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A novel once-weekly capsule loaded with the antipsychotic risperidone, LYN-005, provided similar bioavailability and symptom control as daily doses of the drug in a phase 3 trial of patients with schizophrenia or schizoaffective disorder.
The study was stopped early for success after an interim analysis showed all pharmacokinetic values met primary endpoint criteria.
Weekly LYN-005 could bridge the gap between daily oral medications and long-acting injectable antipsychotics, which are not universally offered or accepted by patients, the researchers noted.
“One of the biggest obstacles in the care of people with chronic illness in general is that medications are not taken consistently. This leads to worsening symptoms, and in the case of schizophrenia, potential relapse, and hospitalization,” lead author Leslie Citrome, MD, MPH, New York Medical College School of Medicine, Valhalla, New York, said in a news release.
“Having the option to take medication by mouth once a week represents an important option that can assist with adherence for the many patients who would prefer oral medications vs injectable formulations,” he added.
The study was published online on June 10 in The Lancet Psychiatry.
More Than a Decade in the Making
The investigational capsule is about the size of a multivitamin and once ingested, the pill unfolds into a star shape designed to prevent it from being passed from the stomach while the drug is released.
Over time, enteric and time-dependent layers on the prongs of the star become more pliable and/or break off, easing passage out of the stomach and through the intestinal tract.
Initial details of the drug-delivery platform were reported in 2016 by researchers at the Massachusetts Institute of Technology, Cambridge, Massachusetts, and Brigham and Women’s Hospital, Boston, with further development of the star capsule by the current study sponsor, Lyndra Therapeutics.
The STARLYNG-1 trial enrolled 83 patients, aged 18-64 years, across five US sites who had schizophrenia or schizoaffective disorder for at least 2 years and were stabilized on any oral antipsychotic drug for 6 weeks or longer.
Participants were also required to have no hospital admission for worsening schizophrenia within the past 6 months, a Clinical Global Impressions Scale-Severity score ≤ 4, and a Positive and Negative Syndrome Scale (PANSS) score ≤ 80.
After a 7-day run-in period with immediate-release daily risperidone (2 mg or 6 mg), participants received five weekly doses of LYN-005 (15 mg or 45 mg, respectively), with a supplemental half-dose of daily immediate-release risperidone during week 1 of LYN-005 dosing.
Participants were inpatients from day -5 to day 8 and from day 14 to the end of treatment and participated as outpatients on days 9-13 to ensure consistent blood sampling and treatment compliance. They were followed for safety for 4 weeks after treatment.
Medications for agitation, anxiety, and insomnia were permitted during the study and nine participants received rescue risperidone. In all, 47 participants completed the study and 44 were included in the pharmacokinetic analysis.
Sustained Release, No Unexpected Safety Signal
The primary endpoints were the minimum concentration (Cmin) of the active moiety of LYN-005 at weeks 1 and 5, and the maximum concentration (Cmax) and average concentration (Cavg) of the active moiety of LYN-005 at week 5 compared with immediate-release risperidone on day -1.
Geometric mean ratios (GMRs) of LYN-005 vs immediate-release risperidone were 1.02 for Cmin at week 1 (90% CI, 0.93-1.12), and 1.04 for Cmin (90% CI, 0.87-1.23), 0.84 for Cmax (90% CI, 0.77-0.92), and 1.03 for Cavg (90% CI, 0.93-1.13) at week 5.
LYN-005 concentrations were maintained above the target threshold (Cmin: GMR, 1.04) and remained below peak concentrations of immediate-release risperidone, suggesting stable drug delivery over time, the authors noted.
Changes in mean PANSS total scores were minimal regardless of LYN-005 dose and scores were maintained in the mid-50s throughout treatment, indicating relatively mild symptom severity and stable disease control with LYN-005, they added.
Among 67 participants who received at least one dose of LYN-005, 56 (84%) had at least one adverse event and nine (13%) participants had an event that led to study withdrawal.
Gastrointestinal-related events were the most common (66%) and most were mild (75%) and lasted < 3 days. GI events that persisted for more than 3 days included gastroesophageal reflux disease, dyspepsia, and constipation.
Other common adverse events were headache (12%), nausea (10%), and back pain (8%). One serious treatment-emergent adverse event (esophagitis) was reported during follow-up and resulted in full recovery. There were no fatal adverse events.
Mean Somatic Symptom Scale-8 scores were none to minimal (0-3 score) across the 5 weeks and were weakly correlated with the number of gastrointestinal-related adverse events reported over the same period.
Two thirds (68%) of patients and 53% of physicians reported a score ≥ 3 on a 5-point Likert scale, with 1 being very dissatisfied and 5 very satisfied with LYN-005.
“It works and the whole point of treating schizophrenia is adherence, getting them to take the medicine,” Ira D. Glick, MD, professor emeritus of psychiatry and behavioral sciences, Stanford University School of Medicine, Stanford, California, told Medscape Medical News. “Some patients will take it oral; some take it injectable; and there are some patients who are very resistant. This sounds like another way a doctor can try.”
The investigators acknowledge that the relatively stable trial population does not represent the heterogeneity seen in clinical practice and that strict inclusion criteria might limit generalizability to the broader schizophrenia population.
Other limitations include few female participants (25%) and that the controlled clinical setting with structured support and regular inpatient monitoring might have allowed for greater adherence.
The double-blind, placebo-controlled trial STARLYNG-2 trial was to evaluate the long-term safety and tolerability of LYN-005 but the trial was withdrawn in April 2025.
Lyndra Therapeutics is investigating the use of the star capsule to deliver other drugs, including weekly levomethadone for treatment of opioid use disorder, monthly contraceptives, and an oral biweekly ivermectin for malaria, according to the company website.
Lyndra Therapeutics funded and designed the trial with assistance from the academic investigators. It also aided in data collection, analysis, and interpretation and writing of the report. Citrome reported serving as a consultant and/or speaker for numerous companies including Lyndra and Medscape. Coauthors Richard Scranton and Nayana Nagaraj are Lyndra employees and coauthor Giovanni Traverso owns stock/stock options in Lyndra. Coauthor Todd Dumas and Glick reported no relevant financial conflicts of interest.
