1. A study to see how well nizubaglustat (AZ-3102) works in participants with GM1 gangliosidosis or GM2 gangliosidosis and how safe it is 2. A study to see how well nizubaglustat (AZ-3102) works in participants with Niemann-Pick type C disease and how safe it is

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Azafaros B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

30 Jun 2025 → ongoing

Decision date (initial)

2024-12-18

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Azafaros B.V.

External identifiers

EU CT number

2024-515778-28-00

WHO UTN

U1111-1311-2777

ClinicalTrials.gov

NCT07054515

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Pharmacokinetic, Others

To demonstrate superior efficacy on ataxic manifestations with oral nizubaglustat dosing compared with placebo when administered over 72 weeks in participants with late-infantile and juvenile forms of NPC disease or late-infantile/juvenile-onset forms of GM1 or GM2 gangliosidosis.

Secondary objectives 4

1. To demonstrate additional efficacy in ataxic and nonataxic manifestations comparing nizubaglustat dosing with placebo when administered over 72 weeks in participants with late-infantile and juvenile forms of NPC disease or lateinfantile/juvenile-onset forms of GM1 or GM2 gangliosidosis.
2. To assess the PK properties of nizubaglustat after administration of the first dose (Visit 1) and at steady state after multiple once daily doses
3. To assess the PD effects of nizubaglustat
4. To assess the safety and tolerability of daily oral nizubaglustat dosing compared with placebo, when administered over 72 weeks in participants with late-infantile and juvenile forms of NPC disease or late-infantile/juvenile-onset GM1 or GM2 gangliosidosis.

Conditions and MedDRA coding

Niemann-Pick type C disease and GM1/GM2 gangliosidoses

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-170051-PIP98-18

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. 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.
2. 10. 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.
3. 11. 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.
4. 12. 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).
5. 13. The participant is willing to give information relating to current drugs/therapies used to manage symptoms of their conditions, including restricted medications.
6. 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.
7. 3. Newly-diagnosed and/or treatment-naïve patients that are unwilling or unable to take NPC-approved treatments (eg. miglustat)
8. 4. Onset of neurological symptoms from 2 to 15 years.
9. 5. 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.
10. 6. Willing and able to complete assessments.
11. 7. Able to take study medication.
12. 8. 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).
13. 9. 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.
14. 14. 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.

Exclusion criteria 17

1. 1. Any condition at Baseline that, in the opinion of the Principal Investigator, could interfere with study assessments (e.g., severe infection, severe cognitive impairment).
2. 6. The presence of severe renal impairment (estimated glomerular filtration rate of <30 ml/min/1.73m2).
3. 7. Total bilirubin of >2x ULN isolated bilirubin of >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
4. 8. Platelet count of <100x109/L.
5. 9. 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.
6. 10. 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.
7. 3.Body weight of <10 kg.
8. 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.
9. 11. Prior participation in a clinical study involving gene therapy or stem cell transplantation.
10. 13. ECG with an average QTcF (corrected QT interval using Fridericia’s formula) interval of >450 msec for males and of >470 msec for females.
11. 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."
12. 15. Known allergy to azasugars or any study drug excipient.
13. 16. 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.
14. 2. 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.
15. 4. The presence of another neurologic disease.
16. 5. 5. 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]).
17. 12. A positive serum pregnancy test (for women of childbearing potential).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline to Week 72 in cale for Assessment and Rating of Ataxia (SARA) score, using both total SARA and functional SARA.

Secondary endpoints 8

1. 1. Change from Baseline to Weeks 24, 48, and 72 in: • SARAGAIT/POSTURE • SARASPEECH • SARAKINETICS • Vineland Adaptative Behavior Scale (VABS) comprehensive interview form • Penetration-Aspiration Scale (PAS)
2. 2. Change from Baseline to Weeks 24, 48, and 72 in: • 9-Hole Peg Test (9-HPT-D): change in time taken to complete the test using the dominant hand • Goal attainment scale (GAS) • Clinical global impression of change (CGI-C) • Participant/caregiver global impression of change (PGI-C) • Seizure frequency and duration, as per the seizure diary
3. Cont.Translation- Portuguese and French
4. 3. Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of: • An increase in total SARA score of ≥2 points and/or an increase in functional SARA of ≥1.5 points • A decrease in PAS of ≥1 point • Participants leaving the study due to participant/caregiver perception of disease progression/lack of efficacy.
5. 4. For subprotocol AZA-001-301-NPC only, change from Baseline in NPC Clinical Severity Scale (NPC-CSS) score
6. 5. The concentrations of nizubaglustat and its metabolites in plasma. The main PK parameters assessed will be: •Maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) • Plasma trough concentration (Ctrough) at Week 4 • Area under the plasma concentration-time curve from the time of dosing (zero) to 24 hours post-dose (AUC0-24) at Baseline • Accumulation ratio for Cmax.
7. 6. Change from Baseline to Weeks 4, 24, 48 and 72 in the plasma GlcCer C16:0; C18:0 concentration.
8. 15. Incidence and severity of treatment-emergent adverse events (TEAEs). Change in vital sign parameters, electrocardiogram (ECG) parameters, and laboratory safety parameters from Baseline to each study visit. Incidence of treatment-emergent abnormal laboratory values and ECG abnormalities.

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Azafaros B.V.

Sponsor organisation

Azafaros B.V.

Address

J.H. Oortweg 21

City

Leiden

Postcode

2333 CH

Country

Netherlands

Scientific contact point

Organisation

Azafaros B.V.

Contact name

Christian Freitag

Public contact point

Organisation

Azafaros B.V.

Contact name

Christian Freitag

Third parties 11

Locations

6 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 102 files

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

Application history

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