Summary

Background/Aims: Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease of older adults (≥50 years) and is associated with long-term glucocorticoid (GC) use. Nearly half of PMR patients relapse despite GC treatment, and increased cumulative GC exposure is associated with multiple adverse outcomes. Elevated IL-17A levels and Th17 cells are observed in patients with PMR. Secukinumab, a fully human monoclonal antibody, selectively neutralizes IL-17A. The Phase 3 REPLENISH trial (NCT05767034) evaluated the efficacy and safety of secukinumab in PMR patients.

Methods: REPLENISH is a randomized, double-blind, placebo-controlled trial that enrolled adults aged ≥50 years with relapsing PMR. Patients were randomized (1:1:1) to receive secukinumab 300 mg (SEC-300), 150 mg (SEC-150), or placebo for 52 weeks, each combined with a protocol-specified 24-week prednisone taper regimen. The primary objective was to determine superiority of SEC-300 over placebo in achieving sustained remission at week (WK) 52. Key secondary endpoints included complete sustained remission, cumulative GC dose, patient-reported outcomes and safety at WK52.

Results: Overall, 381 patients were randomized. The study met its primary and all secondary endpoints. The proportion of patients achieving sustained remission at WK52 was significantly higher in both secukinumab arms vs. placebo (SEC-300: 41.2% vs. 20.4%, p=0.0002; SEC-150: 40.6% vs. 20.4%, p=0.0003). Patients in the secukinumab arms used significantly lower GC dose during the trial than in the placebo arm (adjusted annual GC dose: SEC-300=1603.7 mg, SEC-150=1683.2 mg, placebo=2093.0 mg). Secukinumab showed a consistent safety profile in alignment with approved indications and no new safety signals were identified.

Conclusions: Both doses of secukinumab, combined with a 24-week prednisone taper, demonstrated significant efficacy, including a GC-sparing effect, in patients with PMR, doubling the proportion of those achieving sustained remission compared to placebo plus a 24-week prednisone taper. Safety was in alignment with the known safety profile of secukinumab

Impact on Patient Treatment and Discussion in context of other treatment options

Kommentar: Die Studiendaten, die zum Zeitpunkt dieses Kommentars erst in Abstractform auf dem Netz sind, zeigen überzeugend eine neue therapeutische Option in der Therapie der PMR. Bislang waren Studien über GC-sparende Basistherapien eher ernüchternd, sei es wegen ungenügender Wirksamkeit oder unglücklichem Studiendesign. Was das anti- IL-17 Prinzip mit Secukinumab betrifft, ist an dieser Stelle ein anderer Aspekt in erster Linie interessant: Secukinumab hat in der Phase-III Studie über die Behandlung der Riesenzellarteriitis (RZA) nämlich versagt. (siehe unten: Statement von Novartis; volle Publikation auch noch nicht auf dem Netz). Wie ist dies erklärbar, handelt es sich bei der PMR und der RZA bekanntlich um verwandte Erkrankungen, respektive ein Spektrum von Erkrankungen von der isolierten PMR über gemischte Formen von PMR plus RZA bis zur isolierten Arteritis temporalis? Und wie kommt es, dass anti-IL-6 mit Tocilizumab bei der RZA hervorragend wirksam ist, die Daten bei der PMR aber eher bescheiden ausfallen? Und schliesslich: Weshalb sind die Ergebnisse der TNF-Hemmer Infliximab und Etanercept bei PMR wenig überzeugend?

Das pathophysiologische Korrelat bei der RZA ist eine hochentzündliche Arteriitis, bei der PMR sind mehrere Strukturen wie Bursen, aber vor allem auch Enthesen betroffen. Sprechen wir von Enthesitis, assoziieren wir Spondyloarthritiden. Diese wiederum sind sehr gut therapierbar mit Secukinumab, nicht aber mit anti-IL-6 wie TCZ. Es wäre aber zu erwarten, dass eine TNF-Hemmung eine gute Wirkung entfalten sollte.

Weshalb hat die TNF-Hemmung bei PMR versagt? Tatsächlich gibt es nur kleine Studien mit Infliximab und mit Etanercept. Infliximab wurde wie bei einer RA dosiert, also 3mg/kgKG und nicht in der deutlich höheren Dosis der Spondyloarthritis, also 5mg/kg KG. Damit stellt sich die Frage der Unterdosierung. Etanercept ist bekanntlich der schwächste TNF-Hemmer. Von den anderen TNF-Hemmern, insbesondere Adalimumab gibt es auf dem Netz keine Studien.

Fazit: Es ist pathophysiologisch verständlich, dass anti-IL-17 eine gute Wirkung bei der PMR entfaltet und es ist erfreulich, dass es endlich eine therapeutische Option gibt, bei der therapierefraktären, rezidivierenden PMR toxische GC zu sparen.

