ALS phase II study of NX210c (SEALS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Axoltis Pharma

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05], Diseases [C] - Nervous System Diseases [C10]

Trial duration

25 Oct 2024 → ongoing

Decision date (initial)

2024-03-29

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Axoltis Pharma

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To assess the effect of NX210c on blood neurofilament light chain (NfL) or on a blood and cerebrospinal fluid (CSF) biomarker of BBB integrity at 6-week follow-up.

Secondary objectives 11

1. To assess the effect of NX210c on blood NfL at other follow-up periods.
2. To assess the effect of NX210c on CSF NfL at 6-week follow-up.
3. To evaluate the effect of NX210c on select secondary blood, urine, and CSF biomarkers of BBB integrity, systemic/neuroinflammation and neuronal/synaptic transmission.
4. To evaluate the effect of NX210c on functional capacities, and quantitative strength in ALS.
5. To evaluate the effect of NX210c on disease progression in ALS.
6. To evaluate the effect of NX210c on composite time to event outcome(s).
7. To evaluate the effect of NX210c on ALS survival.
8. To assess the effect of NX210c on the Combined Assessment of Function and Survival (CAFS).
9. To assess the effect of NX210c in ALS patients’ Quality of Life.
10. To assess safety and tolerability of NX210c.
11. To evaluate the pharmacokinetics (PK) profile of NX210c in plasma, on a subset of patients.

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis (ALS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Patient able to provide informed consent, geographically accessible to the site and able and willing to comply with all study requirements of the protocol, including two lumbar punctures.
2. Satisfactory peripheral venous access; no central catheterization will be permitted.
3. Satisfactory CSF volume at screening (i.e., 1.5 mL minimum).
4. Maximum body weight ≤110 kg at baseline.
5. For female patients: not pregnant and have a negative pregnancy blood test (women of childbearing potential [WOCBP] only) at screening and baseline.
6. For female patients: must not be breastfeeding, have no intention of becoming pregnant during the study, and use acceptable methods of contraception or abstain from intercourse. WOCBP must agree to use highly effective contraception consisting of two forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom from the start of dosing throughout the clinical study period, and for 90 days after the final administration of study treatment. Women of non-childbearing potential (WONCBP) will be considered those who are sterilized or post-menopausal. A sterilized patient will have either undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; participant reported information) at least 90 days prior to baseline; postmenopausal patients will have been amenorrheic for > 12 consecutive months before screening and FSH levels > 30 IU/L. Essure® fallopian tube coil placement is not accepted as surgical sterilization because of the high failure rate.
7. Male patients must either declare and confirm abstinence or must be willing and able to use effective contraception. Male patients engaging in sexual intercourse with WOCBP, both the male patient and his female partner must use highly effective contraception consisting of 2 forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom from the start of dosing throughout the clinical study period, and for 90 days after the final administration of study treatment. Males who have had a vasectomy must have a confirmed zero sperm count or must agree after receiving the first dose of study drug either to use acceptable methods of contraception or abstain from intercourse.
8. For male patients: The patient must not donate sperm at any time from the start of dosing, throughout the clinical study period, and for 90 days after the final administration of study treatment.
9. Male or female, 18 years of age or older at the time of signing the ICF.
10. Patients diagnosed as having possible, probable, probable laboratory-supported, or definite ALS, either sporadic or familial, according to El Escorial Revised criteria.
11. Disease duration of ≤ 36 calendar months (i.e., ALS symptom onset to the baseline timepoint) at baseline.
12. King’s Clinical Staging Stage ≤3 at baseline.
13. Any NfL value available before screening should be compatible with the diagnosis of ALS (>10 pg/mL). No NfL value known before screening does not exclude the patient.
14. Serum NfL study value available at baseline.
15. SVC ≥ 55% predicted value as adjusted for gender, height, and age at baseline.
16. Patients who are being treated with riluzole or symptomatic treatment for ALS (including over the counter medication or supplements) must have been on a stable dose for at least 30 days before baseline. Riluzole-naïve patients or having stopped riluzole at least 2 weeks prior to screening are permitted in the study.
17. For the extension follow-up only: the patient must be able to provide informed consent, have participated to the SEALS study and have received at least 50% of the treatment doses.

Exclusion criteria 12

1. Patients with any cognitive or psychological disorder, intellectual disability or other significant impairment that would result in an inability to understand and sign the informed consent.
2. Minors, persons deprived of liberty by judicial or administrative decision, persons receiving psychiatric care and persons admitted to a health or social institution, adult patients under legal protection or unable to express consent.
3. Exposure to an investigational drug within 12 weeks prior to screening, or at least a period of 5 half-lives for the investigational drug, whichever is longer; for antisense therapy targeting SOD1, if the patient has completed treatment within 6 months of the screening visit. Any drug intended for ALS (other than riluzole and symptomatic treatment) will not be allowed, except during the extension follow-up period.
4. Patient with a history of any clinically significant or unstable medical (including hepatic and renal), neurological, psychiatric condition, disorder or disease (other than ALS) or social circumstances that, based on the investigator's judgment, would 1) interfere with the patient's ability to comply with the protocol and all study procedures or 2) compromise study integrity or 3) pose a risk to the patient if they were to participate (e.g., previous acute coronary syndrome within 3 months of screening, major surgery within 2 months of screening) or physical examination, uncontrolled hypertension (blood pressure > 160/100 mm Hg), at screening or baseline.
5. History of malignancy within 3 years of screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 6 months may be eligible, based on the investigator’s judgement.
6. Any clinically significant abnormalities in screening laboratories, including hepatic and renal impairment (e.g., aspartate aminotransferase (AST) >3× upper limit of normal (ULN); alanine aminotransferase (ALT) >3 × ULN; total bilirubin >2 × ULN; serum creatinine >2.0 × ULN). Retesting may be performed, on discussion with the medical monitor.
7. Patient under anticoagulant treatment that cannot be held or stopped without putting at risk the patient’s life.
8. Positive test to human immunodeficiency virus (HIV) or current chronic/active infection with hepatitis C virus or hepatitis B virus.
9. Patients with active infections or, based on the investigator’s judgement, any active/uncontrolled inflammatory condition(s).
10. Any contra-indication to glucose 5% and/or any hypersensitivity to any component of the IMP formulation.
11. Any known significant brain or spinal disease that would interfere with the lumbar puncture process, CSF circulation or safety assessment.
12. Any person who is an employee of the study sponsor or stakeholder partners involved in the conduct of the study, or an immediate relative of an investigator or study staff.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Changes in serum NfL from predose to 6-week follow-up OR Changes in Albumin CSF/serum quotient (Qalb) from predose to 6-week follow-up.

Secondary endpoints 17

1. Changes in serum NfL from predose to 4-month follow-up or intervals from predose to 4-month follow-up.
2. Changes in CSF NfL from predose to 6-week follow-up.
3. Changes in secondary blood biomarkers from predose to 6-week or 4-month follow-up or intervals from predose to 4-month follow-up.
4. Changes in secondary urine biomarkers from predose to 6-week or 4-month follow-up or intervals from predose to 4-month follow-up.
5. Changes in secondary CSF biomarkers from predose to 6-week follow-up.
6. Changes in Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R, subscores and total) from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
7. Changes in Slow Vital Capacity (SVC) from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
8. Changes in hand-held dynamometry (HHD) muscles and bilateral hand grip from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
9. Evaluate disease progression rate: Delta FS (ΔFS) from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
10. Evaluation of time from baseline to the occurrence of either death, or tracheotomy or permanent assisted ventilation (>22 hours daily for >7 consecutive days, hospitalization), or decrease in weight, whichever comes first.
11. Recorded time from baseline to death.
12. Changes in CAFS from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
13. Change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to 4-month follow-up or intervals from baseline to 4-month follow-up.
14. Secondary safety and tolerability endpoints: Incidence of discontinued treatment due to a treatment-emergent adverse event (TEAE), Incidence of dose decision required during the treatment period due to TEAE, Incidence of discontinued patient due to local tolerability issue(s), Incidence of dose decision required during the treatment period due to local tolerability issue.
15. Number of serious adverse events (SAEs), nature, incidence, and severity of TEAEs: Incidence of abnormal vital signs, Incidence of abnormal 12-lead electrocardiogram (ECG) assessments, Incidence of abnormal laboratory tests (hematology, biochemistry, urinalysis).
16. Changes in physical and neurological examination.
17. Assessment of NX210c plasma PK parameters: Cmax, Tmax, AUC0-last, AUC0-inf, T1/2, CL, Vz on a subset of patients.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Axoltis Pharma

Sponsor organisation

Axoltis Pharma

Address

Pepiniere Laennec, 60 Avenue Rockefeller 60 Avenue Rockefeller

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Axoltis Pharma

Contact name

Chief Medical officer

Public contact point

Organisation

Axoltis Pharma

Contact name

Chief Medical officer

Third parties 6

Locations

1 EU/EEA country · 16 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 9 files

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

Application history

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