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

• IB1001 (Drug), also known as N-Acetyl-L-Leucine: IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.

Primary outcomes

• Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] [CI-CS comparing Baseline (Day 1) with IB1001 versus 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) versus the end of 6-weeks post-treatment washout]: The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).

Secondary outcomes

• Key Secondary Endpoint: Individual Components of the CI-CS [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout]: The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
• Key Secondary Endpoint: Change in Severity Based on Average CI-S [CI-CS comparing baseline period and end of treatment period minus the change in CI-S between end of treatment period and end of washout period.]: The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
• Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout]: The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). CI-CS scores <0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores >0 were reclassified as improved (+1).
• Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test [CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 versus Visit 2 and of Visit 6 versus Visit 4 as done for the primary anchor test.]: The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
• Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 Meter Walk Test, 9-Hole Peg Test of Dominant and Non-Dominant Hand (9HPT-D/9HPT-ND) (the 3 tests are timed assessments; each is done twice and values are averaged; the 8MWT and 9HPT-D and 9HPT-ND values are converted from times to rates, and the results expressed as a composite Z-score of each test relative to baseline) and the PATA rate (counted number how often a patient can repeat the syllables "PATA" within 10 seconds), a measure of speech performance. The scores of these 3 were transformed to Z-scores (=individual's average of both trials to perform the respective task - mean of study population at baseline) / SD of study population at baseline). A Z-score of 0 equates to the population mean at baseline. For all 3, higher Z-scores (above mean) mean better performance. The SCAFI total score was calculated as the arithmetic mean of the non-missing Z-scores for the 3. A higher total score means better performance.
• Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch et al, 2006; Subramony, 2007] [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: The Scale for Assessment and Rating of Ataxia has 8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test. The range is 0-40 points, with a lower score representing neurological improvement and a higher score representing neurological worsening.
• EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. EQ-5D VAS is a 0-100 scale where patients are asked to indicate their overall health, with a score of 0 indicating worst health and a score of 100 indicating best health.
• Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] [Baseline to end of treatment with IB1001 (Parent Study 6-weeks 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). The Modified Disability Rating Scale ranges from 0-24, where 0 is the best neurological status and 24 is the worst.
• Investigator's Clinical Global Impressions of Change (CGI-C) [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: The Clinical Global Impression of Change assessed by the investigator is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'
• Parent/Caregiver's Clinical Global Impression of Change (CGI-C) [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: The Clinical Global Impression of Change assessed by the parent/caregiver is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.
• Patient's Clinical Global Impressions (CGI) if Able [Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout]: The Clinical Global Impression of Change assessed by the patient (if able) is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.

Sex: All, ages: 6 Years to any

Inclusion Criteria

Individuals who meet all of the following criteria are eligible to participate in the study:

1. Written informed consent signed by the patient and/or their legal representative/ parent
2. 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.
3. 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:

   1. intrauterine device (IUD);
   2. surgical sterilization of the partner (vasectomy for 6 months minimum);
   3. combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);
   4. progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);
   5. intrauterine hormone releasing system (IUS);
   6. bilateral tubal occlusion.
4. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:

   1. hysteroscopic sterilization;
   2. bilateral tubal ligation or bilateral salpingectomy;
   3. hysterectomy;
   4. 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.
5. 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.
6. If male, patient agrees not to donate sperm from the first dose until 90 days after dosing.
7. Patients must fall within:

   a) A Scale for the Assessment and Rating of Ataxia (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) (Scale for Spinocerebellar Ataxia Functional Index \[SCAFI\] subtest) in 20 ≤ X ≤150 seconds.
8. Weight ≥15 kg at screening.
9. 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:

   1. The Investigator does not believe the medication/therapy will interfere with the study protocol/results
   2. Patients have been on a stable dose/duration and type of therapy for at least 6 weeks before Visit 1 (Baseline 1)
   3. Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study.
10. 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:

1. Asymptomatic patients
2. 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
3. Patients who have any of the following:

   1. Chronic diarrhea;
   2. Unexplained visual loss;
   3. Malignancies;
   4. Insulin-dependent diabetes mellitus.
   5. Known history of hypersensitivity to the N-Acetyl-Leucine (DL-, L-, D-) or derivatives.
   6. History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate).
4. 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.
5. 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.
6. Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to:

   1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN);
   2. Total bilirubin >1.5x ULN, unless Gilbert's syndrome is present in which case total bilirubin >2x ULN.
7. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.
8. Current or planned pregnancy or women who are breastfeeding.
9. 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.
10. 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.
11. 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.

