Clinical Research
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Phase 3 Study on the Efficacy and Safety of Nizubaglustat (AZ-3102) in Late-Infantile and Juvenile Niemann-Pick Type C and GM1/GM2 Gangliosidoses

Trial ID
2024-515778-28-00
Protocol
AZA-001-301
Sponsor
Azafaros B.V.

Trial statistics

science
3
test molecules
location_city
7
research sites
public
6
countries
person_search
8
investigators
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11
vendors

Objectives

The primary objective of this study is to demonstrate the superior efficacy of oral **nizubaglustat** in addressing ataxic manifestations compared to placebo over an 18-month period. This is clinically relevant as it targets late-infantile and juvenile forms of Niemann-Pick type C disease and late-infantile/juvenile-onset forms of GM1 or GM2 gangliosidosis, conditions characterized by progressive neurological decline.

Secondary objectives include:

  • Demonstrating additional efficacy in both ataxic and nonataxic manifestations when comparing **nizubaglustat** dosing with placebo over 18 months in the specified patient population.
  • Assessing the pharmacokinetic (PK) properties of **nizubaglustat** after the first dose and at steady state following multiple once-daily doses at Month 1.
  • Evaluating the pharmacodynamic (PD) effects of **nizubaglustat**.
  • Assessing the safety and tolerability of daily oral **nizubaglustat** dosing compared with placebo over 18 months in the target patient group.

Participants

The clinical trial involves a total of **77 participants** diagnosed with **Niemann-Pick type C disease** and GM1/GM2 gangliosidoses. The study population includes both male and female subjects, encompassing age ranges corresponding to late-infantile and juvenile forms of the diseases. Participants were selected based on specific inclusion criteria, including the onset of neurological symptoms between 2 to 15 years of age and a confirmed diagnosis of the respective conditions. The trial population is characterized by individuals who are either newly diagnosed or treatment-naïve and are unwilling or unable to take NPC-approved treatments. Participants are required to have a baseline disability level with ataxic disturbances, as measured by the Scale for the Assessment and Rating of Ataxia (SARA). The study includes vulnerable populations, and lifestyle considerations such as the ability to take and swallow study medication are taken into account. The trial does not specify any particular dietary or physical activity requirements for participants.

Plans and Procedures

The clinical trial is designed as an 18-month **double-blind**, **randomized**, **placebo-controlled**, multicenter, Phase 3 study. The primary objective is to evaluate the safety and efficacy of oral **nizubaglustat** in participants with late-infantile and juvenile forms of Niemann-Pick type C disease and GM1/GM2 gangliosidoses. The trial aims to demonstrate superior efficacy on ataxic manifestations with nizubaglustat compared to placebo. Participants will be randomly assigned to receive either nizubaglustat or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed diagnosis of the relevant conditions and the ability to complete assessments. Following successful screening, participants will enter the treatment phase, which involves regular follow-up visits at months 1, 6, 12, and 18. These visits are designed to monitor the participants' health, assess the primary and secondary endpoints, and ensure adherence to the study protocol. The primary endpoint is the change from baseline to month 18 in the total Scale for Assessment and Rating of Ataxia (SARA) score. Secondary endpoints include various clinical assessments and biomarker analyses at specified intervals.

The expected duration of participant involvement is 18 months, with conditions for early termination including significant adverse events or participant/caregiver perception of disease progression or lack of efficacy. Participants are required to adhere to specific contraceptive measures and agree not to donate sperm during the study and for a specified period after the final dose. The trial is expected to start recruitment in May 2025 and conclude in November 2027, with the end-of-study visit marking the completion of the trial for each participant.

Treatment

The clinical trial involves the administration of **Nizubaglustat**, an experimental medication, in the form of a **capsule**. The active substance in Nizubaglustat is chemically synthesized and is identified by the chemical name **(2S,3R,4R,5S)-1-[5-(2-Fluoro-biphenyl-4-ylmethoxy)-pentyl]-2-hydroxymethyl-piperidine-3,4,5-triol**. The medication is administered **orally** with a maximum daily dose of **9 mg**. The treatment period extends up to **18 months**. The sponsor product code for Nizubaglustat is **AZ-3102**, and it is designated as an orphan drug under the numbers EU/3/24/2940 and 23/2762. The medication is provided by AZAFAROS B.V.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is composed of **Microcrystalline Cellulose (Avicel PH-102)**, which does not have an active pharmaceutical ingredient. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo. The placebo is administered in a similar **capsule** form and follows the same oral route and dosing schedule as the experimental medication to ensure consistency in administration.

