Primary Objective:- To evaluate the safety and tolerability of ENX-101 following repeated doses in healthy volunteersSecondary Objective:- To evaluate the effects of ENX-101 on the following electrocardiogram (ECG) parameters in healthy volunteers:…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The safety and tolerability of ENX-101 will be assessed by the following:
- AEs
- Vital signs (2-positional blood pressure and HR, respiratory rate, and
tympanic body temperature)
- 12-lead ECG
- 24-hour continuous 12-lead ECG Holter monitoring (Part 1 only)
- Clinical laboratory tests (hematology, serum chemistry, urinalysis)
- Physical examination
- Pregnancy test (where applicable)
- C-SSRS
- MOAA/S
- LSEQ (Part 2 only)
- CSD-Core (Part 2 only)
Secondary outcome
Pharmacokinetic Measures:
Blood will be collected before and after ENX-101 administration for
bioanalytical measurement of plasma levels of ENX-101 and metabolites
(ENX-101-M3, triazole aldehyde, triazole alcohol, and triazole acid). The time
points for collecting blood and the evaluation parameters are as follows:
Part 1
- Day 1: Pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after
dosing
- Day 2: Pre-dose (24 hours after Day 1 dose) and 1, 2, 4, 6, 8, 10, and 12
hours after dosing
- Days 3, 4, 5, 6, 7, and 8: Pre-dose (24 hours after the previous day*s dose)
- Day 9: Pre-dose (24 hours after Day 8) and 1, 2, 4, 6, 8, 10, and 12 hours
after dosing
- Day 10: Pre-dose (24 hours after Day 9) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8,
10, and 12 hours after dosing
- Days 11, 12, 13: At 24, 36, and 72 hours, respectively, after Day 10 dosing
The plasma concentration-time data for ENX-101 and, if possible, its
metabolites will be analyzed using non-compartmental methods. The following PK
parameters will be evaluated: maximum plasma concentration (Cmax), time to
reach maximum plasma concentration (Tmax), area under the plasma
concentration-time curve from administration to the end of dosing (AUC0-t), AUC
from administration to 24 hours after dosing (AUC0 24), AUC extrapolated to
infinite time (AUC0-*), plasma concentration half-life (t1/2),terminal rate
constant (*z), apparent total clearance of the drug from plasma after oral
administration (CL/F), apparent volume of distribution during terminal phase
after non-intravenous administration (Vz/F), and metabolite/parent (M/P) ratio.
Other parameters may be evaluated. Actual elapsed time from dosing will be used
to estimate all subject plasma PK parameters.
Part 2
* Day 1: Pre-dose
* Day 2: 12, 16, and 20 hours post-dose
* Day 3 through Day 10: 12 hours post-dose
* Day 11: 12, 16, and 20 hours post-dose
Day 12 and Day 13
Pharmacodynamic Measures:
PD assessments will be conducted at Baseline on Day *2 and on Day 2 and Day 9
as follows:
- NeuroCart assessments
o Saccadic eye movements, saccadic reaction time (seconds), saccadic peak
velocity (degrees/second), and saccadic inaccuracy (%)
o Smooth pursuit eye movements (percentage of time the eyes of the subject are
in smooth pursuit of the target) (%)
o Adaptive tracking (average performance) (%)
o Body sway (antero-posterior sway) (mm)
o Pupil size
o VAS according to Bond and Lader to assess mood, alertness, and calmness (mm)
o VAS according to Bowdle to assess internal perception, external perception,
and feeling high (mm)
- Cognitive assessment
o VVLT (learning+immediate recall/delayed recall/delayed recognition)
- qEEG
Part 2
PD assessments will be conducted at Baseline either on the evening of Day -1
(PSG) or on the morning of Day 1 (NeuroCart, VVLT), followed by pre-dose
assessments on the evening of Day 1 prior to either PSG electrode placement
(NeuroCart) or approximately 45 minutes prior to night-time dosing (VVLT), and
post-dose assessments in the evening of Day 1 and Day 10 (PSG), and in the
