Summary: Among 28 randomised adults with active, moderate-to-severe Graves orbitopathy, no composite responders were observed with secukinumab or placebo at 16 weeks. Five participants lacked that assessment. The prematurely stopped trial does not support efficacy for the studied indication.
PICO Summary
| Element | Detail |
|---|---|
| Population | 28 adults with active, moderate-to-severe, non-sight-threatening Graves orbitopathy and Clinical Activity Score (CAS) of at least 4; 14 participants per group in a multicentre study. |
| Intervention | Subcutaneous secukinumab 300 mg during the 16-week double-blind phase. An additional 16-week open-label phase offered secukinumab to proptosis nonresponders. |
| Comparator | Matching placebo during the initial 16-week randomised phase; n=14. The subsequent open-label phase did not retain a placebo comparison. |
| Outcomes | Primary composite response at week 16 required a CAS reduction of at least 2 points and a proptosis reduction of at least 2 mm without corresponding deterioration in the fellow eye. No responders were observed: 0/12 assessed with secukinumab and 0/11 assessed with placebo; 2 and 3 participants respectively had missing assessments. No clinically meaningful overall ophthalmic or quality-of-life benefit was demonstrated. No composite responders were observed at week 32 either. Adverse events were mostly mild; no treatment-induced discontinuation or new safety signal was reported. The sample is insufficient to exclude uncommon harms. |
| Study Design | ORBIT: randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Stopped early following a blinded review indicating low likelihood of meeting the primary endpoint; planned superiority testing was replaced by descriptive analysis, with no missing-value imputation. Primary assessment at 16 weeks, followed by open-label treatment. ClinicalTrials.gov NCT04737330. Novartis involvement included manufacturer-affiliated authors. |
Expert Commentary
I regard ORBIT as a negative efficacy study, despite a plausible inflammatory target. Neither group achieved the combined activity and proptosis response, and the broader ophthalmic findings did not provide a persuasive alternative signal. That is more informative than a reassuring tolerability statement: a treatment can be tolerated without improving the condition being treated. The main limitation is the very small sample. Fourteen participants per group cannot exclude a modest effect or reliably characterise uncommon harms, but small size should not be used to turn an entirely absent response into evidence of benefit. The later open-label phase also cannot supply a new randomised comparison. Manufacturer involvement warrants attention when interpreting the biological rationale and safety narrative. Can I use this with my patients? These results do not justify adding secukinumab specifically for active, moderate-to-severe Graves orbitopathy. Management should remain within established specialist pathways, with separate attention to disease activity, severity and threats to vision. Patients with sight-threatening disease were not represented and should not be reassured by this trial. I would explain the distinction between promising laboratory biology and demonstrated clinical efficacy. Future work should clarify whether a biologically defined subgroup merits further investigation before exposing larger patient groups to another trial of this approach.
References
Wolf J, Lorenz K, Othman AE, et al. Secukinumab in Moderate-to-Severe Graves Orbitopathy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study. J Clin Endocrinol Metab. 2026;111(5):1248-1257. doi:10.1210/clinem/dgaf655. PMID: 41362233.
