The future success of new RA drugs or novel strategies will hinge upon more stringent selection of trial participants, better patient stratification and improved outcome measures, experts say.

Analysing recent Phase 3 RA trial failures, Professors René Westhovens and Patrick Verschueren, Katholieke Universiteit Leuven, Belgium, argued that many patients in contemporary RA trials are not truly refractory, and disease control could be improved by incorporating new strategies and approaches (such as treat to target) with existing medicines, better streamlining the pool of patients for clinical trials of novel approaches.

“From our point of view, the ideal candidate for advanced therapy both in clinical practice as in clinical trials would be a patient not responding sufficiently to such an intensive initial strategy,” they wrote in an editorial published in the Annals of the Rheumatic Diseases.

“Today, unfortunately, the treatment history of patients included in clinical trials can be very heterogeneous, with some having previously received delayed or inappropriate treatment. This has an important effect on placebo responses and a priori responsiveness to any kind of new drug.”

Lessons from contRAst trials

Their comments follow a critical analysis of the contRAst programme assessing otilimab, the first investigational therapy to target granulocyte-macrophage colony-stimulating factor (GM-CSF) to enter late-stage development.

In the Phase III contRAst 3 trial, a weekly subcutaneous dose of 150 mg otilimab failed to show a significant benefit or non-inferiority to the active comparator sarilumab in patients with RA refractory to conventional synthetic (cs) DMARDs and advanced therapies such as biologic or targeted synthetic DMARDs.

In the Phase III contRAst 1 and contRAst 2 trials, otilimab had outperformed placebo in patients who failed to respond to csDMARDs or bDMARDs but was less effective than tofacitinib. This followed positive data from preclinical and Phase II studies backing the rationale of targeting GM-CSF in RA.

According to Professors Westhovens and Verschueren, fundamental issues might have contributed to otilimab’s late-stage failure, which should be kept in mind for other future clinical studies in rheumatology.

Phase II trials included DAS28 remission as the primary outcome, previously linked with an increased efficacy mismatch between Phase II and III outcomes.

Professors Westhovens and Verschueren also called for greater attention to pre-existing background therapy with methotrexate and glucocorticoid in future studies, as this could have a significant effect in placebo-controlled trials.

In the Phase II trial with otilumab, 60% of participants took glucocorticoids, which could have skewed results. “While GC use was similar across treatment arms, this will have had an impact on baseline data and the ability to improve during the study. It is unlikely that the influence of GC use in placebo-controlled trials as documented for X-ray damage11 would be limited to this outcome only,” they said.

Also of note, the Phase III contRAst 3 trial showed a high placebo response of around 38% “even for an ACR20 at week 12” which was “stunning as the population studied [was] supposed to be very refractory”.

They noted that international differences in reporting, expectations, and social and cultural environments might have influenced perceptions of treatment effect and adherence and thus impacted the overall results despite randomisation.

Researchers should also consider the role of patient expectation and perception on reporting; the contRAst 3 studio showed a sudden improvement in efficacy following week 12, “probably because patients knew they would receive active treatment from that point onwards”, they said.

Food for thought

According to Professors Westhovens and Verschueren, new drug development in RA will become more challenging in the near future but not impossible.

“Phases 2 and 3 trial designs will need more stringent selection of participants, clever patient stratification and more relevant outcome measures…mastering all this in the world of trials will be demanding and perhaps also more costly but without this there can be no progress,” they wrote.

“Negative trials are disappointing given the lack of a direct return of investment but can sometimes also be excellent food for thought, in view of avoiding future negative and non-contributing trials, which are even more costly,” they added.