morning Day 2 and Day 11 (NeuroCart, VVLT), as follows:
* NeuroCart assessments
o Saccadic eye movements, saccadic reaction time (seconds), saccadic peak
velocity (degrees/second), and saccadic inaccuracy (%)
o Smooth pursuit eye movements (percentage of time the eyes of the subject are
in smooth pursuit of the target) (%)
o Adaptive tracking (average performance) (%)
o Body sway (antero posterior sway) (mm)
o Pupil size
o VAS according to Bond and Lader to assess mood, alertness, and calmness (mm)
o VAS according to Bowdle to assess internal perception, external perception,
and feeling high (mm)
* Cognitive assessment
o VVLT (learning + immediate recall/delayed recall/delayed recognition)
* Polysomnography
o EEG spectra
o total sleep time
o latency to persistent sleep
o wake after sleep onset
o rapid-eye movement (REM) sleep variables
Part 1 only
Optional Genetic Testing:
One additional blood sample will be collected for potential genotyping of
cytochrome P450 (CYP) polymorphisms if the PK data are sufficiently variable to
warrant exploration of potential impact of CYP polymorphisms on ENX-101
exposure.
Background summary
Gamma-aminobutyric acid A (GABAA) receptors are a family of ligand-gated
chloride channels that function as inhibitory neurotransmitter receptors in the
central nervous system (CNS). The GABAA receptor is a pentameric protein with
subtypes composed of *, *, and * subunits. Typical benzodiazepines activate the
receptor in a non-selective manner, binding to an allosteric site at the
interface of a * subunit and either an *1, *2, *3, or *5 subunit (Schwartz,
1988; Rudolph and Knoflach, 2011). Agonism at the *2 and *3 subtypes is
believed to be associated with anxiolytic and spasmolytic activities, whereas
*5 subtype activity is believed to have cognitive effects (McKernan and
Whiting, 1996). Engrail has advanced ENX-101, a non-benzodiazepine, as a
promising subtype-selective GABAA positive allosteric modulator (PAM) for
epilepsy, spasticity, and anxiety disorders.
Seizures frequently result from an imbalance of excitation and inhibition due
to a failure of inhibitory neurotransmission (Marafiga et al., 2020). Most
agents that enhance GABAA receptor function have antiseizure properties due to
their ability to increase inhibitory neurotransmitter tone. The evidence
linking epilepsy with dysfunction of GABAergic inhibition is substantial and
has been extensively reviewed (Mody and Pearce, 2004; Olsen and Sieghart, 2008;
D*Hulst et al., 2009; Rudolph and Knoflach, 2011).
L-838417, which was initially evaluated by Merck as part of a research effort
to identify subtype-selective GABAA anxiolytics with reduced sedation and
ataxia, was reported to possess a particularly attractive subtype-selective
GABAA pharmacologic profile, with partial agonism at *2,3,5 and antagonism at
*1, and it was advanced through non-clinical development into Phase 1 clinical
evaluation. However, despite its desirable GABAA subtype selectivity,
publications from Merck indicate that L-838417 possessed a poor nonclinical PK
profile, and it was not further developed (Scott-Stevens et al., 2005).
ENX-101 is a deuterated analog of L-838417 designed to retain the
pharmacological activity of L-838417 yet with a preferred PK profile. ENX-101
exhibits potent affinity for GABAA *1, *2, *3, and *5 subtypes (pKi = 0.79,
0.67, 0.67, and 2.3 nm, respectively). Whereas ENX-101 lacks functional
activity at *1 (i.e., is an antagonist at *1), it functions as a PAM with
approximately 35% to 40% maximal response at *2, *3, and *5. Furthermore,
ENX-101 demonstrates an improved PK profile as compared to L-838417. Thus,
ENX-101 is an *2,3,5 subtype-selective modulator of the GABAA receptor that
represents a potential new therapeutic modality for the treatment of
spasticity, epilepsy, and other CNS disorders..
