ALS Amyotrophic Lateral Sclerosis
Conditions
Interventions
• Study interventions: DNL343 and matching placebo (as powder-in-capsules and
when available granules-in-capsules or granules either reconstituted in water
for oral or feeding tube administration or
200 mg
QD for OLE treatment period
• Administration route: Oral or feeding tube
Sponsors
Denali Therapeutics Inc
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Participants must satisfy all of the following criteria for study entry: 1. Women of non-childbearing potential and men, aged 18 to 80 years, inclusive 2. BMI of 18 to 35 kg/m2 3. Willing and able to give informed consent (via legally authorized representative is acceptable) for study participation 4. Able to communicate with the investigator and staff 5. Willing and able to comply with the requirements of the study, including scheduled visits, study restrictions, laboratory tests, and all other study procedures 6. Women must have been surgically sterilized (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; proper documentation required) >= 3 months prior to dosing (Essure*fallopian tube coil placement is not accepted as surgical sterilization because of the high failure rate), or be postmenopausal (amenorrheic for >= 12 consecutive months before dosing, with a follicle-stimulating hormone [FSH] level of > 40 IU/L at screening). 7. For men: When engaging in sex with a woman of childbearing potential (WOCBP), both the male participant and his female partner must 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 study period, and for 90 days after the final administration of study intervention. See Section 10.6 of the protocol for contraceptive guidance for female partners. 8. For men: The participant must not donate sperm at any time from the start of dosing, throughout the study period, and for 90 days after the final administration of study intervention. 9. Diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria (Ludolph et al. 2015) 10. Years since symptom onset as follows: a. 3 to 50% predicted, measured within 28 days of screening (forced vital capacity at screening also acceptable) 12. If participant is taking locally approved ALS treatments, the following guidelines must be met: a. If the participant is taking riluzole, doses must be stable for >= 42 days prior to the first dose of study intervention; participant is expected to stay on a stable regimen throughout the double-blind period of the study. Participants who initiated or changed medication doses within 42 days prior to the planned first dose of study intervention may be rescreened after dose stabilization. b. If the participant is taking any other locally approved ALS treatment besides riluzole (e.g., edaravone), doses must be stable for >= 21 days prior to the first dose of study intervention; the participant is expected to stay on a stable regimen throughout the double-blind period of the study. For edaravone, stable treatment regimen means completion of at least the first 14 days of treatment during the first treatment cycle with intent to continue treatment cycles during the double-blind period. Participants who initiated or changed medication doses within 21 days prior to the planned first dose of study intervention may be rescreened after dose sta
Exclusion criteria
Exclusion criteria: Participants who meet any of the following criteria will be excluded from study entry: 1. Any history of unstable or poorly controlled psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders. Well-controlled conditions are permitted if investigator and Sponsor agree. 2. Positive serum pregnancy test or currently lactating or breastfeeding 3. History of malignancy within 5 years, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence, depending on investigator and Medical Monitor agreement 4. History of clinically significant neurologic disorders other than ALS, including stroke, significant cognitive impairment, or seizure within 5 years of the first dose of study intervention, or head trauma with loss of consciousness, documented by a physician, within 1 year of the first dose of study intervention 5. History of serious adverse reaction or serious hypersensitivity to two or more drug classes or clinically significant history of previous allergy or hypersensitivity to DNL343 or any of the excipients contained within theDNL343 drug product 6. History of clinically significant hypersensitivity to local anesthetics that may be used for LP (e.g., lidocaine) 7. Have criteria that would preclude an LP, such as a local infection at the site of the LP, 5 years may be allowed pending investigator and Sponsor review. 10. History of alcoholism, drug abuse, or drug addiction in the previous 12 months Note: Participants who test positive for drugs included in the urine drug screen (see Section 10.2) may be enrolled at the investigator*s discretion. 11. Evidence of hepatic impairment, including alanine aminotransferase (ALT) or aspartate aminotransferase(AST) > 3 x the upper limit of normal (ULN) or bilirubin > 1.5×ULN at screening or baseline. Patients with Gilbert*s syndrome without evidence of hepatic impairment may be enrolled. 12. History of clinically significant renal impairment o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of treatment-emergent adverse events (TEAEs) throughout the double-blind period | — |
Secondary
| Measure | Time frame |
|---|---|
| • DNL343 PK parameters, including, but not limited to, maximum concentration (Cmax), time to reach maximum concentration (tmax), trough concentration (Ctrough), and area under the concentration-time curve from time zero to 24 hours (AUC0-24) • CSF-to-plasma concentration ratio | — |
Countries
Netherlands
Outcome results
None listed