Amyotrophic Lateral Sclerosis (ALS)
Conditions
Interventions
Sponsors
Denali Therapeutics
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1.Healthy male or female of non-childbearing potential between 18 to 65 years of age at screening (inclusive). 2.Subjects must be willing and able to give written informed consent by signing an EC-approved Informed Consent Form prior to admission to this study. 3.Body mass index between 19 to 32 kg/m2 (inclusive) and a weight of at least 50 kg. 4.For males: subject and his female spouse/partners who are of childbearing potential must use highly effective contraception when engaging in sexual activity consisting of 2 forms of birth control (1 of which must be a barrier method such as latex or polyurethane condoms) starting at screening and continuing throughout the clinical study period, and for 90 days after the final study drug administration. 5.For males: subject must not donate sperm starting at screening and throughout the clinical study period, and for 90 days after the final study drug administration. 6.For females: subject must have been surgically sterilized (hysterectomy or bilateral oophorectomy; 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 hematological, renal, neurologic, pancreatic, gastrointestinal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, immunological, allergic disease, or other major disorders. 2. Current significant medical or psychiatric condition. 3. Clinical laboratory test values outside the normal range at screening or baseline unless assessed by the Investigator as clinically non-significant values. 4. History or presence of 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. 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 by at least two ECGs more than 30 minutes 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. *The amount of DNL104 excreted in urine from time zero to 72 hours* post-dose (Ae72) will 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