To date, ENX-101 has been tested in 101 volunteers in both single ascending
dose (SAD) and multiple ascending dose (MAD) studies. Single doses up to and
including 60 mg ENX-101 and multiple daily doses up to and including 12 mg
ENX-101 administered for 10 days were safe and generally well tolerated (see
Section 6.2.2). ENX-101 also demonstrated dose-related target engagement using
positron emission tomography (PET). This study is designed to extend previous
clinical investigation of ENX-101 to higher doses administered daily for 10
days.
Study objective
Primary Objective:
- To evaluate the safety and tolerability of ENX-101 following repeated doses
in healthy volunteers
Secondary Objective:
- To evaluate the effects of ENX-101 on the following electrocardiogram (ECG)
parameters in healthy volunteers: cardiac repolarization (corrected QT interval
[QTc]), heart rate (HR), PR and QRS intervals, T-wave morphology, and U-wave
presence
- To evaluate the pharmacokinetics (PK) of ENX-101 and, if possible, ENX-101
metabolites (ENX-101-M3, triazole aldehyde, triazole alcohol, and triazole
acid), in plasma of healthy volunteers after the first dose and at plasma
steady state
- To determine the effects of ENX-101 on a battery of pharmacodynamic (PD)
measures (NeuroCart®) including saccadic eye movements, smooth pursuit eye
movements, adaptive tracking, body sway, pupil size, Bond and Lader visual
analogue scale (VAS), and Bowdle VAS
- To determine the effects of ENX-101 on the Visual Verbal Learning Task (VVLT)
- To determine the effects of ENX-101 on quantitative electroencephalographic
(qEEG) parameters
- To determine the effects of ENX-101 on sedation with the Modified Observer's
Assessment Alertness/Sedation (MOAA/S)
* To determine the effects of ENX-101 on polysomnography (PSG) parameters
* To evaluate the influence of evening dosing on tolerability of ENX 101
Study design
This is a randomized, double-blind, placebo-controlled, multiple ascending dose
study in healthy volunteers.
The study will be conducted in 2 parts.
Part 1 (daily doses administered in the morning)
Part 2 (daily doses administered in the evening)
Intervention
ENX-101 formulated as Size 2 capsules each containing 5 mg ENX-101, which will
be supplied to the pharmacy in bulk.
Subjects will be administered ENX-101 orally, once daily, in the morning with
water at the following doses:
* Cohort 1: 5 mg (administered as one 5 mg ENX-101 capsule) in the morning with
water
* Cohort 2: 10 mg (administered as two 5 mg ENX-101 capsules) in the morning
with water
* Cohort 3: 15 mg (administered as three 5 mg ENX-101 capsules) in the morning
with water
* Cohort 4: 25 mg (administered as five 5 mg ENX-101 capsules) in the morning
with water
* Cohort 5: 50 mg (administered as ten 5 mg ENX-101 capsules) in the morning
with water
* Cohort 6: maximum of 25 mg administered in the evening with water; exact dose
dependent on DEC review of Part 1 data
Placebo formulated as Size 2 capsules, which will be supplied to the pharmacy
in bulk.
Subjects will be administered placebo orally, once daily, as follows:
* Cohort 1: administered as 1 placebo capsule in the morning with water
* Cohort 2: administered as 2 placebo capsules in the morning with water
* Cohort 3: administered as 3 placebo capsules in the morning with water
* Cohort 4: administered as 5 placebo capsules in the morning with water
* Cohort 5: administered as 10 placebo capsules in the morning with water
* Cohort 6: placebo capsules administered in the evening with water; number of
capsules dependent on DEC review of Part 1 data (up to cohort 4)
Study burden and risks
No therapeutic benefit is anticipated for participants of this study, as is
common for most Phase 1 studies involving healthy participants. The evaluation
of potential risks of ENX-101 in humans is based on available data from
non-clinical toxicology and safety pharmacology studies as well as prior
clinical trial exposure of 101 healthy volunteers.
