Rheumatology · Medical Literature
Phase 3 Trial of Secukinumab in Polymyalgia Rheumatica
Abstract
New England Journal of Medicine, Ahead of Print.
Clinical relevance
In adults aged 50 years or older with recently relapsed polymyalgia rheumatica, does the addition of subcutaneous secukinumab (an IL-17A inhibitor) to a standardized 24-week prednisone taper improve rates of sustained remission at 52 weeks compared with glucocorticoid taper alone? __SNAPSHOT__ {"studyDesign":"Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (REPLENISH)","setting":"Global, multicenter; conducted across 27 countries","sampleSize":"n=381 (SEC-300 group: n=127; SEC-150 group: n=127; placebo group: n=127)","population":"Adults aged ≥50 years with recently relapsed PMR; required history of glucocorticoid treatment (≥10 mg/day prednisone equivalent) for at least 8 consecutive weeks; at least one PMR relapse during glucocorticoid tapering within the preceding 12 weeks; elevated high-sensitivity CRP (≥10 mg/L) or ESR (≥30 mm/h); mean age approximately 70 years; approximately 70% female","intervention":"Subcutaneous secukinumab 300 mg or 150 mg weekly for 4 weeks, then every 4 weeks for 52 weeks, combined with a 24-week prednisone tapering schedule (starting at 15 mg/day or 10 mg/day)","comparator":"Matching placebo combined with the same 24-week prednisone tapering schedule","primaryOutcome":"Sustained remission at week 52, defined as absence of signs or symptoms attributable to PMR and no new diagnosis of giant-cell arteritis warranting escape or rescue treatment, sustained continuously from week 12 through week 52","followUp":"52 weeks","fundingSource":"Industry (Novartis)"}
Key findings
PRIMARY OUTCOME: Sustained remission at week 52 was achieved in 41.2% (95% CI: 32.8–49.7) of patients in the SEC-300 group and 40.6% (95% CI: 32.2–49.0) in the SEC-150 group, compared with 20.4% in the placebo group. Both active arms approximately doubled the remission rate vs. placebo. Absolute risk differences vs. placebo: ~20.8 percentage points for SEC-300 and ~20.2 percentage points for SEC-150 (calculated). NNT: ~5 for both doses (calculated). The primary endpoint was described as statistically significant; specific p-values for the primary outcome comparison were not reported in the abstract. SECONDARY OUTCOMES: Complete sustained remission (requiring normalization of inflammatory markers in addition to clinical remission) was achieved in 28.2% (SEC-300), 24.5% (SEC-150), and 4.7% (placebo)—absolute differences of ~23.5 and ~19.8 percentage points vs. placebo (calculated). Mean adjusted annual cumulative glucocorticoid dose was 1,603.7 mg (SEC-300), 1,683.2 mg (SEC-150), and 2,093.0 mg (placebo); both differences were statistically significant (SEC-300 vs. placebo: p<0.001; SEC-150 vs. placebo: p=0.0015). Escape or rescue glucocorticoid treatment was required by 50.8% (SEC-300), 51.6% (SEC-150), and 75.6% (placebo). Glucocorticoid Toxicity Index Aggregate Improvement Score at week 52 was 32.4 (SEC-300), 54.0 (SEC-150), and 84.3 (placebo), where lower scores indicate fewer toxicities. SAFETY: Overall adverse event rates were similar across groups (SEC-300: 88.1–91.3%; placebo: 89.8%). Serious adverse events occurred in 13.5% (SEC-300), 15.9% (SEC-150), and 14.2% (placebo). Events more common with secukinumab included nasopharyngitis, hypersensitivity reactions, urinary tract infections, fungal infections, and back pain. Discontinuations due to treatment-related adverse events were highest in the placebo group. No new safety signals were identified.
