ORX750 for Narcolepsy and Idiopathic Hypersomnia

(CRYSTAL-1 Trial)

Recruiting at 19 trial locations

Overseen By Centessa Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Centessa Pharmaceuticals (UK) Limited

Disqualifiers: Cardiovascular, Pulmonary, Neurological, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

78 Participants Needed

Trial Summary

What is the purpose of this trial?

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. 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.

Will I have to stop taking my current medications?

Yes, you will need to stop taking all medications used for treating narcolepsy or idiopathic hypersomnia to participate in this trial.

How does the drug ORX750 differ from other treatments for narcolepsy and idiopathic hypersomnia?

ORX750 is unique because it may target the underlying mechanisms of narcolepsy and idiopathic hypersomnia, potentially offering a novel approach compared to existing treatments that primarily focus on symptom management. Current treatments often involve stimulants or medications like modafinil and sodium oxybate, which are less effective for idiopathic hypersomnia and focus on alleviating symptoms rather than addressing the root cause. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults aged 18-65 with a BMI between 17 and 37 who have narcolepsy or idiopathic hypersomnia. Participants must be able to follow the study rules and stop taking their current narcolepsy or hypersomnia meds. They can't join if they have serious health issues like heart, lung, liver diseases, or other conditions causing excessive sleepiness.

Inclusion Criteria

I am between 18 and 65 years old.

BMI ≥17 and ≤37 kg/m2

Is willing and able to adhere to additional protocol requirements

Exclusion Criteria

I have a serious heart, lung, liver, kidney, blood, cancer, hormone, nerve, or mental health condition.

I have a condition causing excessive daytime sleepiness not diagnosed as NT1, NT2, or IH.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ORX750 or placebo to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics

6 weeks

Regular visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ORX750

Trial Overview The trial is testing ORX750 against a placebo to see how safe it is and how it affects the body (PK/PD) in people with narcolepsy or idiopathic hypersomnia. It aims to understand if ORX750 can help manage symptoms better than an inactive substance.

Participant Groups

Group I: Narcolepsy Type 2: ORX750 and Placebo Experimental Treatment 2 Interventions

Group II: Narcolepsy Type 1: ORX750 and Placebo Experimental Treatment 2 Interventions

Group III: Idiopathic Hypersomnia: ORX750 and Placebo Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Centessa Pharmaceuticals (UK) Limited

Lead Sponsor

Trials

2

Recruited

100+

Findings from Research

Idiopathic hypersomnia can present in two forms: a polysymptomatic form with excessive daytime sleepiness and long nocturnal sleep, and a monosymptomatic form characterized only by excessive daytime sleepiness.

Diagnosis can be challenging due to the potential for overdiagnosis and the need to exclude other disorders; treatment typically involves stimulants, which may be less effective and well tolerated compared to treatments for narcolepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idiopathic hypersomnia. Billiard, M.[2019]

Patients with idiopathic hypersomnia (IH) experience more consolidated nocturnal sleep and report feeling more refreshed after naps compared to those with narcoleptic syndrome (NLS), indicating differences in sleep quality between the two conditions.

The onset of excessive daytime sleepiness in IH is often linked to familial factors or viral illnesses, while key variables like the number of awakenings during sleep and changes in sleepiness since onset help distinguish IH from NLS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data. Bruck, D., Parkes, JD.[2019]

Narcolepsy affects a small percentage of the population and is linked to genetic factors and the loss of hypocretin-producing neurons, suggesting an autoimmune component that may be triggered by environmental factors.

Current treatments like sodium oxybate and modafinil effectively manage symptoms such as excessive daytime sleepiness and cataplexy, while emerging therapies focus on both non-hypocretin-based and hypocretin-based approaches to improve outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the management of narcolepsy. Abad, VC., Guilleminault, C.[2020]

Modafinil is recommended as the first-line treatment for excessive daytime sleepiness (EDS) in central hypersomnias like narcolepsy and idiopathic hypersomnia, with other stimulants available for patients who do not respond to it.

New therapies are being developed that aim to restore hypocretin levels or address the autoimmune processes involved in narcolepsy, which could lead to more effective treatments in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

French consensus. Management of patients with hypersomnia: Which strategy? Lopez, R., Arnulf, I., Drouot, X., et al.[2017]

Narcolepsy is a distinct sleep disorder characterized by excessive daytime sleepiness and cataplexy, which involves sudden loss of muscle tone and can lead to sleep paralysis and hallucinations.

Treatment for narcolepsy includes lifestyle adjustments and medications, such as stimulants for daytime sleepiness and tricyclic drugs to manage cataplexy, highlighting the need for a comprehensive approach to care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Narcoleptic syndrome]. Hess, CW.[2015]

References

1. United States pubmed.ncbi.nlm.nih.gov

Idiopathic hypersomnia. [2019]

2. England pubmed.ncbi.nlm.nih.gov

A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data. [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

New developments in the management of narcolepsy. [2020]

4. France pubmed.ncbi.nlm.nih.gov

French consensus. Management of patients with hypersomnia: Which strategy? [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

[Narcoleptic syndrome]. [2015]