What is the mechanism of action of this treatment?

The most common treatments for CDKL5 Deficiency Disorder (CDD) often involve medications that modulate serotonin levels, such as Fenfluramine (ZX008). Fenfluramine works by releasing serotonin and inhibiting its reuptake, which can help stabilize neuronal activity and reduce the frequency of seizures. This mechanism is particularly important for CDD patients, as uncontrolled seizures are a major symptom of the disorder. By influencing serotonin pathways, these treatments aim to provide better seizure control and potentially improve cognitive functions.

What side effects are associated with this type of intervention?

Treatments for CDKL5 Deficiency Disorder, particularly those involving serotonin release and reuptake inhibition like Fenfluramine (ZX008), commonly have side effects such as decreased appetite, fatigue, diarrhea, and somnolence. Additionally, treatments affecting serotonin levels, such as SSRIs, often report side effects including sweating, dizziness, and gastrointestinal disturbances.

What prior FDA approvals exist?

As of now, there are no specific FDA-approved treatments for CDKL5 Deficiency Disorder (CDD). ZX008 (Fenfluramine), which is being studied for its efficacy and safety in treating uncontrolled seizures in CDD, works through serotonin release and reuptake inhibition. This mechanism is similar to other drugs used for seizure management, but no other treatments specifically targeting CDD with this mechanism have been approved by the FDA.

What other types of research exist?

Promising novel alternatives to ZX008 for CDKL5 Deficiency Disorder patients may include gene therapy approaches, such as MECP2 supplementation, and other pharmacologic treatments like trofinetide, which has shown efficacy in related disorders like Rett syndrome. Additionally, ongoing research into targeted therapies and personalized medicine approaches may yield new treatment options by 2024.

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Fenfluramine for CDKL5 Deficiency Disorder

Phase 3

Recruiting

Research Sponsored by Zogenix, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDD with epilepsy onset in the first year of life, plus motor and developmental delays.

Subject is male or female, aged 1 to 35 years, inclusive, as of the day of the Screening Visit.

Must not have

Subject has a current or past history of glaucoma.

Subject has moderate to severe hepatic impairment.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 14 weeks

Awards & highlights

Pivotal Trial

Summary

This trial tests ZX008, a medication added to current treatments, in children and adults with CDD who have uncontrolled seizures. The goal is to see if ZX008 can help better control their seizures.

Who is the study for?

This trial is for children and adults aged 1 to 35 with CDKL5 Deficiency Disorder (CDD) who have seizures starting in the first year of life, along with motor and developmental delays. They must have tried at least two seizure treatments without success and be on a stable epilepsy treatment plan.

What is being tested?

The study tests ZX008 (Fenfluramine Hydrochloride) as an additional therapy against a placebo for reducing uncontrolled seizures in CDD patients. It's double-blind, meaning neither participants nor researchers know who gets the real drug or placebo.

What are the potential side effects?

Potential side effects are not listed here, but since ZX008 contains fenfluramine, possible risks may include heart-related issues like valve problems, pulmonary hypertension, decreased appetite or mood changes.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have a CDKL5 mutation and was diagnosed with CDD, having seizures in my first year along with motor and developmental delays.

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I am between 1 and 35 years old.

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I still have seizures despite trying 2 or more epilepsy treatments.

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I am currently on a treatment for seizures.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have or had glaucoma.

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My liver is not working well.

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I have been diagnosed with high blood pressure in the lungs.

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I do not have any major health issues that could affect my participation in the study.

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I have been treated with Fintepla® before my screening visit.

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I am currently taking more than 4 seizure medications, not counting emergency meds.

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I am not using CBD products other than Epidiolex/Epidyolex or any THC/marijuana products.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 14 weeks

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~14 weeks

This trial's timeline: 3 weeks for screening, Varies for treatment, and 14 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

The median percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency

Secondary study objectives

The median percentage change from Baseline in monthly Generalized Tonic-Clonic (GTC) seizure frequency

The percentage of subjects who achieve a ≥ 50% reduction from Baseline in CMSF

The percentage of subjects who achieve improvement in the Clinical Global Impression-Improvement (CGI-I) rating as assessed by the Investigator

Side effects data

From 2020 Phase 3 trial • 262 Patients • NCT02682927

26%

Decreased appetite

24%

Blood glucose decreased

24%

Echocardiogram abnormal

15%

Diarrhoea

11%

Somnolence

11%

Pyrexia

Nasopharyngitis

Rhinorrhoea

Gait disturbance

Blood pressure diastolic increased

Ear infection

Fatigue

Upper respiratory tract infection

Sinusitis

Status epilepticus

Viral infection

Cough

Blood pressure increased

Constipation

Asthenia

Irritability

Urinary tract infection

Tremor

Heart rate increased

Croup infectious

Influenza

Seizure

Blood prolactin increased

Respiratory distress

Skull fracture

Gastroenteritis

Lethargy

Salivary hypersecretion

Drooling

Headache

Seizure cluster

Abnormal behaviour

Weight decreased

100%

80%

60%

40%

20%

Study treatment Arm

Study 3: ZX008 0.2 mg/kg/Day

Study 1: ZX008 0.2 mg/kg/Day

Study 1: ZX008 0.8 mg/kg/Day

Study 3: Placebo

Study 3: ZX008 0.8 mg/kg/Day

Study 1: Placebo

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

3Treatment groups

Experimental Treatment

Placebo Group

Group I: ZX008 0.8 mg/kg/dayExperimental Treatment1 Intervention

Part 1: ZX008 0.8 mg/kg/day will be administered twice a day (BID) in equally divided doses; maximum of 30 mg/day, (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, \[maximum of 20 mg/day\]) with or without food.

Group II: ZX008Experimental Treatment1 Intervention

Part 2: Open-label ZX008 will be administered using a flexible dosing regimen, up to ZX008 0.8 mg/kg/day; maximum dose: 30 mg/day (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, \[maximum of 20 mg/day\]). ZX008 will be administered twice a day (BID) in equally divided doses with or without food.

Group III: PlaceboPlacebo Group1 Intervention

Part 1: Matching ZX008 placebo will be administered twice a day (BID) in equally divided doses with or without food.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

ZX008 (Fenfluramine Hydrochloride)

2016

Completed Phase 3

~730

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for CDKL5 Deficiency Disorder (CDD) often involve medications that modulate serotonin levels, such as Fenfluramine (ZX008). Fenfluramine works by releasing serotonin and inhibiting its reuptake, which can help stabilize neuronal activity and reduce the frequency of seizures. This mechanism is particularly important for CDD patients, as uncontrolled seizures are a major symptom of the disorder. By influencing serotonin pathways, these treatments aim to provide better seizure control and potentially improve cognitive functions.

Differential effects of antidepressant treatments on fenfluramine-induced increases in plasma prolactin and corticosterone in rats.Reversal of the anorectic effect of (+)-fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK-329.Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes.