A fresh kind of anti-interleukin-6 (IL-6) biologic called olokizumab was as effectual as adalimumab (Humira) in arthritis rheumatoid patients who needed a intensify from methotrexate monotherapy, results from the phase III trial indicated.
Patients assigned to the novel drug for 24 weeks achieved ACR20 responses (20% improvement in symptoms by American College of Rheumatology criteria) at rates of 70.3% to 71.4% across dosing intervals tested, weighed against 66.9% for adalimumab, in accordance with Josef Smolen, MD, of the Medical University of Vienna, and colleagues.
The differences easily met prespecified non-inferiority criteria for olokizumab versus adalimumab, the researchers reported in the New England Journal of Medicine, and both drugs were clearly more advanced than placebo, with which 44.4% of patients achieved ACR20 responses.
Olokizumab also performed well on secondary endpoints. 1 / 2 of patients on the novel drug achieved ACR50 responses (50% improvement) weighed against 46.3% in the adalimumab group. Similarly, about 45% of patients on olokizumab and 38% of the adalimumab group achieved scores below 3.2 on the 28-joint Disease Activity Score with C-reactive protein levels included (DAS28-CRP), indicating minimal disease activity.
Safety findings were unremarkable, like those seen with other biologic anti-rheumatic agents in short-term trials.
Altogether, the findings appears to be to aid quick FDA approval for olokizumab, but there is a catch: its developer is Moscow-based R-Pharm. With sanctions set up against Russian firms in the U.S. along with other Western nations, it’s unclear whether or once the drug could possibly be marketed beyond your Russian sphere. (Russia approved it in 2020 with the brand Artlegia.)
The brand new trial, called CREDO-2, sought to expand on CREDO-1, another phase III study reported in 2020 that tested olokizumab only against placebo. That trial was successful, showing approximately exactly the same difference in response rates between your drug and placebo now observed in CREDO-2. But R-Pharm felt it worthwhile to show non-inferiority to the best tumor necrosis factor inhibitor in arthritis rheumatoid with a head-to-head study.
As background, Smolen and colleagues explained that olokizumab’s mechanism differs from that of other IL-6 inhibitors including tocilizumab (Actemra) and sarilumab (Kevzara). The latter agents target the IL-6 receptor to avoid ligand binding and disrupt signalling from the receptor when already bound by IL-6.
Olokizumab, however, binds right to the IL-6 protein in circulation. Within an interview last December, among the new trial’s co-investigators, Roy Fleischmann, MD, of the University of Texas Southwestern INFIRMARY in Dallas, told Rheumatology Network that difference might yield “better efficacy and perhaps improved safety” weighed against the prevailing IL-6 inhibitors.
CREDO-2 enrolled 1,648 patients with established arthritis rheumatoid who showed inadequate symptom control with methotrexate. These were randomized 2:2:2:1 to olokizumab at 64 mg either every 14 days or four weeks, adalimumab at 40 mg every 14 days, or placebo. (Three patients never received their assigned agent after randomization.) Methotrexate was continued in every patients.
Mean patient age was about 54, three-quarters were women, and mean time since symptom onset was just over 7 years. DAS28-CRP score at baseline averaged 5.9.
Onset of efficacy was quick, with 35%-45% of patients receiving the active drugs achieving ACR20 responses just 14 days following a first dose, then needs to plateau at about week 8. Effectiveness seemed to peak at about week 18. This trajectory was similar for some other efficacy endpoints except DAS28-CRP, which showed a far more linear upsurge in achievement of scores <3.2 as treatment progressed.
One potentially negative finding for efficacy was that none of the groups showed much progress toward Clinical Disease Activity Index scores of 2.8 or less. This benchmark was reached by only 11%-13% of patients on olokizumab, even though placebo group fared even poorer with a 4% rate.
Adverse events were observed in 70.0%-70.9% of the olokizumab groups, 65.4% of these receiving adalimumab, and 63.4% of the placebo group. Serious adverse events overall weren’t notably more prevalent with the active drugs than with placebo.
But it’s uncertain whether Fleischmann’s expect improved safety in accordance with other IL-6 inhibitors (or the biologic class all together) was realized. On the plus side, serious illness rates were exactly the same with olokizumab versus placebo (1.3%-1.5% vs 1.6%), whereas the rate with adalimumab was 3.5%. But olokizumab seemed to have exactly the same propensity toward increasing LDL cholesterol levels that dogged tocilizumab and sarilumab (4.2%-6.3% developing hypercholesterolemia vs 1.2% with placebo and 1.3% with adalimumab).
Also, elevations in liver enzymes were more prevalent with olokizumab. Alanine aminotransferase levels increased in 9.1%-11.1% of the olokizumab groups versus 1.9% and 1.6% of the adalimumab and placebo groups, respectively. Aspartate aminotransferase levels rose in 5.0% of both olokizumab groups versus 1.7% and 0.8% of the adalimumab and placebo groups, respectively. However, in mere two patients were the increases considered serious.
Five patients taking olokizumab died in CREDO-2 (one from hemorrhagic stroke, three from infections, and something from myocardial infarction, in comparison with one fatal infection with adalimumab and something unexplained sudden death in the placebo group). Given these small numbers, you can’t really determine if the difference represents a meaningful safety signal.
Smolen and colleagues acknowledged that the trial didn’t fully establish the drug’s safety profile, “specifically for the assessment of rare events or events requiring longer durations of exposure (e.g., cancers).” Another limitation the group cited was that efficacy was judged solely by clinical evaluation without usage of objective joint-disease measures from imaging.
John Gever was Managing Editor from 2014 to 2021; he could be now a normal contributor.
The analysis was funded by R-Pharm. Several co-authors were R-Pharm employees. Other authors reported relationships with the business and numerous other drugmakers.