Takeda’s oveporexton delivers broad symptom improvements in Phase 3 narcolepsy type 1 studies

Takeda has reported publication in the New England Journal of Medicine of results from two Phase 3 trials evaluating oveporexton, marketed as ORZEYFUL, in people with narcolepsy type 1.

The oral orexin receptor 2 agonist is designed to address orexin deficiency, which is considered the underlying cause of narcolepsy type 1. Oveporexton is the first and only approved orexin agonist developed to target the cause of the condition rather than individual symptoms. It has received approval in the United States, China and Japan, while further regulatory submissions are ongoing.

Narcolepsy type 1 is a rare and chronic neurological disorder caused by a lack of orexin. People with the condition can experience symptoms during both the day and night, including excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, hallucinations and cognitive difficulties. These persistent symptoms can affect education, employment, social activities and other aspects of daily life.

Emmanuel Mignot, principal investigator of the FirstLight Phase 3 study, said the new findings support the potential for oveporexton to change the way narcolepsy type 1 is managed in clinical practice. He explained that the treatment could shift care away from addressing individual symptoms and towards treating the underlying disease.

Takeda evaluated oveporexton through the FirstLight and RadiantLight Phase 3 studies.

FirstLight, also known as TAK-861-3001, enrolled 168 participants who were randomly assigned to receive oveporexton 2 mg twice daily, oveporexton 1 mg twice daily or placebo.

RadiantLight, also known as TAK-861-3002, included 105 participants who were randomly assigned to receive either oveporexton 2 mg twice daily or placebo.

Across the two studies, 14 primary and secondary endpoints were used to assess the effect of treatment on the broader impact of narcolepsy type 1 over a 12 week period. More than 95% of participants who completed the trials chose to enter the ongoing long term extension study.

The publication included primary and key secondary efficacy findings alongside safety and tolerability results. Additional secondary and exploratory analyses assessing quality of life and overall disease severity were also reported.

Across both Phase 3 studies, oveporexton produced consistent, clinically meaningful and statistically significant improvements compared with placebo in wakefulness, sleepiness, cataplexy, disease severity and quality of life. Results across doses achieved p values below 0.001.

Improvements were already evident at the earliest assessment point for each measure and continued throughout the 12 week treatment period.

At week 12, median reductions in weekly cataplexy rates ranged from 79.0% to 88.8% among participants receiving oveporexton. By comparison, reductions among those receiving placebo ranged from 27.7% to 39.1%.

Treatment also improved scores across all domains of the Narcolepsy Severity Scale Clinical Trials, including excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis at both doses. An improvement in the disrupted nighttime sleep domain was also observed with the 2 mg dose.

More than 70% of participants treated with oveporexton reported the lowest category of disease severity on the scale, defined as mild disease with a score between 0 and 14.

Patient reported assessments also showed improvements. Overall, 97% of treated participants said their narcolepsy symptoms had improved according to the Patient Global Impression of Change scale.

All oveporexton dose groups reached normative wakefulness thresholds on the Maintenance of Wakefulness Test, defined as at least 20 minutes. Participants also reached the normative threshold on the Epworth Sleepiness Scale, with scores of 10 or lower.

Most participants additionally reached or exceeded normal thresholds for quality of life outcomes measured using the 36 Item Short Form Survey, which was a secondary endpoint, and the EuroQol 5 Dimensions 5 Levels assessment, which was an exploratory endpoint.

Sarah Sheikh, head of the Neuroscience Therapeutic Area Unit and Global Development at Takeda, said the company designed its Phase 3 programme to reflect the complexity of narcolepsy type 1 and the experiences of people living with the disease.

She added that the scale of improvement seen across the range of symptoms assessed supports the potential for oveporexton to change how patients experience treatment. Sheikh also acknowledged the contributions of patients, caregivers and healthcare professionals involved in the clinical programme.

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Related Topics and Keywords

clinical trials, narcolepsy, Narcolepsy Type 1, neurology, orexin, ORZEYFUL, Oveporexton, pharma news, Phase 3, Takeda