A Phase 2, Parallel-Group, Dose-Range-Finding Study With Randomized Double-Blind Treatment and Open-Label Periods to Evaluate the Safety and Efficacy of ALKS 2680 in Subjects With Narcolepsy Type 1

The primary objective is to evaluate the efficacy of ALKS 2680 for the treatment of excessive daytime sleepiness (EDS) in subjects with narcolepsy type 1 (NT1). This assessment is clinically relevant as EDS represents a cardinal symptom of NT1 that significantly impairs daytime functioning and quality of life in affected individuals.

The secondary objectives include:

• To evaluate the efficacy of ALKS 2680 for the treatment of EDS and cataplexy in subjects with NT1

• To evaluate the safety and tolerability of ALKS 2680 in subjects with NT1

This clinical trial enrolled a total of **132 participants** diagnosed with **Narcolepsy Type 1**. The study population consisted of both male and female subjects aged **18 to 70 years**. Participants were required to have a **body mass index (BMI)** between 18 and 40 kg/m². All subjects met the diagnostic criteria for Narcolepsy Type 1 according to **ICSD-3-TR guidelines**, confirmed by diagnostic evaluations including **polysomnography (PSG)**, **Multiple Sleep Latency Test (MSLT)**, or **cerebrospinal fluid (CSF) hypocretin-1 levels** within the last 10 years. Key selection criteria included the presence of residual **excessive daytime sleepiness (EDS)** with an **Epworth Sleepiness Scale (ESS)** total score greater than 12, positive **HLA-DQB1*06:02** status or documented hypocretin-1 CSF levels of 110 pg/mL or below, an average of more than 4 weekly **cataplexy** events during the last 2 weeks of screening, and a **mean sleep latency (MSL)** of 15 minutes or less across 4 **Maintenance of Wakefulness Test (MWT)** trials. Participants were required to discontinue any medications prescribed for narcolepsy symptom management for at least 14 days or 5 half-lives prior to treatment initiation. Lifestyle considerations included adherence to actigraphy and diary requirements with at least 80% completion. Subjects receiving treatment for **obstructive sleep apnea (OSA)** were required to maintain adherence to their primary therapy, defined as **positive airway pressure (PAP)** use for at least 4 hours per night on at least 70% of nights, or oral appliance use on at least 70% of nights.

This clinical trial evaluates the efficacy and safety of **ALKS 2680** in participants with **narcolepsy type 1**. The study employs a **Phase 2**, **parallel-group**, **dose-range-finding** design consisting of a **randomized**, **double-blind** treatment period followed by an **open-label** period. The investigational medicinal product ALKS 2680 is administered as an **oral tablet** in three different dose levels: 4 mg, 6 mg, and 8 mg daily. A **placebo** matching ALKS 2680 serves as the control intervention. The maximum treatment duration with the investigational product is 91 days, with maximum total doses of 560 mg, 644 mg, and 728 mg corresponding to the respective daily dose levels.

The primary objective is to evaluate the efficacy of ALKS 2680 for the treatment of **excessive daytime sleepiness** in subjects with narcolepsy type 1. The **primary endpoint** is the change in **mean sleep latency** on the **Maintenance of Wakefulness Test** from baseline to Week 6 by dose level. Secondary endpoints include the change in **Epworth Sleepiness Scale** score from baseline to Week 6, mean weekly **cataplexy rate** derived from subject diaries over Weeks 5 and 6, and various safety assessments including **treatment-emergent adverse events**, clinical laboratory assessments, **vital signs**, safety **electrocardiogram**, and **Columbia-Suicide Severity Rating Scale** evaluations by study period.

Eligible participants are adults aged 18 to 70 years with a **body mass index** between 18 and 40 kg/m² who meet diagnostic criteria for narcolepsy type 1 according to **International Classification of Sleep Disorders, Third Edition, Text Revision** guidelines, confirmed by **polysomnography**, **Multiple Sleep Latency Test**, or **cerebrospinal fluid hypocretin-1** levels within the last 10 years. Key inclusion criteria require residual excessive daytime sleepiness with an Epworth Sleepiness Scale total score greater than 12, positive **HLA-DQB1*06:02** status or documented hypocretin-1 cerebrospinal fluid levels of 110 pg/mL or less, an average of more than 4 weekly cataplexy events during the last 2 weeks of the screening period, and a mean sleep latency of 15 minutes or less across 4 Maintenance of Wakefulness Test trials during screening. Participants must be able to safely discontinue any medications prescribed for narcolepsy symptom management for at least 14 days or 5 half-lives, whichever is longer, prior to Day 1 and for the duration of the study. Participants receiving treatment for **obstructive sleep apnea** must demonstrate adherence to primary therapy, defined as **positive airway pressure** use for at least 4 hours per night on at least 70% of nights or oral appliance use on at least 70% of nights.

The study comprises a screening period during which eligibility is assessed through Visit 1 and Visit 4, followed by randomization on Day 1 and a 6-week double-blind treatment period. Study visits include a screening visit for initial assessment, baseline evaluations, weekly or biweekly visits during the treatment period for efficacy and safety monitoring, and an end-of-study visit at Week 6. Participants are expected to maintain compliance with lifestyle restrictions, **actigraphy** and diary requirements with at least 80% completion, and contraception guidance throughout the study. The trial includes overnight visits during which adherence to obstructive sleep apnea therapy and sleep assessments are performed. Early termination from the study may occur due to safety concerns, non-compliance with protocol requirements, withdrawal of consent, or at the discretion of the investigator. The estimated recruitment start date is August 30, 2024, with an estimated study completion date of September 30, 2025.

The experimental medication ALKS 2680, also known by the alternative designations RDC-264177, RDC-264177-00, and CMG-177BFD00, is administered as an oral tablet formulation. The study evaluates three distinct dosage levels of ALKS 2680. The first dosage regimen involves a maximum daily dose of 4 mg, with a maximum total dose of 560 mg administered over a treatment period of up to 91 days. The second dosage regimen consists of a maximum daily dose of 6 mg, with a maximum total dose of 644 mg over the same 91-day treatment period. The third dosage regimen provides a maximum daily dose of 8 mg, with a maximum total dose of 728 mg, also administered over a maximum treatment period of 91 days. The active substance in ALKS 2680 is of chemical origin and is manufactured by Alkermes, Inc.

A matching placebo to ALKS 2680 is utilized as the comparator treatment in this study. The placebo is designed to match the appearance of the active investigational product to maintain blinding during the randomized double-blind treatment period. The placebo formulation contains no active pharmaceutical ingredient and serves as a control for evaluating the safety and efficacy of the experimental medication.

Efficacy will be assessed using multiple parameters measured at specified timepoints throughout the study. The primary efficacy endpoint is the change in mean sleep latency on the Maintenance of Wakefulness Test from baseline to Week 6 by dose level. Secondary efficacy endpoints include the change in Epworth Sleepiness Scale score from baseline to Week 6 by dose level and the mean weekly cataplexy rate as derived from the subject cataplexy diary over Weeks 5 and 6 by dose level. Baseline assessments will be conducted during the screening period, with subjects required to have a mean sleep latency of 15 minutes or less across 4 Maintenance of Wakefulness Test trials and an average of more than 4 weekly cataplexy events during the last 2 weeks of screening. Efficacy measurements will be collected and analyzed according to the protocol-specified schedule to evaluate the treatment effect of ALKS 2680 in subjects with narcolepsy type 1.