A Phase 2a study to evaluate, safety, tolerability, pharmacodynamic markers, and pharmacokinetics of AP-101 in patients with amyotrophic lateral sclerosis (ALS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AL-S Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

12 Jan 2022 → 14 Aug 2025

Decision date (initial)

2024-05-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AL-S Pharma, AG

External identifiers

EU CT number

2024-512343-23-00

EudraCT number

2020-005971-11

ClinicalTrials.gov

NCT05039099

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

Double-blind Phase: To determine the safety and tolerability of AP-101 after multiple intravenous (IV) doses over 6 months of treatment.
Open-label Extension: To determine the safety and tolerability of AP-101 after multiple IV doses.

Secondary objectives 5

1. (Double-blind Phase): To determine the Pharmacokinetic (PK) profile of AP-101 after multiple IV dose administrations
2. (Double-blind Phase): To determine cerebrospinal fluid (CSF) penetration of AP-101 after multiple IV dosing
3. (Double-blind Phase): To determine effects of AP-101 on phospho-neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) levels in CSF and plasma after multiple IV doses of AP-101
4. (Open-label Extension): To determine the PK profile of AP 101 after multiple IV dose administrations
5. (Double-blind Phase): To determine effects of AP-101 on pNfH and NfL levels in CSF and plasma after multiple IV doses of AP 101

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis (ALS)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Male and female participants. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Male participants who agree to use highly effective/effective methods of contraception may participate in this trial: i. All men should refrain from sperm donation for the duration of the study and for 6 months after the final administered dose of AP-101 ii. Male participants with partners of childbearing potential must either remain abstinent (if this is their preferred and usual lifestyle), or must use condoms during intercourse for the duration of the study, and for 6 months after the final administered dose iii. Male participants who are in exclusively same sex relationships are not required to use contraception. b. Male participants must adhere to the contraception restrictions specified in Section 10.6 of the Protocol. c. Female participants of childbearing potential must adhere to contraception restrictions specified in Section 10.6 of the Protocol. Female participants should refrain from egg donation for the duration of the study and for 6 months following the final administered dose of AP101. d. Female participants are considered women not of child bearing potential if i. they have a congenital anomaly such as Mullerian agenesis, ii. they are infertile due to surgical sterilization, or iii. they are post- menopausal (as defined in protocol).
2. Aged 18 years or over.
3. Have possible, clinically probable, clinically probable-laboratory supported or definite familial or sporadic ALS in accordance with the El- Escorial criteria (Appendix 9, Section 10.9 of the Protocol) or who have a diagnosis of ALS as defined by the Gold Coast Criteria; progressive motor impairment documented by history or repeated clinical examination, preceded by normal motor development, and presence of upper and lower motor neuron dysfunction in at least 1 body region or lower motor neuron dysfunction in at least 2 body regions and investigations excluding other conditions.
4. In familial ALS patients, a confirmed pathogenic SOD1 mutation.
5. Onset of symptoms i.e., weakness within past 24 months prior to screening, at the time of obtaining informed consent.
6. Have SVC of ≥50% of predicted values. Participants with SVC of <50% of predicted values may be permitted to enter the OLE, based on the opinion of the investigator.
7. Absence of bilevel positive airway pressure (BiPAP)/proportional assist ventilation (PAV) >4 hours for symptoms attributable to ALS. Use of a CPAP for pre-existing conditions will be allowed.
8. If on riluzole, must be on a stable dose for at least 30 days prior to baseline (randomization) and remain on a stable dose throughout the study. Riluzole cannot be initiated during the double blind phase of the study. Riluzole can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
9. If on edaravone, must have completed 2 cycles at baseline (randomization) and are expected to remain on the same dose throughout the study. Edaravone cannot be initiated once the participant is randomized and for the duration of the double blind phase of the study. Edaravone can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
10. If on sodium phenylbutyrate or taurursodiol, patients must be on a stable dose for at least 30 days prior to baseline (randomization) and remain on a stable dose throughout the study. Treatment with sodium phenylbutyrate or taurursodiol cannot be initiated during the doubleblind phase of the study. Treatment with sodium phenylbutyrate or taurursodiol can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
12. Have venous access sufficient to allow for blood sampling as per protocol.
13. Have clinical laboratory test results within normal reference range for the population or study site, or results with acceptable deviations that are judged to be not clinically significant by the investigator.
14. Are able to visit the study site for outpatient treatment.
15. Are willing to make themselves available for the duration of the study and are willing to follow study specific procedures.

Exclusion criteria 13

1. Are investigator or site personnel affiliated with this study, or the immediate family of any of these. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
2. Are participating in, or have participated in another clinical trial (or have taken an experimental therapy within the context of a clinical trial) within 5 half-lives of baseline (Day 1).
3. Have undergone a tracheostomy for ALS symptoms.
4. Are on nasal intermittent positive pressure ventilation (NIPPV) >4 hours per day for the treatment of ALS related symptoms.
5. Have other causes of neuromuscular weakness.
6. Have severe active psychiatric illness.
7. Have a diagnosis of another neurodegenerative disease (e.g. Parkinson disease, Alzheimer's disease).
8. Have a significant pulmonary disorder not attributed to ALS or who require treatments that might complicate the evaluation of the effect of ALS on respiratory function.
9. Have cognitive impairment, severe disease in the renal, cardiovascular or hematological system.
10. Pregnant or nursing women.
11. Have been exposed to any antisense treatment targeting SOD1, including tofersen, within 6 months of the baseline visit or have known allergies or reactions to AP-101 or any of its excipients.
12. Have undergone stem cell therapy.
13. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study for any reason.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. (Double-blind Phase): Incidence of AEs and SAEs including immunogenicity.
2. (Double-blind Phase): Incidence of abnormalities in vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms and changes in weight.
3. (Open-label Extension): Incidence of AEs and SAEs including immunogenicity.
4. (Open-label Extension): Incidence of abnormalities in vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms and changes in weight.

Secondary endpoints 5

1. (Double-blind Phase): The primary PK parameters are AUC, concentration at the end of infusion and t1/2
2. (Double-blind Phase): AP-101 levels in the CSF
3. (Double-blind Phase): Measurement of pNfH and NfL levels in the CSF and plasma after multiple IV doses of AP-101
4. (Open-label Extension): The primary PK parameters are AUC, concentration at end of infusion and t1/2
5. (Open-label Extension): Measurement of pNfH and NfL levels in CSF and plasma after multiple IV doses of AP-101

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AL-S Pharma AG

Sponsor organisation

AL-S Pharma AG

Address

Wagistrasse 13

City

Schlieren

Postcode

8952

Country

Switzerland

Scientific contact point

Organisation

AL-S Pharma AG

Contact name

Michael Salzmann

Public contact point

Organisation

AL-S Pharma AG

Contact name

Paule Clermont

Third parties 9

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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