A drug that costs more than $50,000 per year needs a better argument than "it reduces prednisone by a few milligrams." That argument works if the developer has designed the trial to capture it. Most have not.

The "steroid-sparing" claim is among the most commercially consequential label assets in autoimmune drug development. Payers confronting the long-term costs of steroid-related morbidity, fractures, new-onset diabetes, serious infections, and hospitalizations want to know whether a new therapy actually reduces that harm. Dose reduction is a proxy. Toxicity reduction is proof.

The two are not the same, and the distinction runs deeper than most developers appreciate.

Dose reduction fails as evidence on its own

John H. Stone, MD MPH, Professor of Medicine at Harvard Medical School, and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, has made this case directly. Recalling a polymyalgia rheumatica trial in which a new drug was promoted for its ability to "spare steroids," Dr Stone observed that the reduction in daily prednisone dose was an amount many clinicians would view as trivial.

There had been no effort to measure the new drug's ability to reduce not just steroids but steroid-toxicity. In this era, we need to ask pointedly: "Does a decrease in prednisone dose deliver a measurable and meaningful reduction in steroid-toxicity on the human body?"

That question now has a regulatory answer. In 2026, three phase 3 trials reported the Steritas Glucocorticoid Toxicity Index (GTI) as a pre-specified endpoint: INDIGO (obexelimab in IgG4-related disease), REPLENISH (secukinumab in polymyalgia rheumatica), and GCAptAIN (secukinumab in giant cell arteritis).

In INDIGO, obexelimab reduced disease flares by 56% versus placebo, with GTI reductions across most domains, in contrast to the competing inebilizumab program, which did not report on steroid-toxicity.^[5]

In REPLENISH, secukinumab doubled sustained remission versus placebo (41.2% versus 20.4%), and the GTI recorded a clinically meaningful reduction in steroid-toxicity across every health domain.^[1]

GCAptAIN may have missed its primary remission endpoint, but the GTI still showed significantly lower steroid-toxicity in the higher-dose secukinumab arm, with a clear dose-response.^[6] Each reduction was compared with the GTI's minimum clinically important difference (MCID), as published in the Journal of Allergy and Clinical Immunology.^[2]

Stone's conclusion is direct:

"Every patient reacts differently to steroids. Measuring the dose is not enough. Directly measuring the toxicity in every patient is the only way to know they have improved from a reduction in steroids."

Andreas Reiff, MD, Senior Vice President and Global Therapeutic Area Head for Inflammation/Immunology at Parexel International, puts the development risk in practical terms:

"Most patients entering clinical trials for new drugs treating autoimmune diseases have to take steroids to keep the disease stable enough to meet the entry criteria. But depending on the dose and because the steroids are so powerful, they do not allow us to show the difference between the effect of the background medication and the experimental drug."

The implication for drug development programs is structural. Only if background steroid harm is measured can a trial demonstrate that the experimental therapy removes it.

Designing trials that capture what matters

The question facing development teams is no longer whether to include steroid-toxicity endpoints, but whether they can demonstrate that the threshold reached is meaningful.

The GTI is the instrument that meets that standard. It was developed by 17 international physician investigators across 11 subspecialties^[4] and has been validated through a real-world cohort of 101 patients with severe asthma beginning mepolizumab treatment,^[2] deployment as a pre-specified endpoint across phase 3 trials,^[1,5,6] and more than 510 patient assessments by 34 clinicians that produced the MCID estimate.^[3] To date, more than 90 studies in 35+ diseases have licensed the GTI, including 12 phase 3 trials.

The LONG-TOX cohort, led by Naomi Patel, MD MPH, at Massachusetts General Hospital, is now generating the real-world longitudinal data. Among the first 90 enrolled patients, every single participant had a steroid-toxicity score at baseline, with some accumulating measurable harm within days of starting treatment.

Patients with more than six months of prior steroid exposure had GT-SNAPSHOT scores of 205 versus 160 for those without prior exposure, and two SF-36 domains, Energy/Fatigue (35 vs. 50, p=0.01) and General Health (30 vs. 60, p less than 0.001), showed clinically and statistically significant decline. Nina Liu, Director of COA Portfolio Management at IQVIA, notes that pairing clinician-reported toxicity measures with patient-reported QoL measures such as the SF-36v2 gives a complete picture of steroid burden, one that reflects both clinical impact and lived experience.

