Big Win for Secukinumab in Polymyalgia Rheumatic

LONDON — The interleukin (IL)-17A inhibitor secukinumab (Cosentyx) was clearly effective in treating polymyalgia rheumatica (PMR) in a phase III trial, researchers reported, even as they also published final data from a failed trial with the drug in giant cell arteritis (GCA).

With two secukinumab dosages tested in the randomized, placebo-controlled PMR study, the drug produced sustained remission at 1 year in 41.2% and 40.6% of patients receiving 300 or 150 mg per injection, respectively, compared with 20.4% of controls (both P<0.001), according to John H. Stone, MD, MPH, of Mass General Brigham in Boston, and colleagues.

Sustained complete remission was harder to achieve, but still significantly favored the active drug: 28.2% and 24.5% of patients at the high and low doses, respectively, versus 4.7% with placebo (P<0.001), the researchers reported in the New England Journal of Medicine. The results are also to be presented here at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

Stone’s group said the rationale for trying an IL-17A inhibitor in PMR and GCA stemmed from earlier research showing elevated levels of this cytokine in patients with these conditions, which appear together in about one-fifth of cases. They also observed that IL-17A “contributes to articular and periarticular inflammation, which is typical of polymyalgia rheumatica.”

The positive findings in PMR should help allay the disappointment that greeted secukinumab’s manufacturer, Novartis, when a similar trial among GCA patients failed to meet its primary endpoint. Novartis disclosed topline results from that study last July, with a final report appearing in NEJM Evidence and presented at EULAR on Wednesday. The company didn’t say so explicitly, but it’s understood that it won’t pursue a GCA indication for the drug.

But, in an editorial referencing both reports, Yoshiya Tanaka, MD, PhD, of the University of Occupational and Environmental Health in Kitakyushu, Japan, still found a positive outcome from the GCA study. The primary finding was that sustained remission rates did not differ significantly between secukinumab at 300 mg versus placebo. Tanaka noted, however, that the prescribed tapering of corticosteroids was longer for the placebo group than in those randomized to active treatment, “which may have masked the detection of superiority of secukinumab.”

The PMR study also clearly showed that secukinumab reduced the need for steroids, insofar as patients did show solid disease control after tapering. These findings “raise hopes for a therapeutic paradigm shift that minimizes the toxic effects of glucocorticoids, especially in older patients, who constitute the majority of patients with polymyalgia rheumatica and GCA,” Tanaka wrote.

Study Details

For the PMR trial, dubbed REPLENISH, Stone and colleagues randomized 381 patients in equal numbers to secukinumab at 150 or 300 mg or to placebo. Injections were given weekly for 4 weeks, then every 4 weeks for 48 weeks. Steroid doses (prednisone in all cases) were to be tapered to zero over the first 24 weeks, but could be continued, restarted, or stepped up to control symptoms as needed.

Mean patient age was 70, and 70% were women. A similar proportion were white. Close to 90% had active PMR symptoms at enrollment. All but one participant had experienced at least one relapse; just over half had more than one.

Besides sustained remission and sustained complete remission, a third outcome was the cumulative prednisone dose over the 1-year treatment period. They were as follows across the three groups:

• Secukinumab 150 mg: 1,683.2 mg
• Secukinumab 300 mg: 1,603.7 mg
• Placebo: 2,093.0 mg

Stone and colleagues also reported the time course of rescue steroid treatment, via Kaplan-Meier curves. In all groups, the need increased most often between weeks 12 and 28, but, of course, more so with placebo than with either secukinumab dose.

Overall adverse event rates were similar across the three arms, at about 90%. Severe events followed a negative dose-response, with the lowest rate (6.3%) in the 300-mg group and the highest (11.0%) with placebo, suggesting disease-related issues as opposed to treatment-related. Some event types were more common with the active drug, and these were the ones seen with the drug in other conditions (secukinumab is approved for psoriasis, psoriatic arthritis, and several other disorders), such as nasopharyngitis and urinary tract infections. Fungal infections were uncommon but still more frequent with the drug.

Novartis is now seeking regulatory approvals for the PMR indication in the U.S., Europe, and Japan.

The GCA trial was somewhat marred by a protocol amendment that shifted the randomization scheme midway through. Initially, only the 300-mg dose was to be tested against placebo, with 2:1 assignments. Then it was decided to add a 150-mg arm with 1:1:1 randomization. In the end, 140 received 300 mg, 98 got 150 mg, and 115 were assigned to placebo.

Unlike the PMR trial, the steroid tapering period differed between the active drug and placebo groups. In the former, steroids were to be withdrawn over 26 weeks, while the placebo group had them tapered over the full 52-week study.

Sustained remission rates were numerically higher with secukinumab than with placebo — approximately 26% for 300 mg, 19% for 150 mg, and 17% for placebo. Neither drug-versus-placebo difference achieved statistical significance, however.

In reviewing both trials, Tanaka pointed to secukinumab’s “relatively modest effect” seen in PMR and the lack of clear efficacy in GCA, suggesting that “further research on targeting other, or multiple, cytokines [besides IL-17A] in the inflammatory network of these diseases is sorely needed.”