- Investigate the safety and tolerability of single ascending doses of DNL104 in healthy volunteers.- Characterize the pharmacokinetics of DNL104 in plasma, CSF, and urine.- Characterize the effect of a high fat meal on the pharmacokinetics of…
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.
*The amount of DNL104 excreted in urine from time zero to 72 hours* post-dose
(Ae72) will 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.
Inhibition of RIP1 kinase activity has been shown to protect against
necroptotic cell death in vitro across a range of cell death models, including
a model of motor neuron cell death related to Amyotrophic Lateral Sclerosis.
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 single ascending doses of DNL104
in healthy volunteers.
- Characterize the pharmacokinetics of DNL104 in plasma, CSF, and urine.
- Characterize the effect of a high fat meal on the pharmacokinetics of DNL104.
- 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 PD of DNL104 in CSF
Study design
This is a first in human, prospective, single center, double blind (subject and
investigator), placebo-controlled, partly cross-over design, single ascending
oral dose study to investigate the safety, tolerability, pharmacokinetics and
pharmacodynamics of DNL104. It is a phase I study in 48 healthy adults (male
and non-fertile female) and the total duration of the study for each subject
will be up to 40 days divided as follows:
*Screening: Up to 33 days before dosing;
*In Clinic period: Days -2 to 3;
*Treatment and study assessments: Days 0 to 3
*Follow-up visit: 6-8 days after last dose.
Subjects will be admitted to the study unit on Day -2 and will be discharged
approximately 72 hours after study drug administration.
Intervention
DNL104 or placebo
Study burden and risks
There is no prior experience of administering 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.
151 Oyster Point Blvd 2nd floor
South San Francisco CA 94080
US
151 Oyster Point Blvd 2nd floor
South San Francisco CA 94080
US
Listed location countries
Age
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 <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.
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 <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.
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 | EUCTR2016-003051-30-NL |
| CCMO | NL58815.056.16 |