* Investigate the safety and tolerability of multiple ascending oral doses of DNL104 in healthy subjects* Characterize the pharmacokinetics (PK) of DNL104 in plasma and measure the trough concentrations of DNL104 in CSF* Explore the pharmacodynamics…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-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 outcome
-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 (%);
Background summary
Receptor-interacting protein kinase 1 (RIP1) is a serine/threonine kinase
involved in the regulation of inflammation and cell death. In response to tumor
necrosis factor (TNF)-alpha signaling, RIP1 is activated, and in turn regulates
activation of downstream targets, including RIPK3, mixed-lineage kinase
domain-like (MLKL) and NF-kB. This complex signaling cascade initiates a number
of cellular processes, including cytokine release, microglial activation, and
necroptosis, a regulated form of cell death.
DNL104 is a novel, potent and selective RIP1 kinase inhibitor that has
favorable pharmacokinetic properties and good penetration across the blood
brain barrier, allowing target inhibition in the central nervous system. As
such, it is a potential therapeutic candidate for neurodegenerative diseases
where histopathology and / or genetics implicates cell death and inflammation,
including amyotrophic lateral sclerosis (ALS), Alzheimer Disease (AD) and
Parkinson Disease (PD).
Study objective
* Investigate the safety and tolerability of multiple ascending oral doses of
DNL104 in healthy subjects
* Characterize the pharmacokinetics (PK) of DNL104 in plasma and measure the
trough concentrations of DNL104 in CSF
* Explore the pharmacodynamics of DNL104 using an ex vivo stimulation assay to
measure the inhibition of phosphorylation of the target protein and downstream
markers that are directly impacted by RIP1 kinase inhibition
* Explore the pharmacodynamics of DNL104 in CSF
Study design
This is a Phase 1, multiple-ascending-dose, randomized, double-blind (subject
and investigator), placebo-controlled, dose-ranging study in healthy subjects
to evaluate the safety, tolerability, and PK of DNL104, a CNS-penetrant kinase
inhibitor.
*Screening: Up to 32 days before dosing;
*In Clinic period: Days -2 to 13;
*Treatment and study assessments: Days 0 to 13
*Follow-up visit: 8-12 days after last dose.
*Group 2 and 3: Follow-up visit: 23-33 days after last dose.
Subjects will be admitted to the study unit on Day -2 and will be discharged
approximately 60 hours after the last study drug administrationon day 10.
The dose level of DNL104 to be administered in each cohort was based on the
pharmacokinetic and safety data obtained from the SAD and will be 50, 100 and
200 mg. Based on data from earlier MAD cohorts, these doses can be adjusted.
Dosing will be trice daily. Available pharmacodynamics will also be evaluated
between dose escalations.
Intervention
DNL104 or placebo
Study burden and risks
The burden for the participants includes the time investment for the briefing,
screening, the occasions, and the follow-up visit. The occasion will consist of
13 days and 14 nights. Furthermore, subjects are asked to adhere to various
lifestyle
regulations. Blood and urine will be collected during the screening, the
occasion and the follow-up visit.
The starting dose was based on the safety, tolerability and PK of the SAD study
with DNL104. The maximum dose to be tested in the MAD study will maintain the
predicted 20-fold Cmax-based safety margin relative to the clinical signs
observed in rats and dogs.
Dose escalation will be stopped in case of an unacceptable tolerability profile
based on the nature, frequency, and intensity of observed AEs, labs and vital
signs judged jointly by the investigator and the sponsor. In addition, the top
dose for this study will not exceed the top dose of the SAD study.
There is no prior experience of administering multiple doses of DNL104 to
humans. Therefore, the side effect profile in humans in currently unknown and
very serious side effects are possible. A drug with the same mechanism of
action (a RIP1 kinase inhibitor) has been tested
previously in humans with an adequate tolerability and safety profile
(ClinicalTrials.gov Identifier: NCT02776033). Toxicology studies
of DNL104 show that doses equivalent to those to be tested in humans are very
well tolerated in rats and dogs. The top dose to be
tested in humans will at Cmax have a >20-fold safety margin with respect to the
Cmax exposure associated with acute, severe
clinical signs in rats. At exposures in animal studies that are higher than the
exposures to be studied in humans, effects on the liver,
gall bladder and urinary bladder were observed, and the animals had mild
decreases in blood pressure and resulting elevations in
heart rate. These are all effects that can be monitored in this first-in-human
study. To minimize the risk of severe clinical signs, a
safety margin of >20-fold will always be maintained.
Oyster Point Blvd, 2nd floor 151
South San Francisco CA 94080
US
Oyster Point Blvd, 2nd floor 151
South San Francisco CA 94080
US
Listed location countries
Age
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 < 200 pmol/L and a 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.
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 <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. 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 <70 mL/min1,73m^2;
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 in at least two ECGs recorded more than 30 min apart;
10. Hemoglobin level <7.5 mmol/L;
11. Any blood donation or other loss of blood greater than 500 mL within 3 months of screening or plasma donation within 2 weeks of screening;
12. Participation in any other investigational drug study within 90 days of first study drug administration, or previous participation in a study with DNL104.
13. Use of any prescription drug within 7 days or 5 half-lives (whichever is longer) of the first dose administration and anticipated use through the follow-up 1 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 1 visit;
15. Any surgical or medical condition possibly affecting drug absorption (e.g., gastrectomy);
16. Poor peripheral venous access;
17. Alcohol, caffeine, or grapefruit consumption within 48 h before dosing;
18. Average daily caffeine intake greater than 450 mg/ day (equivalent to 4 cups per day);
19. History of alcoholism, drug abuse, or drug addiction in the last 2 years;
20. Positive drug or alcohol test at screening;
21. Use of tobacco or nicotine products within the previous month before the first dose administration;
22. Positive serology for HIV, HBV, or HCV, by HIV1 and HIV2 antibodies, Hepatitis B antigen or Hepatitis C antibodies, respectively;
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. Subjects who are unwilling to agree to any food restrictions that may be required.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003859-30-NL |
| CCMO | NL59310.056.16 |