12750 High Bluff Drive Suite 190
San Diego 92130
US
12750 High Bluff Drive Suite 190
San Diego 92130
US
Listed location countries
Age
Inclusion criteria
Subjects must meet all the following criteria to be eligible for the study:
1. Healthy male and female volunteers aged 18 to 55 years, inclusive, at
Screening
2. Capable of giving written informed consent
3. Willing to give written consent to have data entered into *Verified Clinical
Trials*
4. Female subjects
a. Of non-childbearing potential, defined as either permanently sterilized (at
least 4 months after surgical sterilization including bilateral salpingectomy,
tubal ligation, or oophorectomy with or without hysterectomy) or
post-menopausal (defined as amenorrhea for 12 consecutive months and documented
plasma follicle-stimulating hormone level >40 IU/mL; in the event a subject's
menopausal status has been clearly established and yet serum
follicle-stimulating hormone levels are not consistent with a post-menopausal
status, determination of the subject*s eligibility to be included in the study
will be at the Investigator*s discretion following consultation with the
Sponsor), and with a negative pregnancy test at Screening and Day *2; OR
b. Of childbearing potential and willing to use 2 effective methods of
contraception (i.e., established method of contraception + condom) or remain
abstinent (where abstaining from sexual intercourse is in line with the
preferred and usual lifestyle of the subject) from Day *2 through 3 months
after the last dose of study drug, and with a negative pregnancy test at
Screening and Day *2
5. Male subjects who, if fertile (defined as post-pubertal and not permanently
sterile by orchidectomy or vasectomy) must be willing to use a condom or remain
abstinent (where abstaining from sexual intercourse is in line with the
preferred and usual lifestyle of the subject) from Day *2 through 3 months
after the last dose of study drug
6. Body mass index of 18 to 35 kg/m2 at Screening
7. Willing and able to comply with all study requirements including the
following:
a. Reside in the inpatient unit from Day *2 until discharge on Day 13
b. Refrain from strenuous exercise from Day *4 until Day 13
c. Abstain from grapefruit-, alcohol-, caffeine-, or xanthine-containing
products from Day *4 through Day 13
Part 2 Subjects Only
8. Subjects must have sleep pattern of going to bed between 10:00 pm and 12:00
am over the 4 weeks prior to Screening through to Day -2
9. Subjects must have been sleeping at least 6 to 8 hours per night over the 4
weeks prior to Screening through to Day -2
Exclusion criteria
Subjects meeting any of the following exclusion criteria will not be enrolled
in the study:
1. Clinically significant abnormality within 2 years of Screening that in the
Investigator*s opinion may place the subject at risk or interfere with study
outcome variables; this includes, but is not limited to, history of or current
cardiac, renal, neurologic, gastrointestinal, pulmonary, endocrinologic,
hematologic, or immunologic disease or history of malignancy
2. History of convulsions (other than benign febrile convulsions of childhood)
including epilepsy, or personal history of significant cerebral trauma or
central nervous system infections (e.g., meningitis)
3. History or evidence of significant ophthalmologic or neurologic condition
that would adversely affect the eye movement assessments
4. History or evidence of any medical condition potentially altering the
absorption, metabolism, or elimination of drugs; this includes a surgical
history of the gastrointestinal tract affecting gastric motility or altering
the gastrointestinal tract
5. Any of the following cardiovascular conditions at Screening or Day *2:
a. History or evidence of any of the following:
i. Myocardial infarction
ii. Cardiac valvulopathy
iii. Cardiac surgery revascularization (coronary artery bypass grafting or
percutaneous transluminal coronary angioplasty)
iv. Unstable angina
v. Cerebrovascular accident or stroke or transient ischemic attack
vi. Pacemaker
vii. Atrial fibrillation, flutter, or non-sustained or sustained ventricular
tachycardia
viii. Pulmonary arterial hypertension
ix. Sick sinus syndrome, second- or third-degree atrioventricular block
