麻豆传媒

A new type of anti-interleukin-6 (IL-6) biologic called olokizumab was as effective as adalimumab (Humira) in rheumatoid arthritis patients who needed a step up from methotrexate monotherapy, results from a 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, compared with 66.9% for adalimumab, according to 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 , and both drugs were clearly superior to placebo, with which 44.4% of patients achieved ACR20 responses.

Olokizumab also performed well on secondary endpoints. Half of patients on the novel drug achieved ACR50 responses (50% improvement) compared with 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, very much like those seen with other biologic anti-rheumatic agents in short-term trials.

In total, the findings would seem to support quick FDA approval for olokizumab, but there's a catch: its developer is Moscow-based . With sanctions in place against Russian firms in the U.S. and other Western nations, it's unclear whether or when the drug could be marketed outside the Russian sphere. (Russia approved it in 2020 with the brand name Artlegia.)

Rationale

The new trial, called , sought to expand on CREDO-1, another phase III study reported in 2020 that tested olokizumab only against placebo. That trial was a winner, showing approximately the same difference in response rates between the drug and placebo now seen in CREDO-2. But R-Pharm felt it worthwhile to demonstrate non-inferiority to the leading tumor necrosis factor inhibitor in rheumatoid arthritis 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 prevent ligand binding and when already bound by IL-6.

Olokizumab, on the other hand, binds directly to the IL-6 protein in circulation. In an interview last December, one of the new trial's co-investigators, Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, that this difference might yield "better efficacy and maybe improved safety" compared with the existing IL-6 inhibitors.

Study Details

CREDO-2 enrolled 1,648 patients with established rheumatoid arthritis who showed inadequate symptom control with methotrexate. They were randomized 2:2:2:1 to olokizumab at 64 mg either every 2 weeks or 4 weeks, adalimumab at 40 mg every 2 weeks, or placebo. (Three patients never received their assigned agent after randomization.) Methotrexate was continued in all 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 2 weeks following the first dose, then starting to plateau at about week 8. Effectiveness appeared to peak at about week 18. This trajectory was similar for most other efficacy endpoints except DAS28-CRP, which showed a more linear increase 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, although the placebo group fared even poorer with a 4% rate.

Safety

Adverse events were seen in 70.0%-70.9% of the olokizumab groups, 65.4% of those receiving adalimumab, and 63.4% of the placebo group. Serious adverse events overall weren't notably more common with any of the active drugs than with placebo.

But it's uncertain whether Fleischmann's hope for improved safety relative to other IL-6 inhibitors (or the biologic class as a whole) was realized. On the plus side, serious infection rates were the same with olokizumab versus placebo (1.3%-1.5% vs 1.6%), whereas the rate with adalimumab was 3.5%. But olokizumab appeared to have 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 common 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. On the other hand, in only two patients were the increases considered serious.

Five patients taking olokizumab died in CREDO-2 (one from hemorrhagic stroke, three from infections, and one from myocardial infarction, as compared with one fatal infection with adalimumab and one unexplained sudden death in the placebo group). Given these small numbers, it's impossible to determine whether the difference represents a meaningful safety signal.

Smolen and colleagues acknowledged that the trial didn't fully establish the drug's safety profile, "especially 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 use of objective joint-disease measures from imaging.

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