Weekly Oral Risperidone Found Effective and Safe for Schizophrenia in Phase III Trial

Schizophrenia medication non-adherence is an epidemic problem that results in a common relapse, hospitalization, and deterioration of disease course. While long-acting injectable antipsychotics have improved adherence in some patients, a non-invasive, oral, long-acting formulation might prove more acceptable and feasible. LYN-005, a long-acting oral formulation of risperidone for weekly dosing, was developed to fill this gap. The purpose of this study was to determine if LYN-005 was able to produce stable therapeutic levels equivalent to once-daily risperidone without raising new safety issues.

This non-randomized, open-label, phase 3 trial recruited 83 clinically stable subjects with schizophrenia or schizoaffective disorder at five inpatient sites in the USA between April 13 and December 1, 2023. Participants (mean age: 49.3 years, SD 11.5) were 75% male (n=62) and 81% Black or African American (n=67). After 7 days of run-in with daily immediate-release risperidone (2 mg or 6 mg), the participants were administered five weekly doses of LYN-005 (15 mg or 45 mg, respectively) and a half-dose supplement of daily risperidone for the first week in order to taper off the transition.

The trial assessed principal pharmacokinetic parameters—minimum concentration (Cmin), peak concentration (Cmax), and mean concentration (Cavg)—at weeks 1 and 5. Predefined acceptance criteria were on geometric mean ratios of LYN-005 versus immediate-release risperidone.

Findings

• 47 subjects completed the study, and 44 subjects were included in the analysis for pharmacokinetics.

• At week 1, Cmin for LYN-005 was 1.02 (90% CI: 0.93–1.12) versus immediate-release risperidone.

At week 5, the ratios were:

• Cmin: 1.04 (90% CI: 0.87–1.23)

• Cmax: 0.84 (90% CI: 0.77–0.92)

• Cavg: 1.03 (90% CI: 0.93–1.13)

All results were within or near the pre-established ranges of acceptance, confirming pharmacokinetic equivalence.

• Gastrointestinal treatment-emergent adverse events occurred in 66% (n=44) of 67 patients treated with LYN-005, and these were predominantly mild.

• A single serious adverse event was reported, with no safety signals outside expectations.

• Patients were clinically stable during the study, reaffirming the efficacy of the formulation.

This phase 3 trial concludes that oral LYN-005 weekly administers steady therapeutic risperidone levels with equal bioavailability compared to daily risperidone. The preparation was tolerable, with no emerging safety issues, and achieved clinical stability among subjects. These findings attest to the promise of LYN-005 as an alternative long-acting oral agent for schizophrenia and schizoaffective disorder management, with the potential to enhance adherence and long-term outcomes.

Reference:

Citrome, L., Nagaraj, N., Traverso, G., Dumas, T., & Scranton, R. (2025). Long-acting oral weekly risperidone (LYN-005) for schizophrenia in the USA (STARLYNG-1): a multicentre, open-label, non-randomised phase 3 trial. The Lancet. Psychiatry, 12(7), 504–512. https://doi.org/10.1016/s2215-0366(25)00135-x