Efficacy

The efficacy of oral **nizubaglustat** in treating late-infantile and juvenile forms of Niemann-Pick type C disease, as well as late-infantile and juvenile-onset forms of GM1 and GM2 gangliosidosis, will be assessed in a Phase 3, double-blind, randomized, placebo-controlled, multicenter clinical trial. The primary endpoint for evaluating efficacy is the change from baseline to month 18 in the total Scale for Assessment and Rating of Ataxia (SARA) score. Secondary endpoints include changes from baseline to months 6, 12, and 18 in various parameters such as SARAGAIT/POSTURE, SARASPEECH, SARAKINETICS, Vineland Adaptive Behavior Scale, and Penetration-Aspiration Scale. Additional secondary endpoints involve assessments like the 9-Hole Peg Test, goal attainment scale, clinical global impression of change, participant/caregiver global impression of change, and seizure frequency and duration.

Time-to-event comparisons will be conducted for pre-defined detrimental events, including an increase in SARA score of ≥2 points and a decrease in PAS of ≥1 point. For subprotocol AZA-001-301-NPC, changes in the NPC Clinical Severity Scale (NPC-CSS) score will be evaluated. Pharmacokinetic parameters such as maximum observed plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration-time curve (AUC0-24) will be measured. Changes in serum/plasma concentrations of biomarkers like GlcCer, Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL) will also be assessed at specified time points. The incidence and severity of treatment-emergent adverse events (TEAEs), as well as changes in vital signs, electrocardiogram (ECG) parameters, and laboratory safety parameters, will be monitored throughout the study.

Inclusion and Exclusion Criteria

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Inclusion Criteria

  • Provide written informed consent signed by the participant or their legal guardian, or parent. The parent and/or legal guardian can read, understand, and sign informed consent. Where appropriate, assent will also be sought for participants aged <18 years. If a participant reaches the age of legal consent during the study, they will be re-consented at the next scheduled visit upon attaining that age.
  • Non-vasectomized male participants are eligible if they consent to use a spermicide-impregnated condom or abstain from sexual activity until 90 days after the last dose of study medication; their female partner is required to consent to comply with this inclusion criterion.
  • A vasectomized male who had the procedure at least 6 months before starting the study is eligible if they consent to use a condom during sexual activity. A man vasectomized less than 6 months before commencement of the study must adhere to the same restrictions as a non-vasectomized male.
  • Male participants agree not to donate sperm from the start of study treatment until 90 days after the final dose. Female participants agree not to donate eggs from the start of treatment of treatment until 90 days after the final dose (though this would not be permitted because of the nature of the underlying disease).
  • The participant is willing to give information relating to current drugs/therapies used to manage symptoms of their conditions, including restricted medications.
  • 2a. Confirmed diagnosis of NPC disease based on: •The presence of biallelic pathogenic or likely pathogenic variants according to the American College of Medical Genetics and Genomics classification OR •One pathogenic or likely pathogenic variant and one variant of unknown significance, if clinical symptomatology is compatible with the disease and at least one disease biomarker (PPCS or C-triol) is over the normal laboratory range.
  • Newly-diagnosed and/or treatment-naïve patients that are unwilling or unable to take NPC-approved treatments (eg. miglustat)
  • Onset of neurological symptoms from 2 to 15 years.
  • Disability level at Baseline: Ataxic disturbances with a total SARA score of ≥3 and <30 at Baseline OR a functional SARA score of ≥1 and ≤12 at Baseline. Individuals with a total SARA score of ≥5 can enter the study automatically; inclusion of individuals with a total SARA score of 3 to 5 should be discussed with and approved by the Medical Monitor.
  • Willing and able to complete assessments.
  • Able to take study medication.
  • Females of childbearing potential (defined as a premenopausal female capable of becoming pregnant) are eligible if: • sexually inactive and willing to stay inactive during the study (sexual abstinence for the 14 days prior to the first study drug dose and confirmation of continued abstinence until 28 days after the last dose) • using one of the following highly-effective contraceptives (i.e. <1% failure rate when used consistently and correctly) for 14 days prior to the first study drug dose and continuing until 28 days after the last dose: intrauterine device; surgical sterilization of the partner (vasectomy for a minimum of 6 months); combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable or intrauterine hormone releasing system).
  • Females of non-childbearing potential • who have undergone one of the following sterilization operations at least 6 months prior to receiving the first dose of study drug: hysteroscopic sterilization, bilateral salpingectomy, hysterectomy, bilateral oophorectomy OR • who are postmenopausal with at least 1 year of amenorrhea and follicle stimulating hormone (FSH) serum values consistent with postmenopausal status. At Screening postmenopausal women will have their FSH levels analyzed and central laboratory FSH levels should fall within the postmenopausal range. "• are pre-menarchal at Screening and agree to stay sexually inactive during the study and until 28 days after the last dose or are using one of the contraceptive methods listed in inclusion criterion 8.
  • For subprotocol AZA-001-301-NPC only: Patient is unable or willing to take miglustat, or is, in the opinion of the investigator, unsatisfactorily treated with miglustat.
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Exclusion Criteria