x. Uncontrolled hypertension
xi. Congestive heart failure
xii. Family history of sudden death or personal history of long QT syndrome
xiii. Hypokalemia
xiv. Unexplained syncope or syncope within the last 3 years regardless of
etiology
b. Electrographically and clinically significant abnormalities, as judged by
the Investigator, that might interfere with ECG analysis, including evidence of
a previous myocardial infarction, significant left ventricular hypertrophy,
flat T waves (particularly in the inferior leads), or more than minor
non-specific ST-T*wave changes
c. Rhythm other than sinus rhythm
d. Mean HR <50 beats per minute (bpm) or >100 bpm
e. Mean systolic blood pressure >140 mm Hg; mean diastolic blood pressure >90
mm Hg
f. QTc interval using Fridericia*s formula (QTcF) >450 msec in males or >470
msec in females
g. QRS interval *120 msec
h. PR interval >200 msec
6. Reports having experienced suicidal ideation (Type 4 or 5 on the C-SSRS)
within 30 days prior to Screening, any suicidal behavior within 2 years prior
to Screening (any *Yes* answers on Suicidal Behavior section of C-SSRS), and/or
the Investigator assesses the subject to be a safety risk to him/herself or
others
7. Diagnosis of any sleep disorder (including narcolepsy, central sleep apnea,
sleep related hypoventilation, circadian rhythm sleep-wake disorders,
substance/medication induced sleep disorder or parasomnias - NREM sleep arousal
disorders, nightmare disorder, REM sleep behavior disorder for Part 2) in the
last 6 months or current complaints of sleep disturbance or daytime symptoms
attributable to unsatisfactory sleep or shift worker whose routine work hours
overlap with the typical sleep period (including habitual daytime naps, travel
across 3 different time zones in the last 2 weeks for Part 2).
8. History or evidence of moderate or severe Substance Use Disorder as defined
by the Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
9. Is a smoker or has used nicotine or nicotine-containing products within 90
days of Screening and/or will not agree to abstain from nicotine use during the
study; this includes cigarettes, e-cigarettes, and nicotine replacement or
nicotine-containing products
10. Has a positive qualitative drug or alcohol test at Screening or Day *2
11. Ingested any concomitant medication (excluding hormonal birth control)
within 5 half-lives or 30 days (whichever is longer) prior to Day 1
12. Any subject who has received any known hepatic- or renal-clearance-altering
agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazines, etc.) for
a period of 90 days prior to Day 1
13. Clinically significant abnormal findings in serum chemistry, coagulation,
hematology, or urinalysis results at Screening or Day *2
14. Elevated >2 × upper limit of normal liver enzymes (alanine aminotransferase
and/or aspartate aminotransferase) and/or bilirubin at Screening or Day *2
15. Clinically significant abnormal findings in vital sign assessments at
Screening or Day *2
16. History of hepatitis B or hepatitis C or demonstration of hepatitis B
surface antigen or hepatitis C antibody at Screening
17. History of human immunodeficiency virus (HIV) infection or demonstration of
HIV antibodies at Screening
18. History of any confirmed significant allergic reactions (urticaria or
anaphylaxis) against any drug or any multiple drug allergies (non-active hay
fever is acceptable)
19. Donated >500 mL blood or plasma within 30 days prior to Day 1 or has lost
>1200 mL of blood within 4 months prior to Day 1
20. Receipt of an investigational drug within 90 days or 5 half-lives,
whichever is longer, prior to Day 1 or currently in the follow-up period of
another clinical trial at the time of Screening
21. Any other condition that, in the Investigator's opinion, might indicate
that the subject is unsuitable for the study (e.g., information provided by the
general practitioner, if available)
22. Subject is unable to comply with the requirements of the study or, in the
opinion of the Investigator, should not participate in the study
Design
Recruitment
Medical products/devices used
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 | EUCTR2020-006074-73-NL |
| CCMO | NL76363.056.21 |