A Study of ORX750 in Participants With Narcolepsy and Idiopathic Hypersomnia (CRYSTAL-1)

A Phase 2a, Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ORX750 in Subjects With Narcolepsy and Idiopathic Hypersomnia (CRYSTAL-1)

Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2), and Idiopathic Hypersomnia (IH) are rare conditions that make people feel very sleepy during the day (often referred to as excessive daytime sleepiness [EDS]). People living with these conditions might find it hard to stay alert and pay attention when they are at school, working, driving, or performing other daily activities.

While all conditions result in feeling sleepy, there are some differences in other common symptoms:

• NT1: People with NT1 often feel very tired during the day and experience cataplexy. Cataplexy is a sudden loss of muscle strength, which can cause someone to collapse or lose control of their muscles for a short time. This is often triggered by strong emotions, such as laughter or surprise. They may also have trouble sleeping well at night.
• NT2: People with NT2 feel sleepy during the day, just like NT1, but they do not have cataplexy.
• IH: People with IH feel tired during the day, even after sleeping a lot at night. They may sleep for long periods, take long naps, and find it hard to wake up.

Orexin is a protein in the brain that helps coordinate a system that plays an important role in helping people to stay awake during the daytime. Cleminorexton (also known as ORX750) is designed to mimic the action of orexin. The purpose of this study is to see how safe and tolerable ORX750 is in NT1, NT2, and IH, and learn about what the drug does to the body. Another goal of the study is to see if ORX750 can help people with NT1, NT2, and IH feel less sleepy and make other symptoms better.

Study Overview

• Status: Recruiting
• Conditions: Idiopathic Hypersomnia; Narcolepsy Type 1; Narcolepsy Type 2
• Intervention / Treatment: Drug: ORX750; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 248
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Centessa Pharmaceuticals; Phone Number: +1 617-468-5770; Email: CRYSTAL-1@centessa.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5S 3A3
      • Recruiting
      • Toronto, Ontario
• France
  • Bordeaux
    • Léon, Bordeaux, France, 33000
      • Recruiting
      • Leon, France
• Italy
  • Bologna, Italy, 40139
    • Recruiting
    • Bologna, Italy
  • Pozzilli, Italy, 86077
    • Recruiting
    • Pozzilli, Italy
  • Verona, Italy, 37134
    • Recruiting
    • Verona, Italy
• Spain
  • Madrid, Spain, 28036
    • Recruiting
    • Madrid, Spain
  • Madrid, Spain, 28043
    • Recruiting
    • Madrid, Spain
  • Vitoria-Gasteiz, Spain, 01009
    • Recruiting
    • Vitoria-Gasteiz, Spain
• United States
  • Alabama
    • Auburn, Alabama, United States, 36832
      • Recruiting
      • Auburn, Alabama
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Recruiting
      • Chandler, Arizona
    • Scottsdale, Arizona, United States, 85253
      • Recruiting
      • Scottsdale, Arizona
  • California
    • Long Beach, California, United States, 90805
      • Recruiting
      • Long Beach, California
    • Santa Ana, California, United States, 92705
      • Recruiting
      • Santa Ana, California
  • Florida
    • Brandon, Florida, United States, 33511
      • Recruiting
      • Brandon, Florida
    • Miami, Florida, United States, 33155
      • Recruiting
      • Miami, Florida
    • Miami, Florida, United States, 33176
      • Recruiting
      • Miami, Florida
    • Orlando, Florida, United States, 32807
      • Recruiting
      • Orlando, FL
    • Winter Park, Florida, United States, 32789
      • Recruiting
      • Winter Park, Florida
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Recruiting
      • Atlanta, Georgia
    • Atlanta, Georgia, United States, 30281
      • Recruiting
      • Atlanta, Georgia
    • Riverdale, Georgia, United States, 30274
      • Recruiting
      • Riverdale, Georgia
  • Louisiana
    • New Orleans, Louisiana, United States, 70127
      • Recruiting
      • New Orleans, Louisiana
  • Massachusetts
    • Newton, Massachusetts, United States, 02459
      • Recruiting
      • Newton, Massachusetts
  • Michigan
    • Southfield, Michigan, United States, 48075
      • Recruiting
      • Southfield, Michigan
    • Sterling Heights, Michigan, United States, 48314
      • Recruiting
      • Sterling Heights, Michigan
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Recruiting
      • Henderson, Nevada
  • North Carolina
    • Denver, North Carolina, United States, 28037
      • Recruiting
      • Denver, North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Recruiting
      • Huntersville, North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Recruiting
      • Cincinnati, Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Cleveland, OH
    • Dublin, Ohio, United States, 43017
      • Recruiting
      • Dublin, Ohio
  • Pennsylvania
    • Willow Grove, Pennsylvania, United States, 19090
      • Recruiting
      • Willow Grove, Pennsylvania
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • Recruiting
      • Columbia, South Carolina
    • North Charleston, South Carolina, United States, 29406
      • Recruiting
      • North Charleston, South Carolina
  • Texas
    • Austin, Texas, United States, 78731
      • Recruiting
      • Austin, Texas
    • El Paso, Texas, United States, 79912
      • Recruiting
      • El Paso, TX
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • San Antonio, Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18-65 years of age
• BMI ≥17 and ≤37 kg/m2
• Meets the diagnostic criteria of Narcolepsy Type 1 (NT1), Type 2 (NT2) or Idiopathic Hypersomnia (IH) according to ICSD-3-TR criteria
• Is willing and able to discontinue all medications used for the treatment of narcolepsy or idiopathic hypersomnia
• Is willing and able to adhere to additional protocol requirements

