An open-label, single-arm extension study to evaluate the long-term safety, tolerability, and efficacy of KL1333 (napazimone) in patients with primary mitochondrial disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharming Technologies B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Decision date (initial)

2026-05-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To study the safety and tolerability of 48 weeks of open-label KL1333 treatment in subjects previously treated with KL1333 or placebo in the FALCON study.

Secondary objectives 1

1. To describe the efficacy of 48 weeks of open-label KL1333 treatment in subjects previously treated with KL1333 or placebo in the FALCON study on • Fatigue symptoms and impacts on daily living • Functional lower extremity strength and endurance • Physical function and activities of daily living • Treatment impact and health related quality of life • Assessment of mitochondrial disease progression • Glycemic control – in subjects with diabetes

Conditions and MedDRA coding

Adult patients with primary mitochondrial disease

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Completed the FALCON study (age 18 years or older) and, in the opinion of the investigator and Sponsor, has been compliant with the study requirements.
2. 2. Willingness and ability to provide informed consent.
3. 3. Willingness and ability to attend study appointments within the specified time windows.
4. 4. Willingness and ability to complete electronic patient-reported outcomes (ePROs).
5. 5. Concomitant medications likely to remain stable throughout participation in the study where clinically possible.
6. 6. Willingness to continue suspension of idebenone during the study.
7. 7. Female subject is not pregnant and at least one of the following conditions apply: a. Not a woman of childbearing potential (WOCBP) b. WOCBP must agree not to try and become pregnant and use a highly effective method of contraception from the time of informed consent through at least 36 days (~5 half-lives of KL1333 plus 30 days) after the last dose of IMP administration.
8. 8. Male subjects with female partner(s) of childbearing potential must agree to use a male condom in addition to using highly effective contraception throughout the treatment period and for 96 days after the last dose of IMP administration. The requirement to use a male condom also applies to male subjects with a pregnant or breastfeeding partner.
9. 9. Female subjects must agree not to breastfeed throughout the study period and for 36 days after the last dose of IMP administration.
10. 10. Female subjects must agree to not donate ova throughout the study period and for 36 days after the last dose of IMP administration, and male subjects must agree to not donate sperm throughout the study period and for 96 days after the last dose of IMP administration.

Exclusion criteria 13

1. 1. The subject is, in the investigator’s opinion, unlikely to comply with the protocol, e.g., due to cognitive impairment, or is unsuitable for any reason.
2. 2. Any medical, psychiatric, laboratory, or other condition that may negatively affect the benefit-risk considerations of study participation or interfere with the interpretation of study results and, in the judgment of the investigator and/or the medical monitor, would make the subject inappropriate for entry into this study.
3. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 3. General fatigue or muscle weakness due to causes other than mitochondrial disease, in the opinion of the investigator.
4. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 4. Significant cardiovascular disease (e.g., sustained or symptomatic arrhythmia, dilated heart chambers or reduced function, Mobitz II atrioventricular block or greater) OR abnormal ECG that is clinically significant, as determined by the investigator. Any QT interval corrected using Fridericia’s formula (QTcF) >450 msec for male subjects and >470 msec for female subjects is exclusionary. In the case of an exclusionary QTcF, the ECG can be repeated twice and the average of 3 QTcF intervals should be used to determine the QTcF eligibility.
5. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 5. Recent history of unstable disease, inadequately controlled neurological manifestations or not recovered from stroke-like episodes including but not limited to: a. stroke-like episodes within the last 6 months b. more than 1 seizure/month within the last 6 months c. hospitalized for Status Epilepticus within the last 6 months d. more than 4 days of migraine episodes/month within the last 6 months
6. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 6. History of inflammatory bowel disease, gastric erosions, peptic ulcer disease, or gastrointestinal bleeding episodes. Gastroesophageal reflux disease diagnosed by objective endoscopic or radiographic means, and clinically symptomatic at any point over the last 6 months.
7. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 7. The subject has 1 or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the screening visit, that are of potential risk to the subject’s safety, or the subject has, at the screening visit: a. estimated glomerular filtration rate calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation <30 mL/min/1.73 m2 b. a serum total bilirubin value >1.5 times the upper limit of the reference range unless elevation is related to Gilbert’s syndrome and the investigator can rule out any underlying liver dysfunction based on other tests, the subject has a Child-Pugh score ≤6, and after discussing the case with the medical monitor c. a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2 times the upper limit of the reference range. Values between 2 and 3 times the upper limit of the reference range may be allowed if concomitant to elevation in creatine kinase as long as the investigator can rule out any underlying liver dysfunction based on other tests, the subject has a Child-Pugh score ≤6, and after discussing the case with the medical monitor
8. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 8. The subject has, in the investigator’s opinion, severe ataxia, neuropathy, balance problems, or other medical conditions that would interfere the evaluation of the 30s STS.
9. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 9. Untreated or undertreated sleep apnea, in the opinion of the investigator.
10. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 10. Use of idebenone within 14 days prior to the first dose.
11. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 11. Subjects have a history of unstable or severe pulmonary, immunological, oncological, hepatic disease, renal disease, or another medically significant illness other than PMD or takes medication that could, in the investigator’s opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the study.
12. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 12. Female subjects with a positive pregnancy result at screening.
13. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional exclusion criteria below during the screening visit: 13. A subject cannot participate if they received an investigational drug 30 days or 5 half lives prior to the screening visit (whichever is longer), or plans to use an investigational drug (other than the study intervention) during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. All safety parameters (including AEs, physical examination, vital signs, ECG, C-SSRS, and safety laboratory [hematology, blood chemistry, and urinalysis]).
2. Occurrence of metabolic decompensation and lactic acidosis or image-verified stroke-like episodes consequent to GI AEs are AESIs and will be monitored throughout the study.

Secondary endpoints 8

1. Patient-reported mitochondrial fatigue: • PROMIS® Fatigue PMD short form
2. Functional outcome: • 30-second Sit-to-Stand Test
3. Patient-reported lower extremity function: • Neuro-QOL Lower Extremity Function (Mobility) - short form
4. Other patient-reported outcomes: • Patient Global Impression (multiple) - severity and change
5. Other patient-reported outcomes: • EQ-5D-5L
6. Global impression of severity of PMD disease expression: • Clinician Global Impression of PMD - severity and change
7. Assessments of mitochondrial disease progression: • NMDAS, Subscales I-III
8. Mitochondrial diabetes, subgroup analysis: • HbA1c (in subjects with diabetes)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharming Technologies B.V.

Sponsor organisation

Pharming Technologies B.V.

Address

Darwinweg 24

City

Leiden

Postcode

2333 CR

Country

Netherlands

Scientific contact point

Organisation

Pharming Technologies B.V.

Contact name

Clinical Research Department

Public contact point

Organisation

Pharming Technologies B.V.

Contact name

Clinical Research Department

Third parties 1

Locations

7 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 57 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications