The purpose of this study is to evaluate the safety, tolerability, PK, and PD of AP-101 in participants with fALS and sALS.
This Phase 2a, multicenter, randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of AP-101 in adults with sporadic ALS or SOD1-associated ALS. A total of 73 participants were randomized within each ALS cohort in a 2:1 ratio to receive AP-101 or placebo during a 24-week double-blind treatment period. Participants assigned to AP-101 received a 500 mg intravenous loading dose on Day 1, a 2500 mg intravenous dose on Day 2, and 2500 mg intravenously every 3 weeks beginning on Day 22 through Week 24. Participants assigned to placebo received matching intravenous infusions on the same schedule. Stable use of locally approved ALS treatments was permitted. Participants who completed the double-blind period could enter an optional 24-week open-label extension in which all participants received AP-101. To maintain the integrity of the double-blind period, the initial dose in the open-label extension remained blinded. Participants were followed for safety and pharmacokinetic assessments for up to 16 weeks after their final study dose. The primary assessments evaluated adverse events, serious adverse events, immunogenicity, vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms, and changes in weight. Secondary assessments included serum pharmacokinetics, AP-101 concentrations in cerebrospinal fluid, and the neurofilament biomarkers phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL). Exploratory assessments included the ALS Functional Rating Scale-Revised, slow vital capacity, muscle strength, King's staging, survival and ventilation outcomes, quality of life, and cerebrospinal fluid total and misfolded SOD1.
Inclusion Criteria:
- All participants must adhere to contraception restrictions
- Female participants of childbearing potential must adhere to contraception
restrictions
- Have possible, clinically probable, clinically probable-laboratory supported or
definite familial or sporadic ALS in accordance with the El-Escorial criteria 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
- In familial ALS participants, a confirmed pathogenic superoxide dismutase 1 (SOD1)
mutation
- Onset of symptoms (i.e, weakness) within past 24 months prior to screening, at the
time of obtaining informed consent
- Have slow vital capacity (SVC) of greater than or equal to (> or =) 50 percentage
(%) of predicted values. Participants with SVC of <50% of predicted values may be
permitted to enter the open-label extension, based on the opinion of the
investigator
- 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
- If on riluzole, must be on a stable dose.
- If on edaravone, must have completed 2 cycles and are expected to remain on the same
dose throughout the study
- Able to provide informed consent which includes compliance with the requirements and
restrictions
- Have venous access sufficient to allow for blood sampling
- Have clinical laboratory test results within the 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
Exclusion Criteria:
- Have participated or currently participating in another clinical trial within 5
half-lives of baseline (Day 1)
- Have undergone a tracheostomy for ALS symptoms
- Are on nasal intermittent positive pressure ventilation (NIPPV) >4 hours per day for
the treatment of ALS related symptoms
- Have other causes of neuromuscular weakness
- Have cognitive impairment, severe disease in the cardiovascular, hematological,
renal system, neurodegenerative disease, pulmonary disorder, or psychiatric illness
- Pregnant or nursing women
- Have been exposed to any antisense treatment targeting SOD1 within 6 months of the
baseline visit
- Have undergone stem cell therapy