Open-label, Single-arm Trial of Ganaxolone in CDD Patients 6 Months to Less Than 2 Years Old

Key Inclusion Criteria:

1. A diagnosis of CDD, including molecular confirmation of a pathogenic or likely pathogenic CDKL5 variant.

2. Male or female participants aged 6 months to less than 2 years at the Baseline Visit.

3. Failure to control seizures despite appropriate use of 1 or more anti-seizure medications at therapeutic doses. At least 3 participants will be included who failed to control seizures despite appropriate use of at least 2 anti-seizure medications.

4. Participants will have refractory seizures with a history of at least 8 countable seizures of primary seizure types during the 28 days prospective Baseline Period prior to the Baseline Visit. Primary seizure types are seizures with or without impairment of consciousness with a clear motor component, including generalized tonic-clonic, focal to bilateral tonic-clonic, atonic/drop, bilateral clonic, bilateral tonic (sustained motor activity ≥ 3 seconds). Clusters of uncountable seizures will be counted as a single seizure.

   1. Primary seizures exclude epileptic spasms. Patients with epileptic spasms are eligible for enrolment but epileptic spasms will not be counted as qualifying countable seizures for eligibility. Epileptic spasms should not constitute the dominant seizure type during the Baseline Period.
   2. Primary seizures exclude myoclonic, absence, generalized non-motor seizures, and focal motor or non-motor seizures with or without impairment of awareness.

5. Participants should be receiving a stable regimen of anti-seizure medications at Screening through to the end of the 4-week prospective Baseline Period and have no foreseeable change for the duration of Part A.

   1. Concurrent use of adrenocorticotropic hormone, prednisone, other glucocorticoids, or vigabatrin are permitted.
   2. Vagus nerve stimulator (VNS) settings, ketogenic diet, or a modified Atkins diet should be unchanged for 1 month prior to the Screening Visit, throughout the Screening Period and the 4-week prospective Baseline Period and without foreseeable change for the duration of Part A at the time of the Baseline Visit.

6. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure diary for the duration of the trial.

Key Exclusion Criteria:

1. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance imaging).
2. Have any disease or condition (medical or surgical; other than CDKL5 deficiency) that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product or would place the participant at increased risk.
3. History of or present AST (aspartate aminotransferase/serum glutamic-oxaloacetic transaminase) or ALT (alanine aminotransferase/serum glutamic-pyruvic transaminase) >3 times the upper limit of normal (ULN) at Baseline and confirmed by a repeat testing.
4. History of or present total bilirubin levels greater than the ULN at trial Baseline and confirmed by a repeat testing. In cases of a documented, stable medical condition (i.e., Gilbert's Syndrome) resulting in levels of total bilirubin greater than the ULN, the Medical Monitor will determine if an exception can be made.
5. Participants with significant renal insufficiency, with an estimated glomerular filtration rate (eGFR) <30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric eGFR calculator or Bedside Schwartz).
6. Regular use of St. John's Wort or strong CYP3A4 inducers, e.g., phenytoin, carbamazepine or phenobarbital (N.B. phenytoin and phenobarbital are permitted as rescue medication on as-need basis but are not permitted as continuous maintenance medication).
7. Have been exposed to any other investigational drug within 30 days or less than its 5 half-lives prior to the Screening Visit.
8. Previous treatment with ganaxolone.
9. Participation in any other trial involving administration of an investigational medication or device.