Patients on long-term steroids for autoimmune and inflammatory diseases know the damage that these drugs cause. The question for sponsors has long been whether a trial can prove it. In June 2026, three phase 3 readouts answer in the affirmative: REPLENISH (secukinumab in polymyalgia rheumatica; Novartis)^[1]; GCAptAIN (secukinumab in giant cell arteritis; Novartis)^[2]; and INDIGO (obexelimab in IgG4-related disease; Zenas BioPharma)^[3].

All three trials pre-specified the Glucocorticoid Toxicity Index (GTI) as an endpoint, and the results speak for themselves.

Three diseases, one instrument, consistent signal

REPLENISH is the largest PMR trial conducted to date.^[1] The randomized, double-blind, placebo-controlled phase 3 trial enrolled 381 patients across 148 sites in 28 countries. The patients were randomized 1:1:1 to secukinumab 300 mg, 150 mg, or placebo. All three groups received a standardized 24-week prednisone taper. The primary endpoint was sustained remission at week 52.

The GTI was included as an exploratory endpoint in REPLENISH. Secukinumab doubled the proportion of patients who achieved sustained remission compared with placebo (41.2% vs 20.4%) and reduced annual steroid exposure by 20-25%. The GTI confirmed what the headline numbers alone cannot show: a clinically meaningful reduction in patient harm across all GTI health domains. For patients with comorbidities and limited physiological reserve, that is the outcome that matters.

GCAptAIN studied the same drug in a related disease.^[2] PMR and giant cell arteritis are pathophysiologically linked; PMR symptoms are common in patients with GCA, and about a third of patients in GCAptAIN presented with PMR symptoms at baseline. GCAptAIN enrolled 354 patients across 104 sites in 27 countries. The two secukinumab arms (either 300 mg or 150 mg, as in REPLENISH) received a 26-week steroid taper. The placebo group received a 52-week taper. The GTI was a secondary endpoint in GCAptAIN. The GCAptAIN trial did not achieve its primary remission endpoint, perhaps in part because the asymmetric taper design between trial arms gave the placebo group an efficacy advantage that neither secukinumab group was able to overcome. The higher-dose secukinumab arm fell just short of statistical superiority.

The GTI, however, told a clearer story. Patients in the higher-dose secukinumab arm had significantly less steroid-toxicity than those on placebo, and there was a clear dose-response relationship: higher secukinumab dosing was associated with lower steroid-toxicity. Thus, a trial that fell short of the primary endpoint nevertheless demonstrated benefit to patients because of its steroid-toxicity profile, which was derived from a direct measure of harm rather than from dose inference.

INDIGO extended the case to a third disease with a different drug class.^[3] The randomized, double-blind, placebo-controlled phase 3 trial enrolled 194 patients with active IgG4-related disease (IgG4-RD) across 114 sites in 19 countries. The investigational agent was obexelimab, a bifunctional antibody targeting two molecules on the B cell surface: CD19 and FcγRIIb. The GTI was an exploratory secondary endpoint. Obexelimab reduced disease flare by 56% versus placebo, and the GTI showed a reduction in steroid-toxicity across the majority of health domains.

The comparison with the MITIGATE trial matters here: MITIGATE supported inebilizumab's FDA approval as the first treatment for IgG4-RD and reported steroid use, but did not assess steroid-toxicity. The INDIGO trial used the GTI to quantify steroid-toxicity reduction, yielding results that may be a decisive differentiator in label discussions and payer conversations in a competitive market.

Table 1. Trial design and GTI status across REPLENISH, GCAptAIN, and INDIGO. The GTI was pre-specified in all three trials. Note GCAptAIN: the primary remission endpoint was not met, but the GTI documented clinically meaningful steroid-toxicity reduction.

What changes for patients, payers, and sponsors

For patients, the change is overdue. Cumulative steroid burden drives the bone fractures, the diabetes onset, the cataracts, the infections, the mood disturbance and weight gain that define the lived experience of chronic autoimmune disease. Dose metrics overlook all of that. The GTI captures these health burdens directly with a structured, validated approach that is consistent across treatments and diseases.

For payers, the implications are sharper than they used to be. Theoretical steroid-sparing arguments have become harder to fund. Quantified steroid-toxicity reduction, demonstrated in a phase 3 trial against placebo, opens a different conversation.

For sponsors, the strategic question has shifted. Phase 3 evidence using the GTI now spans four indications and programs from Zenas BioPharma, Novartis, and ChemoCentryx (now part of Amgen). Pipelines in steroid-dependent autoimmune disease now have a clear pathway to demonstrating a new and important advantage of their products over standard care and differentiating their drugs from competitors.

References

1. 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
2. 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
3. Della-Torre E, Baker MC, Zhang W, Perugino CA, Katz G, Tanaka Y, Khosroshahi A, Kleger A, Schleinitz N, Martinez-Valle F, Schulze-Koops H, Nakayamada S, Rebours V, Okazaki K, Dong L, Carruthers M, Chen LYC, Frulloni L, Meysami A, Takahashi H, Kawano M, Liu Y, Saeki T, Ebbo M, Alexander T, González García A, Karadag O, Maślińska M, Quinn SM, Poma A, Wells A, Greene TJ, Stone JH, Culver EL, for the INDIGO Trial Investigators. Obexelimab for the Treatment of IgG4-Related Disease. N Engl J Med. 2026. https://doi.org/10.1056/NEJMoa2601337