    1. Aminopyridines (including sustained-release form);
    2. N-Acetyl-DL-Leucine (e.g. Tanganil®);
    3. N-Acetyl-L-Leucine (prohibited if not provided as IMP);
    4. Riluzole;
    5. Gabapentin;
    6. Varenicline;
    7. Chlorzoxazone;
    8. Sulfasalazine;
    9. Rosuvastatin.

Extension Phase Inclusion Criteria

1. Completed Visit 6 of the IB1001-201 Parent Study
2. The Principal Investigator determines further treatment with IB1001 to be in patient's best interest
3. Written informed consent signed by the patient and/or their legal representative/parent/ impartial witness for participation in the Extension Phase
4. Patients are willing to continue to remain without the following prohibited medication from Visit 6 throughout the duration the Extension Phase:

   1. Aminopyridines (including sustained-release form);
   2. N-Acetyl-DL-Leucine (e.g. Tanganil®);
   3. N-Acetyl-L-Leucine (prohibited if not provided as IMP);
   4. Riluzole;
   5. Gabapentin;
   6. Varenicline;
   7. Chlorzoxazone;
   8. Sulfasalazine;
   9. Rosuvastatin.

Participant flow

Outcome results

• Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] (Primary), Mean, score on a scale: Parent Study 0.86 +/- 2.52 (p 0.029)
• Key Secondary Endpoint: Individual Components of the CI-CS (Secondary), Mean, score on a scale: Parent Study 0.48 +/- 1.34
• Key Secondary Endpoint: Change in Severity Based on Average CI-S (Secondary), Mean, score on a scale: Parent Study 0.08 +/- 1.12 (p 0.318)
• Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale (Secondary), Count of participants, Participants: Parent Study: 9
• Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test (Secondary), Mean, score on a scale: Parent Study: -0.20 +/- 1.41
• Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] (Secondary), Mean, Z-scores: Parent Study: 0.0995 +/- 0.3058 (p 0.084)
• Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch et al, 2006; Subramony, 2007] (Secondary), Mean, score on a scale: Parent Study: -1.19 +/- 2.02 (p 0.001)
• EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) (Secondary), Mean, score on a scale: Parent Study: 72.7 +/- 19.3
• Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] (Secondary), Mean, units on a scale: Parent Study: -0.012 +/- 0.050 (p 0.121)
• Investigator's Clinical Global Impressions of Change (CGI-C) (Secondary), Mean, score on a scale: Parent Study: 3.4 +/- 0.9 (p <0.001)
• Parent/Caregiver's Clinical Global Impression of Change (CGI-C) (Secondary), Mean, score on a scale: Parent Study: 3.4 +/- 1.0 (p 0.005)
• Patient's Clinical Global Impressions (CGI) if Able (Secondary), Mean, score on a scale: Parent Study: 3.3 +/- 1.0 (p 0.003)

Adverse events

Time frame: From signing of the informed consent form through to End of Study (Day 84, scheduled at 42 days post last IB1001 dose).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: This study was ongoing during the coronavirus disease 2019 (COVID-19) pandemic, and the conduct of this study was impacted by the COVID-19 pandemic.

• Results publication: Bremova-Ertl T, Claassen J, Foltan T, Gascon-Bayarri J, Gissen P, Hahn A, Hassan A, Hennig A, Jones SA, Kolnikova M, Martakis K, Raethjen J, Ramaswami U, Sharma R, Schneider SA. Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C. J Neurol. 2022 Mar;269(3):1651-1662. doi: 10.1007/s00415-021-10717-0. Epub 2021 Aug 13. PMID 34387740
• Results publication: Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, Platt FM, Galione A. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021 Aug 4;11(1):15812. doi: 10.1038/s41598-021-95255-5. PMID 34349180
• Results publication: Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S, Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang L, Verburg C, Factor M, Strupp M. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021 Jan 22;22(1):84. doi: 10.1186/s13063-020-05009-3. PMID 33482890

• Study Protocol (PDF, 2022-10-10)
• Statistical Analysis Plan (PDF, 2023-01-26)