N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)

Effects of N-Acetyl-L-Leucine on Niemann Pick Type C Disease: A Multinational, Multicenter, Open-label, Rater-blinded Phase II Study.

This is a multinational, multicenter, open-label, rater-blinded prospective Phase II study which will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the treatment of Niemann-Pick type C disease (NPC). There are two phases to this study: the Parent Study, and the Extension Phase. The Parent Study evaluates the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the symptomatic treatment of NPC. The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of NPC.

In the Parent Study, Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If within 6 weeks prior to the initial screening visit, a patient has received any of the prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration) a wash-out study-run in of 6 weeks is required prior to the first baseline assessment. All patients will receive the study drug during the treatment period. For each individual patient, the Parent Study lasts for approximately 3.5 - 4 months during which there are 6 visits to the study site. This Extension Phase allows patients who have completed the Parent Study to, at the discretion of the Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001). Patients will receive treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients will receive the study drug during the two one-year treatment periods. For each individual patient, the Extension Phase lasts for approximately 25.5 months, during which there are 6 visits to the study site.

In both the Parent Study and Extension Phase, patients will be assessed during three study phases: a baseline period (with or without a study run-in), a treatment period, and a washout period. Patients who complete the Parent Study have the opportunity to, at the discretion of their Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001) in an Extension Study, provided they fulfill the inclusion/exclusion criteria.

The primary evaluation of the Clinical Impression of Change in Severity (CI-CS; Primary Endpoint) will be performed by two independent neurologists whose assessments are based on videos of patient's performance on either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT) taken at each visit.

Parent Study: 6-weeks treatment with IB1001 administered orally. Extension Phase: 1-year treatment with IB1001 administered orally. Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day). Patients 6-12 years old will receive weight-tiered doses: Patients aged 6-12 years weighing 15 to <25 kg will take 2 g per day: 1 g in the morning and 1 g in the evening. Patients aged 6-12 years weighing 25 to <35 kg will take 3 g per day: 1 g in the morning, 1 g in the afternoon, and 1 g in the evening. Patients aged 6-12 years weighing ≥35 kg will take 4 g per day: 2 g in the morning, 1g in the afternoon and 1 g in the evening (as per adults)

After both the Parent Study 6-week treatment period, and Extension Phase one-year treatment period, patients will enter a 6-week post-treatment washout period.

The CI-CS assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9HPT-D or 8MWT changed (improved or worsened) in 6-weeks as observed in the second video?' The CI-CS is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).

CI-CS comparing Baseline (Day 1) with IB1001 verses the end of 6-weeks treatment with IB1001 (Approximately Day 42) MINUS the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) verses the end of 6-weeks post-treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Overall neurological status based on six domains (ambulation, manipulation, language, swallowing, seizures and ocular movements).

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment; Extension Phase 1-year treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Inclusion Criteria Individuals who meet all of the following criteria are eligible to participate in the study: Written informed consent signed by the patient and/or their legal representative/ parent Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of NPC at the time of signing informed consent. Patients must have clinical features of NPC and a positive genetic test for mutations in both copies of NPC1 or in both copies of NPC2. Females of childbearing potential, defined as a premenopausal female capable of becoming pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first dose continuing through 28 days after the last dose) or using one of the following highly effective contraceptives (i.e. results in <1% failure rate when used consistently and correctly) 14 days prior to the first dose continuing through 28 days after the last dose: intrauterine device (IUD); surgical sterilization of the partner (vasectomy for 6 months minimum); combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal); progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable); intrauterine hormone releasing system (IUS); bilateral tubal occlusion. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose: hysteroscopic sterilization; bilateral tubal ligation or bilateral salpingectomy; hysterectomy; bilateral oophorectomy; OR be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. FSH analysis for postmenopausal women will be done at screening. FSH levels should be in the postmenopausal range as determined by the central laboratory. Non-vasectomized male patient agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion criteria 3 or 4. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male. If male, patient agrees not to donate sperm from the first dose until 90 days after dosing. Patients must fall within: a) A SARA score of 5 ≤ X ≤ 33 points (out of 40) AND i. Within the 2-7 range (out of 0-8 range) of the Gait subtest of the SARA scale OR ii. Be able to perform the 9 Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI subtest) in 20 ≤ X ≤150 seconds. Weight ≥15 kg at screening. Patients are willing to disclose their existing medications/therapies for (the symptoms) of NPC, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. miglustat, concomitant speech therapy, and physiotherapy) are permitted provided: The Investigator does not believe the medication/therapy will interfere with the study protocol/results Patients have been on a stable dose/duration and type of therapy for at least 6 weeks before Visit 1 (Baseline 1) Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study. An understanding of the implications of study participation, provided in the written patient information and informed consent by patients or their legal representative/parent, and demonstrates a willingness to comply with instructions and attend required study visits (for children this criterion will also be assessed in parents or appointed guardians). Exclusion Criteria Individuals who meet any of the following criteria are not eligible to participate in the study: Asymptomatic patients Patient has clinical features of NPC and a positive biomarker screen and/or filipin test, but a negative result on a previous genetic test for NPC Patients who have any of the following: Chronic diarrhea; Unexplained visual loss; Malignancies; Insulin-dependent diabetes mellitus. Known history of hypersensitivity to the N-Acetyl-Leucine (DL-, L-, D-) or derivatives. History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate). Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; 'study drug') within 6 weeks prior to Visit 1. Patients with a physical or psychiatric condition which, at the investigator's discretion, may put the patient at risk, may confound the study results, or may interfere with the patient's participation in the clinical study. Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN); Total bilirubin >1.5x ULN, unless Gilbert's syndrome is present in which case total bilirubin >2x ULN. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol. Current or planned pregnancy or women who are breastfeeding. Patients with severe vision or hearing impairment (that is not corrected by glasses or hearing aids) that, at the investigator's discretion, interferes with their ability to perform study assessments. Patients who have been diagnosed with arthritis or other musculoskeletal disorders affecting joints, muscles, ligaments, and/or nerves that by themselves affects patient's mobility and, at the investigator's discretion, interferes with their ability to perform study assessments. Patients unwilling and/or not able to undergo a 6-week washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6. Aminopyridines (including sustained-release form); N-Acetyl-DL-Leucine (e.g. Tanganil®); N-Acetyl-L-Leucine (prohibited if not provided as IMP); Riluzole; Gabapentin; Varenicline; Chlorzoxazone; Sulfasalazine; Rosuvastatin. Extension Phase Inclusion Criteria Completed Visit 6 of the IB1001-201 Parent Study The Principal Investigator determines further treatment with IB1001 to be in patient's best interest Written informed consent signed by the patient and/or their legal representative/parent/ impartial witness for participation in the Extension Phase Patients are willing to continue to remain without the following prohibited medication from Visit 6 throughout the duration the Extension Phase: Aminopyridines (including sustained-release form); N-Acetyl-DL-Leucine (e.g. Tanganil®); N-Acetyl-L-Leucine (prohibited if not provided as IMP); Riluzole; Gabapentin; Varenicline; Chlorzoxazone; Sulfasalazine; Rosuvastatin.

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