Designing trials that capture what matters requires steroid-toxicity to be pre-specified as a structured endpoint, not collected ad hoc. The GTI generates two scores at each assessment: the Cumulative Worsening Score and the Aggregate Improvement Score. Both are sensitive to change.

Both have now appeared in a label-generating trial. A wave of phase 3 trials across GCA, PMR, IgG4-related disease, and myositis are currently using the GTI Family of outcome measures; GCAptAIN (NCT04930094), REPLENISH (NCT05767034), INDIGO (NCT05662241), and ALKIVIA+ (NCT05979441) are all in this cohort. Their readouts will establish what the next generation of market-access submissions looks like.

The Target Product Profile (TPP) is where the case is won or lost

Paul Brunetta, MD, Chief Medical Officer at Hinge Bio, frames the strategic opportunity directly:

"If the GTI is included in a Target Product Profile over the course of a clinical development program, it can really help a company capture the benefits of a therapy in reducing steroid dosage and steroid-related toxicity, alongside key elements of efficacy, safety, dosage, and administration."

The TPP is not documentation. It is the commercial aspiration in structured form. A TPP that specifies a target reduction in GTI score creates an internal standard for what "steroid-sparing" means in a given program. That standard can be communicated to regulators in IND meetings and end-of-phase 2 interactions. It frames the label negotiation. It gives commercial teams a concrete, defensible claim to take to payers.

The TPP is the stage at which most programs leave value on the table. Toxicity data collected retrospectively cannot substitute for a pre-specified endpoint with a published MCID.

The GTI Family is now used by argenx across its entire Immunology Innovation Program, including clinical trials, HEOR, and real-world evidence. Glenn Phillips, PhD, Global Head and VP of HEOR at argenx, described the scope of that commitment:

"Evaluating the burden of steroids in the different conditions we treat is generating important data about the extent of their use and detrimental long-term effects. This alliance has been essential in helping us explore and better understand the measurable negative impact of long-term steroid use and the potential benefit to patients of reducing the burdens associated with steroid-toxicity."

From claims data to lifetime cost and market value

The HEOR case for steroid-sparing therapies relies on the same data used in the regulatory narrative: structured, validated, change-sensitive toxicity measures at multiple time points. A GTI score reduction of 16.8 points by week 26 is the raw input for a health economics model. That model translates the reduction into concrete outcomes: hospitalizations avoided, fractures prevented, diabetes cases not initiated, and infections that did not require inpatient treatment.

Payers evaluating an expensive therapy will need more than dose-reduction data alone to make an economic argument for approval. They will ask what clinical harm was actually prevented and what that prevention is worth over a patient's lifetime. The lifetime cost of long-term steroids across the nine domains captured by the GTI - neuropsychiatric, cardiometabolic, bone density, ophthalmologic, infections, skin, endocrine - is measurable. With trial- and regulatory-grade toxicity data, HEOR models can credibly fill that gap.

The GTI Family is deployed across more than 35 diseases in 80 countries.

For drug developers and HEOR teams that consider steroid-toxicity measurement optional, the 2026 phase 3 readouts have set the precedent: steroid-toxicity reduction, measured with a validated instrument, can differentiate a new therapy from a competitor that measured steroid dose alone. Programs that capture this data are building a market-access case that will hold up under payer scrutiny.

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. McDowell PJ, Stone JH, Zhang Y, Honeyford K, Dunn L, Logan J et al. Quantification of glucocorticoid-associated morbidity in severe asthma using the Glucocorticoid Toxicity Index. The Journal of Allergy and Clinical Immunology: In practice. 9: 365–372. 2021 https://doi.org/10.1016/j.jaip.2020.08.032

3. John H. Stone, P. Jane McDowell, David R.W. Jayne, Peter A. Merkel, Joanna Robson, Naomi J. Patel, Yuqing Zhang, Huibin Yue, Pirow Bekker, Liam G. Heaney, The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time, Seminars in Arthritis and Rheumatism, Volume 55, 2022, 152010, ISSN 0049-0172, https://doi.org/10.1016/j.semarthrit.2022.152010.

4. Miloslavsky EM, Naden RP, Bijlsma JWJ et al. Development of the Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann. Rheum. Dis. (2017). 76:543-546. DOI: 10.1136/annrheumdis-2016-210002

5. Della-Torre E, Baker MC, Zhang W, et al; INDIGO Trial Investigators. Obexelimab for the Treatment of IgG4-Related Disease. N Engl J Med. 2026. https://doi.org/10.1056/NEJMoa2601337

6. 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