Amyotrophic Lateral Sclerosis (ALS)
Conditions
Interventions
Sponsors
Denali Therapeutics
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Healthy men or women between 18 and 55 years of age at screening (inclusive); 2. Subjects must be willing and able to give written informed consent, and must sign an ethics-committee-approved Informed Consent Form prior to any study-related procedures being performed; 3. Body mass index between 19 to 32 kg/m2 (inclusive) and a weight of at least 50 kg; 4. For males: When engaging in sexual activity with a woman of childbearing potential, both the subject and his female partner must use highly effective contraception, consisting of 2 forms of birth control (1 of which must be a male barrier method such as latex or polyurethane condoms) from screening, throughout the clinical study period, and for 90 days after the final study drug administration; 5. For males: The subject must not donate sperm from screening, throughout the clinical study period, and for 90 days after the final study drug administration; 6. For females: The subject must have been surgically sterilized (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; proper documentation required) at least 6 months before screening, or be postmenopausal (defined as 24 months without menses before screening, with an estradiol level of 40 IU/L at screening); 7. Able to communicate with the investigator and study staff; 8. Willing and able to comply with the requirements of the study, scheduled visits, laboratory tests, and other study procedures; 9. Agrees to abide by study restrictions and agrees to remain in the study unit for the confinement period.
Exclusion criteria
Exclusion criteria: 1. History of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders; 2. Current significant medical or psychiatric condition, including suicidal ideation in the last 6 months (as assessed by the C-SSRS) or a lifetime suicide attempt; 3. Clinical laboratory test values outside the normal range at screening or baseline unless assessed by the investigator as clinically non-significant values; 4. Supine systolic blood pressure 140 mmHg, supine diastolic blood pressure 90 mmHg, pulse rate 110 bpm, or elevated body temperature at screening or baseline; 5. History of serious adverse reaction or serious hypersensitivity to any drug; 6. Evidence of clinically significant hepatic or renal impairment including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 x the upper limit of normal (ULN), or bilirubin >1.2 x ULN, or GGT > 2.5 x ULN, or creatinine clearance (determined by MDRD) of 450 msec or QRS >120 msec demonstrated in at least two ECGs recorded more than 30 min apart; 10. Hemoglobin level
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| -Safety and tolerability *Treatment-emergent (serious) adverse events ((S)AEs). *Concomitant medication *Clinical laboratory tests o Hematology o Chemistry o Coagulation o Urinalysis *Vital signs o Pulse Rate (bpm) o Systolic blood pressure (mmHg) o Diastolic blood pressure (mmHg) o Temperature (degrees Celsius) o Respiratory rate (breaths per minute) *Electrocardiogram (ECG) o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF, QtcB *Cardiac Holter o Heart rate o Arrhythmias (4 or more successive beats) o Ectopy (up to three successive beats) -Pharmacokinetic *The area under the plasma concentration-time curve from zero to infinity(AUC0-inf); *The maximum plasma concentration (Cmax); *The area under the plasma concentration-time curve from zero to t of the last measured concentration above the limit of quantification (AUC0-last); *The time to reach maximum plasma concentration (tmax); *The terminal disposition rate constant (*z) with the respective half-life (t*). *Other parameters, including Vz/F, CL/F, and other parameters as appropriate, as well as dose adjusted parameters, may be determined. | — |
Secondary
| Measure | Time frame |
|---|---|
| -Pharmacodynamic *pS166-RIP1 kinase level in stimulated PBMCs *Total RIP1 kinase protein level in stimulated PBMCs *Cytokine levels in stimulated plasma (exploratory) *Possible other relevant markers such as MLKL, pMLKL and other exploratory biomarkers -Pharmacogenomic A blood sample for DNA isolation will be collected from each subject pre-dose on Day 1 for potential pharmacogenetic analysis of genes that may affect the pharmacokinetics, pharmacodynamics, efficacy, or safety of DNL104 NeuroCart tests: Saccadic eye movements: o saccadic reaction time (msec), o saccadic peak velocity (deg/sec), and o saccadic inaccuracy (%); Smooth pursuit eye movements: o percentage of time the eyes of the subjects are in smooth pursuit of the target (%); Body sway: o antero-posterior sway (mm); Adaptive tracking: o average performance (%); | — |
Countries
Netherlands
Outcome results
None listed