the mechanisms that regulate the reactivation of TRM cells and their key interactions with innate im- mune and stromal cell populations in recurring lesions may help identify new treatment strategies for durable remission in psoriasis and potentially other diseases.

The study, “Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis The PAUSE Randomized Clinical Trial,” was published online in JAMA Dermatology.