Exclusion Criteria:

• A medical disorder other than NT1, NT2, or IH that is associated with excessive daytime sleepiness (EDS).
• Presence of significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, hematological, malignancy, endocrine, neurological or psychiatric disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Narcolepsy Type 1: ORX750 and Placebo	Drug: ORX750; ORX750 capsule.; Drug: Placebo; ORX750 matching placebo capsule.
Experimental: Narcolepsy Type 2: ORX750 and Placebo	Drug: ORX750; ORX750 capsule.; Drug: Placebo; ORX750 matching placebo capsule.
Experimental: Idiopathic Hypersomnia: ORX750 and Placebo	Drug: ORX750; ORX750 capsule.; Drug: Placebo; ORX750 matching placebo capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs	Up to Day 35
Number of Participants With Abnormal Changes From Baseline in Laboratory Tests	Up to Day 35
Number of Participants With Abnormal Change From Baseline in Vital Signs	Up to Day 35
Number of Participants With Abnormal Change From Baseline in Electrocardiograms (ECG)	Up to Day 35
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)	Up to Day 35

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: Maximum Observed Plasma Concentration for ORX750		Day 1, 15, 28
Tmax: Time of Maximum Concentration for ORX750		Day 1, 15, 28
AUC0last: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ORX750		up to Day 28
Cmax,ss: Maximum Observed Concentration at Steady State for ORX750		Day 1, 15, 28
AUCτ: Area Under the Concentration-time Curve During a Dosing Interval at Steady State for ORX750		Day 1, 15, 28
Mean sleep latency (average of the first 4 trials) in the Maintenance of Wakefulness Test (MWT) for ORX750 versus placebo.	Mean sleep latency is determined by averaging the time to falling asleep across trials	Baseline up to Day 28
Change From Baseline in Epworth Sleepiness Scale (ESS)		Baseline up to Day 28

Collaborators and Investigators

• Sponsor: Centessa Pharmaceuticals (UK) Limited

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 23, 2024
• First Submitted That Met QC Criteria: December 23, 2024
• First Posted (Actual): December 31, 2024

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Disorders of Excessive Somnolence; Idiopathic Hypersomnia; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ORX750-0201; 2024-518929-15-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No