- To evaluate the safety and tolerability of four different single oral doses of LTI-291 in healthy subjects.- To characterize the plasma pharmacokinetics (PK) of LTI-291 following single oral dosing in healthy subjects.- To evaluate theā¦
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Safety and tolerability endpoints
- Pharmacokinetic endpoints
- Pharmacodynamic endpoints
Secondary outcome
-Wet biomarker measurements
-Genotyping
Background summary
Approximately 10% of patients with clinically diagnosed Parkinson*s disease,
Lewy Body Dementia, or Diffuse Lewy Body disease have a GBA1 mutation. More
recently, it has become clear that even carrying one mutated allele of GBA1
significantly increases the lifetime risk of developing parkinsonism. Existing
treatments are symptomatic in nature, and do not modify the underlying disease
progression. For patients with GBA-associated parkinsonism (GBA-AP), some
approaches eg DBS and anti-cholinergic agents may be contra-indicated due to
the risk of worsened cognitive decline (Sasagasako et al., 1994; Thaler et al.,
2017). Therapies targeting underlying pathogenesis could slow disease
progression in this population. Preclinical studies demonstrate that LTI-291
penetrates the blood brain barrier, to access GCase within the brain and
central nervous system (CNS). Activation of GCase in the periphery or CNS may
be measured by a reduction in the levels of the GCase substrates GluCer or
GluSph. Several lines of evidence suggest that activation of GCase enzymatic
activity could provide therapeutic benefit to patients carrying a heterozygous
mutation in the GBA1 gene, and that activation of the enzyme via allosteric
modulation, as with LTI-291, represents a novel, first-in-class potential
treatment for patients with GBA-AP.
Study objective
- To evaluate the safety and tolerability of four different single oral doses
of LTI-291 in healthy subjects.
- To characterize the plasma pharmacokinetics (PK) of LTI-291 following single
oral dosing in healthy subjects.
- To evaluate the pharmacodynamics (PD) of LTI-291 following single oral dosing
in healthy subjects using NeuroCart assessments.
- To evaluate the pharmacodynamics of LTI-291 following single oral dosing in
healthy subjects using biomarker assessments (i.e. GluCer) in plasma and in
isolated peripheral blood mononuclear cells (PBMCs).
- To Investigate the effect of high-caloric breakfast on PK and PD of LTI-291.
Study design
Randomized, double-blind, placebo-controlled, single ascending dose study in 40
healthy adults.The following dose levels will be investigated in ascending
order: 3 mg, 10 mg, 30 mg and 90 mg. Each cohort will consist of 10 subjects
where subjects are randomized to receive LTI-291 or placebo in an 8:2 ratio.
The effect of food on PK and PD will be investigated in one cohort. In this
cohort, subjects will return for a second visit for dosing (in the same 8:2
randomization) in the fed state after a wash-out of at least 1 week. Cohort 1
will be dosed using a sentinel approach
Intervention
LTI-291 capsules (API-in-capsule) dosed at 3 mg, 10 mg, 30 mg or 90 mg and
matching capsules containing 15 mg of Avicel as placebo.
Study burden and risks
Based on a review of nonclinical safety findings (including daily oral
administration of high LTI-291 doses to rats and dogs for 28 days), this
single-dose protocol is expected to be reasonably safe to initiate and conduct
as designed. There is an acceptably-large margin between proposed clinical
doses and exposures and animal-study NOAELs, and the planned sentinel approach
as well as protocol-specified clinical monitoring are expected to adequately
ensure the safety of human subjects
Blackstone St 19
Cambridge MA 02139
US
Blackstone St 19
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.
2. Healthy male or female subjects of non-childbearing potential (defined as postmenopausal with amenorrhea for at least 12 months) or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of pregnancy, 18 to 65 years of age (inclusive) at screening.
3. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, and with a minimum weight of 50 kg at screening.
4. All males must practice effective contraception and abstain from sperm donation during the study and be willing and able to continue contraception and abstain from sperm donation for at least 90 days after their last dose of study treatment.
5. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions.
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature), 12-lead electrocardiogram (ECG), and clinical laboratory parameters (hematology, blood chemistry, and urinalysis)). Minor deviations of laboratory values from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.
2. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects.
3. Positive Hepatitis B surface antigen (HBsAg), Hepatitis B antibodies, Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
4. Systolic blood pressure (SBP) greater than 150 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 95 or less than 50 mm Hg at screening or baseline.
5. Abnormal findings in the resting ECG at screening defined as:
a. QTcF > 450 msec for males or > 470 msec for females;
b. Notable resting bradycardia (HR < 40 bpm) or tachycardia (HR > 100 bpm);
c. QRS > 120 msec;
d. Personal or family history of congenital long QT syndrome or sudden death;
e. ECG with QRS and/or T wave judged to be unfavorable for a consistently accurate QT measurement (e.g., neuromuscular artefact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T- and U-waves, prominent U waves);
f. Evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker.
6. Use of any medications (prescription or over-the-counter [OTC]), within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to 1g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator. No exceptions will be made for any known inducer or inhibitor of CYP3A4, CYP1A2 or CYP2D6.
7. Use of any vitamin, mineral, herbal, and dietary supplements within 7 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions will only be made if the rationale is clearly documented by the investigator.
8. Participation in an investigational drug or device study within 3 months prior to first dosing.
9. History of abuse of addictive substances (alcohol, illegal substances) or current use of more than 21 units of alcohol per week, drug abuse, or regular use of sedatives, hypnotics, tranquillizers, or any other addictive agent.
10. Positive test for drugs of abuse at screening or pre-dose.
11. Use of tobacco or nicotine products within 14 days before the first dose administration.
12. Demonstrates an excess in xanthine consumption (more than eight cups of coffee or equivalent per day).
13. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable).
14. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening or intention to donate blood or blood products during the study.
15. If a woman: pregnant, or breast-feeding, or planning to become pregnant during the study.
16. Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.
17. Food Effect Cohort only: Subjects who are unwilling or unable to consume the required high fat test meal.
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
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2017-002233-37-NL |
CCMO | NL62047.056.17 |
OMON | NL-OMON23087 |