Acelyrin, Inc. (Nasdaq: SLRN) has announced promising Phase 2 data and the design of its Phase 3 program for lonigutamab in Thyroid Eye Disease (TED). The company plans to initiate the Phase 3 LONGITUDE program in the first quarter of 2025, with topline data expected in the second half of 2026. This strategic move follows the discontinuation of further investment in izokibep after it failed to meet the primary endpoint in a Phase 2b/3 trial for uveitis. The company is focusing on lonigutamab, a subcutaneously delivered monoclonal antibody targeting IGF-1R, as its lead program. The company held a virtual investor event on January 6, 2025, to discuss the new Phase 2 data and the Phase 3 program design for the treatment of TED.
Phase 2 Data Highlights
New data from the ongoing Phase 2 trial in TED showcased clinically meaningful and competitive improvements across all manifestations of TED. These include proptosis, Clinical Activity Score (CAS), diplopia, and the Graves Ophthalmopathy-Quality of Life (GO-QoL) tool. Notably, a significant proptosis response rate was observed with a 50 mg loading dose followed by 25 mg weekly subcutaneous administration of lonigutamab. The data also indicated that efficacy was achieved with lower levels of exposure compared to IV-administered anti-IGF-1R agents. Furthermore, no cases of hearing impairment, hyperglycemia, or menstrual disorders were reported at any dose level, suggesting a potentially favorable safety profile. A 100 mg loading dose was shown to achieve target therapeutic concentrations within days.
Phase 3 LONGITUDE Program Design
The Phase 3 LONGITUDE program will consist of two global, double-masked, placebo-controlled trials, LONGITUDE-1 and LONGITUDE-2, involving approximately 350 patients. These trials will evaluate the safety and efficacy of a subcutaneously delivered 100 mg loading dose of lonigutamab, followed by 50 mg every two weeks. Patients will be randomized 2:1 to either lonigutamab or placebo arms during the first 24 weeks. The primary endpoint for both trials will be the proptosis response rate at 24 weeks. All patients will receive lonigutamab after 24 weeks through to 52 weeks of treatment, designed to potentially enable longer-term treatment.
LONGITUDE-1 will enroll a minimum of 81 active TED patients, with the primary endpoint being the proptosis response rate at 24 weeks for active patients. A secondary endpoint will assess the proptosis response rate at 24 weeks for all enrolled patients. LONGITUDE-2 will recruit both active and chronic TED patients, with the primary endpoint being the proptosis response rate at 24 weeks for all patients. Secondary endpoints for both trials include CAS, diplopia response, and GO-QoL at 24 weeks. Acelyrin has secured alignment with the FDA on the proposed LONGITUDE-1 and LONGITUDE-2 Phase 3 trial designs following an End of Phase 2 (EOP2) meeting in Q3 2024.
Strategic Focus on Lonigutamab
The advancement of lonigutamab into Phase 3 trials marks a strategic shift for Acelyrin. This decision comes after the company announced that its Phase 2b/3 trial of izokibep in non-infectious, non-anterior uveitis did not meet the primary endpoint. The treatment failure rate at 24 weeks was 45.0% (p-value: 0.4914) for izokibep and 50.7% for placebo. Statistical significance was not reached for any secondary endpoint, and no clinical benefit was observed. As a result, Acelyrin will discontinue further investment in izokibep and focus on its late-stage development program for lonigutamab in TED.
Financial Position
Acelyrin's financial position remains strong, with $562.4 million in cash, cash equivalents, and short-term marketable securities as of September 30, 2024. The company projects that its existing cash resources will provide runway to mid-2027, including completion of planned Phase 3 trials and BLA-enabling activities for lonigutamab, as well as selective pipeline expansion.
Mina Kim, CEO of Acelyrin, expressed confidence in lonigutamab's potential to optimize patient benefit and risk and transform the TED treatment paradigm. Shep Mpofu, M.D., Chief Medical Officer at Acelyrin, emphasized the company's commitment to addressing the significant unmet needs of TED patients with this novel therapy.