  • Any condition at Baseline that, in the opinion of the Principal Investigator, could interfere with study assessments (e.g., severe infection, severe cognitive impairment).
  • The presence of severe renal impairment (estimated glomerular filtration rate of <30 ml/min/1.73m2).
  • Total bilirubin of >2x ULN isolated bilirubin of >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
  • Platelet count of <100x109/L.
  • The dose of any anti-epileptic treatment(s) was not stable (required a change in dose within the previous 3 months) and/or a new anti-epileptic treatment (drug or procedure) was prescribed in the month before Baseline.
  • Prior use of an investigational drug within the 3 months prior to Screening, unless the product has since been approved and the participant is receiving a stable dose. Any patient previously determined to have late-onset disease, including for prior clinical trial or expanded access program participation, is not eligible for inclusion.
  • 3.Body weight of <10 kg.
  • For subprotocol AZA-001-301-NPC only: 14. Current treatment with miglustat, provided the patient • has been using the recommended dose as specified in the Summary of Product Characteristics for miglustat (see Appendix 4) for most of the past 12 months AND • is, in the opinion of the investigator, satisfactorily treated with miglustat. Any participants receiving miglustat are required to undergo a 1-month washout period before starting study medication.
  • Prior participation in a clinical study involving gene therapy or stem cell transplantation.
  • ECG with an average QTcF (corrected QT interval using Fridericia’s formula) interval of >450 msec for males and of >470 msec for females.
  • For subprotocol AZA-001-301-GMx only: 14. Received migulstat in the 12 months prior to Baseline, unless •the dose was lower than the maximum dose specified in the miglustat Summary of Product Characteristics for patients with NPC disease, OR •the total duration of miglustat dosing was less than 12 months. Any participants receiving miglustat are required to undergo a 1-month washout period before starting study medication."
  • Known allergy to azasugars or any study drug excipient.
  • Evidence of suicidal ideation with intent (Type 4 to 5) on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening; this requirement is only applicable to participants judged by the Principal Investigator to be cognitively capable of understanding the concept of suicide.
  • A history of medical conditions other than NPC or GM1 or GM2 gangliosidosis that, in the opinion of the Principal Investigator, would confound scientific rigor or the interpretation of results.
  • The presence of another neurologic disease.
  • The presence of moderate or severe hepatic impairment (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and gamma-glutamyl transferase levels of >3x the upper limit of normal [ULN]).
  • A positive serum pregnancy test (for women of childbearing potential).

Trial Status by Country

Country Status Start of Recruitment Planned Patients
France FranceRecruiting01 May 202510
Germany GermanyRecruiting01 May 202511
Italy ItalyRecruiting01 May 20253
Portugal PortugalRecruiting01 May 202510
Spain SpainRecruiting01 May 202515
Sweden SwedenRecruiting01 May 20255

Sites & Investigators

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name Role in Trial Formulation Administration Max Daily Dose Treatment Duration EU MP Number
Nizubaglustat
TestORODISPERSIBLE TABLETORAL918PRD12403300
Microcrystalline CelluloseAvicel PH-102
PlaceboN/A———N/A
Nizubaglustat
TestORODISPERSIBLE TABLETORAL918PRD12403302

Interventions Studied in This Trial

vaccines
NIZUBAGLUSTAT
1 trial