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Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy (MIT-E)

A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy (MIT-E)

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Vatiquinone (n=34) - Age (mean): 8.7 years - Gender: Female: 16, Male: 18 Placebo (n=34) - Age (mean): 6.6 years - Gender: Female: 21, Male: 13 Primary Endpoint: Change in Frequency of Observable Motor Seizures per 28 Days During the Double-Blind Period

This study was a parallel-arm, double-blind, placebo-controlled trial, with a screening phase that included a 28-day run-in phase to establish baseline seizure frequency. The 28 days immediately prior to the baseline visit were considered the run-in phase. Screening was followed by a 24-week randomized placebo-controlled phase during which subjects were randomized in a 1:1 ratio to receive either vatiquinone or placebo, with approximately 30 subjects in each arm. Randomization was stratified by disease subtype. Subjects who completed the randomized, placebo-controlled phase of the study had the option to enter a 48-week, long-term extension phase of the study to continue receiving open-label vatiquinone followed by a safety follow- up, as needed. For subjects entering the extension phase who initially received vatiquinone, they continued to receive the same dose of vatiquinone. For subjects entering the extension phase who initially received placebo, the dose of vatiquinone was determined based on body weight.

A majority (>79%) of subjects in both treatment groups were reported with AEs during the double-blind and open-label treatment periods of the study. Long-term treatment with vatiquinone was well tolerated. Approximately 15% of subjects who were treated with vatiquinone during the double-blind period discontinued treatment due to a TEAE.

Vatiquinone did not meet the primary endpoint of reducing the frequency of observable motor seizures per 28 days during the placebo-controlled, double-blind phase relative to placebo, but directional improvements were observed in subjects with Leigh syndrome.

The study was terminated prematurely since Vatiquinone did not meet the primary endpoint. Likewise, there were no statistically significant or clinically relevant treatment-related changes in key and other secondary efficacy endpoints over the 24-week double-blind treatment period or overall treatment period. No new or unexpected safety findings were identified.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2011210075

Vinay Penematsa

PTC Therapeutics, Inc.

500 Warren Corporate Center Drive Warren, N.J. 07059 USA

medinfo@ptcbio.com

Rosario Chikako

Parexel International

Kayabacho Tower Building 1-21-2, Shinkawa, Chuo-ku, Tokyo

+81-80-8929-3137

Clinicaltrial-registration@parexel.com

Complete

Mar. 22, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Evidence of signed and dated informed consent/assent document(s) indicating that the subject (and/or his/her parent/legal guardian) has been informed of all pertinent aspects of the trial
2. Age <21 years at time of randomization
3. Subject or parent/legal guardian is able and willing to complete seizure diaries for the duration of the study
4. Subjects with genetic confirmation of inherited mitochondrial disease with associated epilepsy phenotype (Alpers/POLG, Leigh syndrome, MELAS), or other genetically confirmed mitochondrial diseases secondary to mitochondrial mutations (Pontocerebellar Hypoplasia Type 6 [PCH6], nuclear DNA RARS2 mutation) or myoclonic epilepsy with ragged red fibers (MERRF, mitochondrial DNA [mtDNA] mitochondrially encoded tRNA lysine [MT-TK] mutation) are eligible.
5. Despite treatment with at least 2 AEDs:
- Have >=6 observed motor seizures occurring during the 28 days prior to the Baseline Visit
- Have >=2 observed motor seizures in the first 14 days and >=2 in the second 14 days of
the Run-in period
- Do not have a consecutive 20-day seizure free period and
- Have at least 80% of seizure diary data
- No changes to the AED regimen will be allowed (except weight-based dose adjustments) during the first 24-week period.
6. Documented medical history of epilepsy associated with mitochondrial disease for at least 6 months prior to screening except for subjects who are <2 years of age at the time of screening (Subjects <2 years of age can be considered for enrollment if all other screening criteria are met due to the potential for rapid progression in these subjects)
7. Consent to abstain from non-approved therapies for 30 days prior to the Screening Visit and for the duration of the study
8. Stable dose regimen of antiepileptic therapies 30 days prior to the Screening Visit
9. Stable regimen of dietary supplements 30 days prior and, if on a ketogenic diet, stable ketogenic diet 90 days prior to the Screening Visit and for duration of the study
10. Electroencephalogram (EEG) at Screening or historical EEG up to 6 months prior to screening for diagnostic confirmation of epilepsy

1. Allergy to vatiquinone or sesame oil
2. Aspartate transaminase (AST) or alanine transaminase (ALT) >=3xULN at time of screening
3. INR >ULN at time of screening
4. Serum creatinine >=1.5xULN at time of screening
5. Participation in another interventional clinical trial 60 days prior to randomization or for the duration of this clinical trial
6. Previously received vatiquinone
7. Concomitant treatment with drug(s) that have not received regulatory agency approval for the treatment of mitochondrial diseases and use of artisanal (non-Epidiolex cannabidiol) cannabidiol therapies
8. Concomitant treatment with idebenone
9. Currently being treated with anticoagulants (except when anticoagulants are for limited use [eg, flushing and locking intravenous catheters])
10. Ongoing treatment with strong cytochrome P450 (CYP) inhibitors such as itraconazole or strong CYP inducers such as rifampin. Treatment with these agents must be completed at least 4 weeks prior to enrollment. During the study, subjects should not use grapefruit/grapefruit juice or St John's wort extract.
11. Pregnant or lactating subjects or those male or female sexually active subjects who are unwilling to comply with proper birth control methods as defined in the protocol from the time consent is signed until 30 days after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test at Screening and during the Baseline Visit.
12. Comorbidities that may confound study results (eg, fat malabsorption syndrome, other mitochondrial disorders) in the opinion of the investigator.
13. Subjects who are >=7 years of age, have the ability to understand and respond to the CSSRS, and have suicidal tendencies and suicidal behavior. This exclusion does not apply to subjects who are <7 years of age and/or are not able to respond or understand the questions or concepts in the C-SSRS in the investigator's opinion.

Both

Mitochondrial Disease with Refractory Epilepsy

Vatiquinone:
15 milligrams/kilogram (mg/kg) if body weight <13 kg, and 200 mg if body weight >=13 kg, administered orally, 3 times per day (TID) or up to 72 weeks
Placebo:
Vatiquinone-matching placebo, administered orally, TID for up to 24 weeks followed by vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight >=13 kg, administered orally, TID for up to 48 weeks.

The percent change from baseline in frequency of observable motor seizures per 28 days during the placebo-controlled phase

Key secondary efficacy endpoints
- Number of disease-related hospitalization days
- Occurrence or recurrence of status epilepticus

Other Secondary endpoints
- Number and percent of subjects with disease-related in-patient hospitalization/emergency room visits
- Number of disease-related in-patient hospitalization admissions/emergency room visits
- Percent change from baseline in total seizure frequency per 28 days of all types
- Proportion of subjects with >=25%, >=50%, >=75%, and 100% reduction in motor seizures
- Proportion of subjects with >=25%, >=50%, >=75%, and 100% reduction in total seizures
- Number of rescue seizure medications
- Health-related quality of life as measured by the CarerQoL-7D questionnaire
- Number of seizure clusters as defined by "too many to count" entries in the seizure diaries

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Dec. 21, 2021

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