Key Takeaways

• Sycume (IBI311) met the primary endpoint of the phase 3 RESTORE-3 trial, achieving a 60.4% proptosis response rate at Week 24 compared with 23.5% for placebo in patients with inactive thyroid eye disease

• Treatment resulted in statistically significant reductions in proptosis in both study and non-study eyes, with most treatment-emergent adverse events reported as mild to moderate and no new safety signals identified

• The findings support the potential use of IGF-1R inhibition as a nonsurgical treatment option for patients with chronic, inactive TED, with longer-term follow-up and complete study results still pending

Innovent Biologics announced that Sycume (teprotumumab N01 injection; IBI311), its independently developed recombinant anti-insulin-like growth factor 1 receptor (IGF-1R) antibody, met the primary endpoint in the phase 3 RESTORE-3 clinical trial evaluating the treatment in Chinese patients with inactive thyroid eye disease (TED).

The multicenter, randomized, double-blind, placebo-controlled study demonstrated statistically significant improvements in proptosis response rates and reductions in proptosis at Week 24 compared with placebo. According to the company, the investigational treatment also demonstrated a favorable safety and tolerability profile, with no new safety signals identified.

The findings provide additional clinical evidence supporting IGF-1R inhibition in patients with chronic, inactive TED, a population with historically limited nonsurgical treatment options.

RESTORE-3 study design and patient characteristics

RESTORE-3 enrolled 116 patients with inactive TED who were randomized in an approximately 2:1 ratio to receive IBI311 or placebo.

The study's primary endpoint was the proptosis response rate in the study eye at Week 24, while the key secondary endpoint evaluated change from baseline in study-eye proptosis at the same time point. Eligible participants had inactive disease, defined by a bilateral Clinical Activity Score (CAS) of 2 or lower.

At baseline, participants had a mean disease duration of 4.3 years and a mean study-eye proptosis measurement of 22.16 mm. Approximately 74.1% of patients had a baseline CAS of 0 or 1, indicating minimal inflammatory activity. These characteristics reflect a population with longstanding TED in which inflammation had largely subsided but residual proptosis remained.

Significant improvements in proptosis observed at Week 24

The trial met its primary endpoint, with a significantly greater proportion of patients receiving IBI311 achieving a proptosis response compared with those receiving placebo.

At Week 24, the proptosis response rate in the study eye was 60.4% in the IBI311 group compared with 23.5% in the placebo group, representing a treatment difference of 36.9 percentage points (P = .0003).

The study also met its key secondary endpoint, demonstrating a statistically significant reduction in study-eye proptosis. The least-squares mean change from baseline was −1.88 mm in the IBI311 group compared with −0.88 mm in the placebo group, resulting in a treatment difference of −1.00 mm (P < .0001).

Additional secondary analyses demonstrated improvements in the non-study eye, suggesting that the treatment effect extended beyond the designated study eye. At Week 24, the non-study-eye proptosis response rate was 46.0% with IBI311 compared with 19.8% with placebo (P = .0071). The least-squares mean change in non-study-eye proptosis was −1.77 mm in the treatment group compared with −0.91 mm in the placebo group (P < .0001).

According to Innovent, the results were generally consistent with previously reported findings for Tepezza (teprotumumab) in inactive TED. However, the company noted that baseline mean proptosis was lower in RESTORE-3 than in the Tepezza study. Because these findings represent an indirect comparison across separate trials, they do not establish comparative efficacy between the treatments.

IBI311 demonstrated a favorable safety and tolerability profile during the double-blind treatment and follow-up period, according to the company. Most treatment-emergent adverse events were mild to moderate in severity, and investigators identified no new safety signals.

Patient follow-up remains ongoing, and Innovent indicated that complete study findings will be presented at future scientific conferences or published in peer-reviewed journals.

Potential implications for inactive TED management

Inactive TED represents a substantial proportion of the overall TED population, with Innovent estimating that approximately two-thirds of patients have inactive disease.

Although inflammatory activity may decrease over time, patients can continue to experience persistent proptosis, changes in appearance, and functional impairment. Historically, rehabilitative surgery has been a principal treatment option for patients with residual manifestations of inactive TED.

Sycume is an IGF-1R-targeting monoclonal antibody developed by Innovent Biologics for the treatment of TED. According to the company, Sycume is the first IGF-1R antibody approved in China and the second approved worldwide for TED.

Lei Qian, MD, chief R&D officer for the general biomedicine pipeline at Innovent Biologics, said the findings represent an important milestone in the company's efforts to expand treatment options for TED.

"With these positive Phase III trial results, Sycume now achieves comprehensive disease coverage ranging from 'early acute control' to 'chronic phase tissue remodeling,'" Dr. Qian said.

Dr. Qian added that Innovent plans to collaborate with clinical experts to translate the findings into clinical practice and expand access to treatment.

Although the results support the potential clinical benefit of IBI311 in inactive TED, additional data will be needed to assess the durability of proptosis reduction, longer-term safety, and effects on other patient-centered outcomes. The ongoing RESTORE-3 follow-up and subsequent publication of complete results are expected to provide further insight into the role of IGF-1R inhibition in the management of chronic, inactive TED.