For the majority of patients with polymyalgia rheumatica, glucocorticoids do not provide a durable solution. They induce remission, but they do not maintain it. REPLENISH, the largest PMR clinical trial ever conducted, establishes secukinumab as the first biologic to change that, and at the same time quantifies the reduction in steroid-toxicity that comes with it.
Reported by John H. Stone, MD MPH, Frank Buttgereit, MD, Alain Saraux, MD, PhD, and colleagues, the phase 3 trial met its primary endpoint and all secondary objectives. It also deployed the Glucocorticoid Toxicity Index (GTI) as an exploratory endpoint, providing the first validated measure of steroid-toxicity reduction in a pivotal PMR trial.[1]
Why glucocorticoids fall short
PMR is the second most common idiopathic inflammatory rheumatic disease, occurring almost exclusively in adults over 50 with a strong female predominance. Glucocorticoids are recommended as first-line treatment by both EULAR and ACR, and their initial efficacy is not in question. Around 78% of patients achieve remission by week 12.
The problem is durability. Only 20% remain in remission at one year. Approximately 43% relapse within the first year of initiating therapy, and a substantial proportion continue taking glucocorticoids for five years or more, accumulating steroid-toxicity throughout. For a population that is predominantly elderly, often frail, and already carrying significant comorbidities, prolonged steroid exposure is not a minor inconvenience; it is a major clinical risk.
The unmet need has been clear for years. REPLENISH is the first phase 3 trial to address it at scale.
Trial design
The REPLENISH trial was a randomized, double-blind, placebo-controlled phase 3 trial conducted at 148 sites across 28 countries, funded by Novartis Pharma AG. A total of 381 patients with a recent PMR relapse were randomized 1:1:1 to secukinumab 300 mg (SEC-300), secukinumab 150 mg (SEC-150), or placebo, each combined with a standardized 24-week prednisone taper. The primary endpoint was sustained remission at week 52, defined as remission achieved at week 12 and maintained without recurrence through week 52.
Efficacy results
Both SEC-150 and SEC-300 secukinumab arms met the primary endpoint. Sustained remission rates were 41.2% (SEC-300) and 40.6% (SEC-150) versus 20.4% with placebo (P<0.001 for both comparisons), approximately doubling the proportion of patients achieving durable disease control.
The secondary endpoints reinforced the headline result across multiple dimensions:
Complete sustained remission, requiring normalization of inflammatory markers (CRP and ESR), was achieved in 28.2% (SEC-300) and 24.5% (SEC-150) of patients versus just 4.7% with placebo.
Median time to first escape or rescue treatment was 337 days (SEC-300) and 282 days (SEC-150) versus 157 days with placebo, with secukinumab reducing the risk of requiring rescue treatment by 50% versus placebo.
Annual cumulative glucocorticoid dose was reduced by 20-25% in secukinumab-treated patients: SEC-300, 1,604 mg; SEC-150, 1,683 mg; placebo, 2,093 mg.
Patients in the secukinumab arms reported significantly better fatigue scores (FACIT-Fatigue) and physical function (HAQ-DI) at week 52.
Steroid-toxicity: what the dose reduction means in practice
A 20-25% reduction in cumulative glucocorticoid dose is clinically meaningful. But dose alone does not capture the full picture of harm. Reducing steroid dose and reducing steroid-toxicity are not the same thing.
The inclusion of the GTI as an exploratory endpoint in REPLENISH directly addresses that fact. Patients treated with SEC-300 showed statistically significant reduction on both the GTI Aggregate Improvement Score (GTI-AIS: 32.4 versus 84.3 with placebo; P=0.006) and the GTI Cumulative Worsening Score (GTI-CWS: 69.0 versus 123.5 with placebo; P=0.007). These scores reflect change across the nine domains of glucocorticoid toxicity that a single cumulative-dose figure cannot distinguish. The GTI delivers evidence of reduced patient harm.
Safety
The safety profile of secukinumab in REPLENISH was consistent with its established profile across approved indications, supported by ten years of real-world data. Overall adverse event rates were similar across all three arms. AEs leading to treatment discontinuation were numerically less frequent in both secukinumab arms (3.2%) than in the placebo arm (6.3%). Infections and hypersensitivity reactions were slightly more common with secukinumab, with fungal infections occurring at higher rates, though most were mild to moderate and did not lead to discontinuation. No new safety signals were identified.
A new standard for PMR trials
REPLENISH establishes that sustained remission in PMR is achievable beyond glucocorticoid monotherapy, and that a meaningful steroid-sparing effect translates directly into reduced steroid-toxicity, as measured by the GTI. For drug developers working in PMR and steroid-dependent diseases more broadly, the trial makes the case on two fronts: secukinumab as an effective treatment option, and validated steroid-toxicity measurement as the standard by which its benefits should be judged.
Frank Buttgereit, M.D., Professor of Rheumatology at Charité-Universitätsmedizin Berlin and a REPLENISH co-author,discussed the clinical case for measuring steroid-toxicity in a recent interview. The GTI evidence base now spans from ADVOCATE in ANCA-associated vasculitis to REPLENISH in PMR. Trials that quantify steroid-toxicity alongside efficacy tell a more complete story, and increasingly, that is the story regulators, payers, and clinicians need to hear.
REPLENISH phase 3 trial: secukinumab doubles sustained remission rates in PMR versus glucocorticoids alone and reduces steroid-toxicity measured by the GTI.
References
- Stone JH, Buttgereit F, Saraux A, et al. Phase 3 Trial of Secukinumab in Polymyalgia Rheumatica. New England Journal of Medicine. 2026; Published online June 3, 2026. https://doi.org/10.1056/NEJMoa2602567
- Stone JH, Venhoff N, Buttgereit F, et al. Secukinumab for Giant Cell Arteritis. NEJM Evidence. Published online June 3, 2026. https://doi.org/10.1056/EVIDoa2600112