Olesoxime, a small molecule once considered a potential treatment, failed to slow motor and respiratory decline in people with spinal muscular atrophy (SMA) types 2 and 3 who were unable to walk, according to final results from an extension Phase 2 clinical trial.
Data covering nearly 2.5 years of treatment also found a more pronounced functional decline in patients younger than 15, and in those with SMA type 2, a more severe form of the disease.
In 2018, trial data reaching out 18 months already showed a decline in treated patients’ motor function after one year of motor stabilization, prompting Roche, its developer, to stop the therapy’s clinical development.
Final trial data are now detailed in the study, “Long-term follow-up of patients with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial,” published in the journal Neuromuscular Disorders.
An experimental, orally available molecule, olesoxime works to preserve mitochondria, the cells’ powerhouses whose malfunction is thought to contribute to motor neuron degeneration in SMA. Motor neurons are specialized nerve cells that control voluntary movement.
In this way, olesoxime was thought to be neuroprotective and to help motor neurons avoid further degeneration.
Preclinical studies showed that daily doses of olesoxime were superior to placebo at improving survival in a mouse model of severe SMA. Based on these promising data, the therapy was designated an orphan drug in the U.S. and in Europe to support and speed its clinical development.
A previous placebo-controlled, Phase 2 study (NCT01302600) evaluated olesoxime’s safety and effectiveness in 160 people with SMA types 2 or 3 who were unable to walk without assistance (non-ambulatory).
Results showed that olesoxime was generally safe, but failed to meet the trial’s main goal of improving patients’ motor function. However, motor abilities among olesoxime-treated patients seemed to stabilize over two years of treatment, while those on a placebo declined.
These findings suggested that olesoxime could potentially prevent disease progression in these SMA patients.
To confirm the therapy’s potential long-term benefits, Roche launched a five-year, open-label, extension Phase 2 study (OLEOS; NCT02628743) involving 131 SMA type 2 and 3 patients who participated in previous olesoxime trials, regardless of whether they were assigned to the therapy or a placebo.
Participants’ mean age was 14.7 (range, 8–34 years) and most (68.7%) had type 2 disease. All were treated with 10 mg/kg of oral olesoxime either once or twice a day for up to five years or until intolerable toxicity.
This extension study’s main goal was to assess olesoxime’s long-term safety. Secondary goals included its long-term effectiveness as measured through changes in the Motor Function Measure compared with the disease’s natural history, and changes in patients’ lung function as measured by forced vital capacity.
A total of 71 untreated type 2 and 3 patients, matched with study patients, were included in the natural history comparison population.
The study’s last assessment was completed at 130 weeks (nearly 2.5 years of treatment) after Roche ended the trial in December 2018 due to the lack of evidence of therapy benefits.
Results showed that long-term treatment with olesoxime was generally well tolerated, with no new safety concerns identified and most side effects being mild to moderate. Olesoxime-related side effects were reported in 13% of participants, with the most common being diarrhea.
No patient died during the trial, and one patient discontinued treatment due to a non-serious adverse event.
A total of 128 patients received at least one therapy dose and completed at least one clinical assessment post-treatment during OLEOS, and were included in effectiveness analyses.
Previously reported one-year data showed that the therapy continued to sustain patients’ motor function. However, final data highlighted that motor function steadily declined after that point, and until the last assessment at 130 weeks, which was completed by 50% of the initial participants.
In addition, motor function changes in the first year were not significantly different from those reported in the matched natural history population, emphasizing the absence of therapeutic benefits with olesoxime.
Subgroup analyses showed that the greatest motor function decline was seen in patients up to 15 years of age, regardless of disease type, while older patients showed stabilization or slight improvement in motor function.
Those with SMA type 2 had a faster decline than those with type 3 disease after about six months of treatment in OLEOS.
Patients’ lung function also showed a steady drop during the study, except in type 3 patients older than 15 years, in whom it stabilized or improved.
OLEOS’ findings “did not confirm the results observed in the [previous] Phase 2 study,” the researchers wrote, noting that “there was no stabilization of motor function and FVC declined over the course of the study.”
Therefore, these data “did not support significant benefit of olesoxime in patients with SMA,” the team concluded.