Practice implications
IMPORTANT LIMITATION: Only the abstract and conference/press-release data are available for this summary; the full dataset, pre-specified statistical analysis plan, subgroup analyses, and supplementary material have not been independently reviewed. Findings must be interpreted with this constraint. WHAT WAS ESTABLISHED: In adults with recently relapsed PMR, the addition of secukinumab (at either 300 mg or 150 mg) to a 24-week prednisone taper significantly increased the proportion achieving sustained remission at 52 weeks compared with prednisone taper alone, and meaningfully reduced cumulative glucocorticoid exposure. The effect was consistent across both doses, with the 300 mg dose associated with a modestly lower cumulative steroid burden. WHAT WAS NOT ESTABLISHED: This trial enrolled exclusively patients with relapsing PMR on background glucocorticoids—it does not establish efficacy in treatment-naïve PMR or as first-line therapy. Long-term safety and durability of remission beyond 52 weeks are unknown. The trial does not address whether secukinumab can facilitate complete glucocorticoid discontinuation. APPLICABILITY: Results are most directly applicable to patients aged ≥50 with PMR who have relapsed during glucocorticoid tapering and have elevated inflammatory markers. Patients with newly diagnosed PMR, those who have never received glucocorticoids, and those with concomitant giant-cell arteritis were not the primary target population. CLINICAL IMPORTANCE: The absolute benefit (~20 percentage points improvement in sustained remission, NNT ~5) is clinically meaningful, particularly in an elderly, predominantly female population at high risk of glucocorticoid toxicity (osteoporosis, diabetes, cardiovascular complications). The reduction in cumulative steroid dose (~489 mg/year with SEC-300 vs. placebo) may translate to clinically relevant reductions in steroid-related morbidity, though the minimum clinically important difference in cumulative dose has not been formally established. An accompanying editorial noted the effect was characterized as 'modest,' calling for research on additional cytokine targets. Notably, secukinumab did not achieve its primary endpoint in a concurrent Phase 3 trial in giant-cell arteritis, underscoring disease-specific immunopathology. REGULATORY CONTEXT: Novartis has submitted secukinumab for PMR regulatory review in the US, EU, and Japan as of June 2026; approval is not yet granted. __LIMITATIONS__ 1. ABSTRACT/PRESS-RELEASE ONLY: Full peer-reviewed data, pre-specified statistical hierarchy, and subgroup analyses are not available for independent review; specific p-values for the primary endpoint comparison were not reported in the abstract. 2. INDUSTRY SPONSORSHIP: Fully funded by Novartis (manufacturer of secukinumab), introducing risk of outcome reporting bias and selective emphasis on positive results. 3. RESTRICTED POPULATION: Exclusively enrolls patients with relapsed PMR on glucocorticoids; does not address treatment-naïve PMR or primary prevention of relapse. 4. MODERATE ABSOLUTE REMISSION RATES: Even in the active arms, only ~41% achieved sustained remission at 52 weeks, meaning the majority of treated patients did not sustain remission; determinants of non-response are not characterised from the abstract. 5. COMPOSITE/OPERATIONALIZED PRIMARY ENDPOINT: The sustained remission definition (continuous from week 12 to week 52) is a composite clinical endpoint; constituent elements were not separately reported in the abstract. 6. NO ACTIVE COMPARATOR: The trial does not compare secukinumab to sarilumab (the only other advanced therapy with evidence in PMR), limiting head-to-head positioning. 7. FOLLOW-UP LIMITED TO 52 WEEKS: Durability of remission and safety beyond one year are unknown. 8. GENERALIZABILITY: A global, multicenter trial conducted across 27 countries may have variable standard-of-care background practices; degree to which results apply to any single health system requires further consideration. 9. DOSE EQUIVALENCE: Both doses achieved numerically similar primary endpoint results, raising questions about dose selection rationale that cannot be resolved from the abstract alone. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In adults with recently relapsed PMR, the addition of subcutaneous secukinumab (300 mg or 150 mg) to a 24-week glucocorticoid taper approximately doubled the rate of sustained remission at 52 weeks (41% vs. 20%) and meaningfully reduced cumulative glucocorticoid exposure compared with taper alone, with a clinically important NNT of approximately 5 (calculated). The safety profile was consistent with secukinumab's established class effects, with no new signals identified. Pending regulatory approval and full publication review, this trial positions IL-17A inhibition as a potentially important glucocorticoid-sparing strategy specifically in relapsing PMR, though it does not yet replace the need for individualized clinical decision-making, particularly regarding cost, patient selection, and long-term safety.