A First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Oral Doses of DNL104 in Healthy Subjects
- Conditions
- Amyotrophic Lateral Sclerosis (ALS)10029317
- Registration Number
- NL-OMON42834
- Lead Sponsor
- Denali Therapeutics
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 48
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 <200 pmol/L and follicle-stimulating hormone 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.
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 <90 or >140 mmHg, supine diastolic blood pressure <50 or >90 mmHg, pulse rate <40 or >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 <30 mL/min.
7. History of seizures.
8. History or presence of an abnormal ECG, including, but not limited to, complete left bundle branch block, second- or third-degree heart block, evidence of prior myocardial infarction, or any other abnormality that is clinically significant in the investigator*s opinion or precludes accurate interpretation and calculations of cardiac intervals (e.g., QT, QRS).
9. A QTcF value >450 msec or QRS >120 msec demonstrated by at least two ECGs more than 30 minutes apart.
10. Hemoglobin level <7.5 mmol/L.
11. Any blood or plasma donation or other loss of blood greater than 500 mL within 3 months of screening.
12. Participation in any other investigational drug study within 90 days of first study drug administration.
13. Use of any prescription within 7 days or 5 half-lives (whichever is longer) of the first dose administration and anticipated use through the follow-up visit.
14. Use of any over-the-counter medication (including vitamin/mineral supplements, and herbal medicines such as St. John's Wort) within 7 days of the first dose administration and anticipated use through the follow-up visit.
15. Any surgical or medical condition possibly affecting drug absorption (e.g., gastrectomy).
16. Poor peripheral venous access.
17. Alcohol, caffeine, and grapefruit consumption within 48 h before dosing.
18. Average daily caffeine intake greater than 450 mg / day (equivalent to 4 cups per day) from screening onwards through follow-up.
19. History of alcoholism, drug abuse, or drug addiction in the last 2 years.
20. Positive drug or alcohol test.
21. Use of tobacco or nicotine products within the previous month before the first dose administration.
22. Positive serology for HBV, HCV, or HIV by HIV1 and HIV2 antibodies, Hepatitis B antigen or Hepatitis C antibodies.
23. Subjects who are part of the clinical staff personnel or family members of the clinical site staff.
24. Any other issue which, in the opinion of the Investigator, will make the subject ineligible for study participation.
25. Food Effect Cohort: Subjects who are unwilling to consume the required high fat test meal.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method