Comment: The study data, which by now are available online as an abstract only, convincingly demonstrates a new therapeutic option for the treatment of PMR. Until now, studies on glucocorticoid-sparing maintenance therapies have tended to be disappointing, whether due to insufficient efficacy or to questionable study design. As for the anti-IL-17 approach with Secukinumab, another aspect is of primary interest here: Secukinumab failed in the Phase III study on the treatment of giant cell arteritis (GCA). (See below: Statement from Novartis; full publication not yet available online.) How can this be explained, given that PMR and GCA are known to be related conditions, or rather, a spectrum of conditions ranging from isolated PMR to mixed forms of PMR plus GCA to isolated temporal arteritis? And how is it that anti-IL-6 therapy with Tocilizumab is highly effective in GCA, yet the data for PMR are rather modest? And finally: Why are the results of the TNF inhibitors Infliximab and Etanercept less than convincing in PMR?

The pathophysiological correlate in GCA is a highly inflammatory arteriit; in PMR, multiple structures such as bursae, but above all entheses, are affected. When we speak of enthesitis, we associate it with spondyloarthropathies. These, in turn, are very well treatable with Secukinumab, but not with anti-IL-6 agents such as TCZ. It would therefore be reasonable to expect that TNF inhibition would be effective.

This leaves the question: why did TNF inhibition fail in PMR? In fact, there are only small studies with infliximab and etanercept. Infliximab was dosed as for RA, i.e., 3 mg/kg body weight, and not at the significantly higher dose used for spondyloarthritis, i.e., 5 mg/kg body weight. This raises the question of underdosing. Etanercept is known to be the weakest TNF inhibitor; unfortunately, there are no available studies on Adalimumab.

Conclusion: It is pathophysiologically understandable that anti-IL-17 has a beneficial effect in PMR, and it is encouraging that there is finally a therapeutic option that allows for the avoidance of toxic corticosteroids in treatment-refractory, relapsing PMR.

Additional Studies

Secukinumab in GCA Phase III

Phase III GCAptAIN study evaluating Cosentyx® (secukinumab) in adults with newly diagnosed or relapsing giant cell arteritis (GCA) https://www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-gcaptain-study-cosentyx-giant-cell-arteritis-gca

The GCAptAIN trial (NCT04930094) is a global Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted across 27 countries, evaluating the efficacy and safety of Cosentyx in patients with giant cell arteritis (GCA). Patients were randomized into three treatment arms: Cosentyx 300 mg, Cosentyx 150 mg, or placebo, all in combination with a glucocorticoid (GC) taper regimen. The primary endpoint of the trial is to assess whether secukinumab 300 mg s.c. plus a 26-week GC taper is superior to placebo plus a 52-week GC taper in achieving sustained remission at Week 52 and the first secondary endpoint is the cumulative GC dose through Week 528.

Update on Phase III GCAptAIN study of Cosentyx® in giant cell arteritis (GCA) by Novartis (3.7.2025)

· The GCAptAIN study did not meet its primary endpoint of sustained remission at Week 52 in adults with newly diagnosed or relapsing GCA1

· Safety in GCA patients was consistent with known safety profile of Cosentyx® (secukinumab)1

Comment: Cosentyx did not demonstrate a statistically significant improvement in sustained remission at Week 52 compared to placebo. While the secondary outcomes did not show statistical superiority, Cosentyx showed numerically better outcomes compared to placebo for cumulative steroid dose and steroid-related toxicity. Safety in GCA was consistent with the known safety profile of Cosentyx, which is supported by robust evidence and 10 years of real-world data across its approved indications.

Secukinumab in GCA Phase II

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial; The Lancet Rheumatology; 2023; 5/6: 341-350 doi: 10.1016/S2665-9913(23)00101-7.

Abstract

Background: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis.

Methods: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788.

Findings: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the

placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment.

Interpretation: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis.

Kommentar: Das Ausmass der Unterschiede von Phase-II Resultate und Phase-III Resultate ist überraschend. Phase-II Daten völlige überzeugend und Phase-III enttäuschend. Die Vollpublikation wird vermutlich potentielle Erklärungen diskutieren.

Comment: The extent of the differences between the Phase II and Phase III results is surprising. The Phase II data were convincing, while the Phase III results were disappointing. The full publication will likely give us explanations.

References:

The Role of Tumor Necrosis Factor Alpha Antagonists (Anti TNF-α) in Personalized Treatment of Patients with Isolated Polymyalgia Rheumatica (PMR): Past and Possible Future Scenarios - PMC

J Pers Med. 2022 Feb 22;12(3):329. doi: 10.3390/jpm12030329 The Role of Tumor Necrosis Factor Alpha Antagonists (Anti TNF-α) in Personalized Treatment of Patients with Isolated Polymyalgia Rheumatica (PMR): Past and Possible Future Scenarios Ciro Manzo et al

Carlo Salvarani, MD, and Gene G. Hunder; Tumor Necrosis Factor–Blocking Agents in Polymyalgia Rheumatica and Giant Cell Arteritis; Annals of Internal Medicine, 2008; 148: 2 https://doi.org/10.7326/0003-4819-148-2-200801150-00018

Composed by

Prof. Dr. med. Peter Villiger, Ordinarius of Rheumatology and Clinical Immunology em, University Hospital and University of Bern