Drug Trials Snapshots: ZTALMY
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
Refer to the ZTALMY Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
ZTALMY (ganaxolone)
(zuh-tal’mee)
Marinus Pharmaceuticals Inc
Approval date: March 18, 2022
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
ZTALMY is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older.
How is this drug used?
ZTALMY is administered by mouth three times daily and must be taken with food.
Who participated in the clinical trials?
The FDA approved ZTALMY based on evidence from a clinical trial of 101 patients with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) who were 2 years of age and older. The trial was conducted at 36 sites in 8 countries including Australia, France, Israel, Italy, Poland, Russian Federation, United Kingdom, and the US. Forty-four (40.7%) of the patients were from U.S. sites.
Safety was assessed from a pool of two Clinical Studies. These include the study of patients with CDKL5 deficiency disorder and a clinical study that included 7 additional patients from a trial of ZTALMY in children and young adults.
What are the benefits of this drug?
Patients taking ZYTALMY had less frequent major motor seizures than patients taking placebo.
Table 1 Change in Frequency of Major Motor Seizures per 28 days in Patients with CDD†
| Frequency of Major Motor Seizures (per 28 days) | Placebo (N=51) | ZTALMY (N=49) |
|---|---|---|
| Prospective Baseline Phase Median Seizure Frequency | 49 | 54 |
| Median Percent Change from Baseline During Treatment | -7 | -31 |
| p-value compared to placebo | 0.0036 |
†A negative percent change from baseline in seizure frequency indicates reduction in seizure frequency
*Statistically significant compared to placebo
Source: FDA Review
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: ZTALMY appears to work better in males than females but because of the location of the gene for CDKL5, this disorder mainly affects females with fewer males in the study.
- Race: The number of patients of races other than White was small. Therefore, differences in how well the drug worked among races could not be determined.
- Age: ZTALMY worked similarly in younger and older patients.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 2 Summary of Percent Change in Seizure Frequency by Age Group and Sex
| Placebo | ZYTALMY | ZYTALMY vs. Placebo | ||||
|---|---|---|---|---|---|---|
| N | Median % change | N | Median % change | Treatment difference | 95% CI | |
| Age | ||||||
| <7 years | 22 | -9.0% | 29 | -30.7% | -27.0% | (-63.2, 4.4) |
| >=7 years | 29 | -1.5% | 20 | -30.1% | -31.1% | (-56.2, -9.4) |
| Sex | ||||||
|
Male |
10 | 7.4% | 11 | -32.0% | -42.1% | (-95.2, -8.4) |
|
Female |
41 | -10.2% | 38 | -27.5% | -22.2% | (-48.4, -1.4) |
Source: FDA Review
What are the possible side effects?
Treatment with ZTALMY was associated with the following common side effects, including: sleepiness, fever, excessive saliva or drooling, and seasonal allergy.
What are the possible side effects (results of trials used to assess safety)?
Table 3 Adverse Reactions that Occurred in ZTALMY-Treated Patients with Seizures Associated with CDD at a Rate of At Least 3% and Greater Than in Placebo
| Adverse Reactions | ZTALMY (N=50) % |
Placebo (N=51) % |
|---|---|---|
| Somnolence | 38 | >20 |
| Pyrexia | 18 | >8 |
| Upper respiratory tract infection | 10 | >6 |
| Sedation | 6 | >4 |
| Salivary Hypersecretion | 6 | >2 |
| Seasonal allergy | 6 | >0 |
| Bronchitis | 4 | >0 |
| Influenza | 4 | >2 |
| Gait disturbance | 4 | >2 |
| Nasal congestion | 4 | >2 |
Source: FDA Review
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was similar in males and females
- Race: The number of patients of races other than White was small. Therefore, differences in the occurrences of side effect among races could not be determined.
- Age: The occurrence of side effects decreased with increasing age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 4 Study 3001 DB Treatment, Distribution of Unique Patient TEAE Frequency by Treatment arm and Sex.
| Sex | ZTALMY | Placebo |
|---|---|---|
| Female | 34/39 (87%) | 35/41(85%) |
| Male | 9/11 (82%) | 10/10 (100%) |
Source: FDA Review
Table 5 Frequency of Any Adverse Event (AE) by Age Group and Treatment Arm
| Age group | ZTALMY | Placebo |
|---|---|---|
| 2 ≤ to <6 | 28/29 (97%) | 21/21 (100%) |
| 6≤ to <12 | 10/12 (83%) | 19/20 (95%) |
| 12≤ | 5/9 (56%) | 5/10 (50%) |
Source: FDA Review
DEMOGRAPHICS SNAPSHOT
Baseline Demographics by Sex
Figure 1 summarizes how many males and females were enrolled in the clinical trial used to evaluate the efficacy of ZTALMY.
Figure 1 Percent of Patients by Sex in the Efficacy Study
Source: FDA Review
Figure 2 below summarizes how many patients by sex were in the two pooled clinical studies used to evaluate the side effects of ZTALMY.
Figure 2 Percent of Patients by Sex from the Pooled Safety Studies 1 & 2
Source: FDA Review
Baseline Demographics by Race
Figure 3 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy of ZTALMY.
Figure 3 Percent of Patient by Race in the Efficacy Study
Source: FDA Review
Figure 4 below summarizes how many patients by race were in the two pooled clinical studies used to evaluate the side effects of ZTALMY.
Figure 4 Percent of Patients by Race from the Pooled Safety Studies 1 & 2
Source: FDA Review
Baseline Demographics by Age
Figure 5 below summarizes the distribution of patients by age who were enrolled in the clinical trial used to evaluate the efficacy of ZTALMY.
Figure 5 Percent of Patients in Efficacy Trial by Age Groups, 2 ≤ to <6 Years, 6≤ to <12 Years and ≥ 12
Source: FDA Review
How were the trials designed?
The effectiveness of ZTALMY for the treatment of seizures associated with CDD in patients 2 years of age and older was established in a single, double-blind, randomized, placebo-controlled study in patients 2 to 19 years of age (Study 1, NCT03572933).
Patients enrolled in Study 1 (N=50 for ZTALMY; N=51 for placebo) had molecular confirmation of a pathogenic or likely pathogenic mutation in the CDKL5 gene, seizures inadequately controlled by at least 2 previous antiseizure medications, and a minimum of 16 major motor seizures (i.e., bilateral tonic generalized tonic-clonic, bilateral clonic, atonic, focal to bilateral tonic-clonic) every 28 days during the two months period prior to screening for the study.
The benefit of ZTALMY was evaluated by measuring the difference from baseline in number of seizures per 28 days of treatment and comparing it to the placebo.
How were the trials designed?
Patients were randomized in a 1:1 ratio to receive either ZTALMY or placebo. Following a 21-day titration period, patients treated with ZTALMY who weighed 28 kg or less received a dosage of 21 mg/kg three times daily (with a maximum daily dose of 1800 mg) while patients treated with ZTALMY who weighed more than 28 kg received a dosage of 600 mg three times daily.
Bilateral tonic generalized tonic-clonic, bilateral clonic, atonic, focal to bilateral tonic-clonic) were counted as major motor seizures.
The primary efficacy endpoint was the percentage change in the 28-day frequency of major motor seizures (defined similarly as in the 2-month period prior to screening) from a 6-week prospective baseline phase during the 17-week double-blind phase. Patients treated with ZTALMY had a significantly greater reduction in the 28-day frequency of major motor seizures compared to patients receiving placebo.
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.