A Phase I, Single Ascending Dose Study of HTL0014242 in Healthy Adults
Research type
Research Study
Full title
A Phase I, Randomised, Double-blind, Placebo controlled, Single Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of Oral HTL0014242 in Healthy Adults
IRAS ID
248186
Contact name
Jim Bush
Contact email
Sponsor organisation
Heptares Therapeutics Ltd
Eudract number
2018-002302-31
Duration of Study in the UK
0 years, 6 months, 27 days
Research summary
Research Summary:
HTL0014202 is a drug being developed by Heptares Therapeutics for the treatment of dystonia (a condition causing abnormal muscle tone leading to muscle spasms and abnormal posture). The drug acts on a receptor called mGlu5, which is involved in modulating the whole central nervous system. Being able to target these receptors may help in treating some psychiatric and neurological disorders.
There are no licensed oral treatments for dystonia, and this study will be the first in human study to evaluate the safety, tolerability and pharmacokinetics (how the body handles the drug) of HTL0014242.
The study is a sequential group, single ascending dose design, with 48 subjects in 6 groups of 8, who will reside in the unit for 6 days and then return for a follow up visit 7-14 days after dosing.
In each of the groups, 6 subjects will receive the drug and 2 will receive a placebo. Each group will be split into three cohorts of 2, 3 and 3 subjects. Subjects in different cohorts will be dosed on different days to accommodate sentinel dosing. This will ensure that the dosages are safe and well tolerated before the next cohort are dosed. There will be an interval of at least 48 hrs between each cohort.
It is planned that each group will have an increased dose of the study drug, which will be discussed in the dose escalation meeting once the data from the previous group has been assessed. However, doses may be reduced if considered necessary. The starting dose will be 1mg.Summary of Research:
This study investigated the safety and tolerability of single doses of a potential new medicinal product (known as HTL0014242) which acts through a sub-type of ‘metabotropic’ glutamate receptors (known as mGlu5) and which play an important role throughout the central nervous system. Glutamate receptors are specialised proteins located on the surface of cells which respond to the presence of the signalling chemical glutamate in the cellular environment. There is evidence that modulation of these receptors could be beneficial in a variety of clinical disorders including movement disorders (including Parkinson’s disease), dystonia, and amyotrophic lateral sclerosis, cocaine withdrawal and cocaine dependence, and neuroprotection (including Alzheimer’s disease). The purpose of this study was to ensure that the drug was safe and well tolerated when given in single oral doses to healthy subjects and also to measure the levels of drug in plasma and urine over time (known as the pharmacokinetic or PK profile).
This study was conducted at a single specialist clinical pharmacology centre at Covance in Leeds UK between Nov 2018 and Mar 2021. The study was sponsored by the developer of the potential new medicine, Heptares Therapeutics Ltd, based in Cambridge UK. Heptares Therapeutics Ltd and Covance would like to thank all those who participated and provided their data in this clinical study.
In order to minimise bias in reporting findings, the study included capsules containing both active medication (at varying doses) and also some with no medication (known as placebo). Neither the trial subjects nor the clinical staff were aware of exactly what was the treatment for each person on each day. This was revealed at the end of the study. This is described as ‘double-blind’ and ‘placebo-controlled’. The study was divided into a number of cohorts with up to 8 subjects in each cohort. At each cohort the dose of active medication increased from the previous group. All capsules were taken by subjects in the fasted state (so as not to add variability caused by taking food at the same time). All subjects were assessed before qualifying for inclusion in this study to ensure they met certain general and safety characteristics including health, sex, age, weight, BMI. In addition, as this was a new treatment that potentially could affect mood and behaviour, all subjects were assessed not to have any personal or family history of significant mental, behavioural or neurodevelopmental disorders.
Safety was assessed by recording the occurrence of adverse events after treatment. In addition, blood samples were taken to check for unusual findings along with heart rate, blood pressure, ECG and general physical well-being. Any effects on the brain were measured using specialised questionnaires (Brief Psychiatric Rating Scale (BPRS), Clinician-Administered Dissociative States Scale (CADSS) and Montreal Cognitive Assessment (MoCA). The levels of the drug in plasma and in urine were measured after treatment. This included the highest concentration, the time to reach the highest concentration and the change in concentration over time. From this the time it took for the plasma concentration to reduce by half (half-life) was calculated. From urine it was also possible to calculate the amount of drug excreted over time.
Overall, 70 subjects entered and completed this study of whom 17 received placebo treatment and 53 received active treatment at one of nine single oral doses. There were no effects of the treatment on clinical laboratory tests, ECG or physical examination findings in the study. Similarly, there were no notable treatment or dose-related trends in the psychiatric monitoring data during the study. At dose levels of mid-range and above more than half the subjects in each group reported at least one adverse event due to treatment with the highest number at the highest dose tested. None of these adverse events were considered to be serious or severe. The most commonly reported adverse events (40%) involved the nervous system (mainly dizziness) and these were mostly seen in the two highest dose groups. In the highest dose group, two subjects reported closed-eye hallucinations although causality with active treatment was not proven. There was a small increase in systolic and diastolic blood pressure at the higher dose groups at around the time that blood levels were at their highest however none of these findings were considered to be clinically important.
Data measuring drug levels in plasma showed that the rate that the drug was absorbed was steady across the dose range with the highest concentrations measured between 2 to 5 hours after dose. Plasma concentrations declined in a biphasic manner (in two stages) with the first stage lasting for approximately 3 to 6 hours followed by a second stage which lasted approximately 19 to 35 hours (apparent terminal elimination half-life). The amount of exposure to the drug over time was variable between subjects across the dose range tested and was not related to their body weight. Only small amounts of drug were detectable in urine suggesting that excretion of the drug through the kidneys was negligible.
In conclusion, single oral doses of the test drug HTL0014242 were well tolerated over the range tested. There were no clinically important findings in vital signs, ECG, clinical laboratory tests and physical examination although increases in blood pressure were seen at higher doses. The majority of treatment emergent adverse events were mild with the most frequent being dizziness at higher doses. All of these resolved during the course of the study. The time to maximum plasma concentration was around 2 to 5 hours and declined in a two stage manner with a terminal half-life up to approximately 35 hours. Exposure to the drug after treatment showed a high level of variability. Excretion from the kidneys, as measured in urine, was negligible. These data show that this drug is generally well tolerated and can now progress to further studies to understand the effects on the body when given at multiple doses and subsequently how it can be developed to be made available to patients with those disorders for whom evidence indicates that modulation of the mGlu5 pathway could lead to significant medical benefit.
REC name
South Central - Berkshire B Research Ethics Committee
REC reference
18/SC/0280
Date of REC Opinion
1 Oct 2018
REC opinion
Further Information Favourable Opinion