* PIPE-307 PET study in healthy volunteers
Research type
Research Study
Full title
A Phase 1, open-label study of PIPE-307 to determine muscarinic Type I receptor occupancy (M1AChR) parameters by [11C] PIPE-307 PET imaging in healthy volunteers. (21-007)
IRAS ID
300997
Contact name
Stephen Huhn
Contact email
Sponsor organisation
Pipeline Therapeutics
Eudract number
2021-002319-67
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 8 months, 22 days
Research summary
Research Summary
The study medicine (PIPE-307) is an experimental treatment for multiple sclerosis (MS), a condition that can affect the brain and spinal cord and can sometimes lead to serious disability. MS occurs when the body’s immune system (which usually protects the body from harmful substances and fights infection) attacks the protective layer (called myelin) that surrounds the nerve fibres, causing damage. We hope that the study medicine will work by binding to sites in the brain and spinal cord (called M1AchR) which will lead to the repair of the damaged myelin and nerve fibres, and so improving the symptoms of MS and preventing any further nerve damage.
We’re doing this study in up to 8 healthy volunteers (aged 25–65 years) to measure how much PIPE-307 gets into the brain and attaches to M1AchR. To find out, we’ll do PET (positron emission tomography) scans, which make images of the brain. We’ll also assess blood levels of the study medicine and whether it causes any side effects.
Participants will take a single dose of PIPE-307, by mouth, and have 3 PET scans. They’ll take up to about 1.5 weeks to finish the study. They’ll have up to 2 screening visits, during which they’ll have one MRI (magnetic resonance imaging) scan, they’ll stay on the ward for 2 nights (in 1 study session) and make 1 outpatient visit.
Before each PET scan, well give participants an injection of a small amount of radioactive tracer containing carbon-11. The radioactive tracer binds to M1AchR in the brain, and the PET scan shows where the tracer is. Participants will be exposed to radiation levels similar to 3 years’ background radiation.
A pharmaceutical company (Pipeline Therapeutics, Inc) is funding the study.
The study will take place at 1 research centre and 1 imaging centre in London.Summary of Results
The clinical study PTI-307-102 titled, “A Phase 1, Open-label Study of PIPE-307 to Determine Muscarinic Type I Receptor (M1AChR) Occupancy Parameters by [11C] PIPE-307 PET Imaging in Healthy Volunteers” was funded by Pipeline Therapeutics, a private pharmaceutical company.
Six people ages 25-65 years who were considered in good general health, known as “healthy volunteers”, participated in the Phase 1 research study. Participants underwent screening up to 21 days before the dose of study medication to confirm if they met the study criteria to participate, including an MRI. Once they passed screening, each participant took one dose of the medication being tested, and three doses of a radioligand (a radioactive substance used to image a compound). There were three different dose strengths of study drug tested. Each subject was in the study for about two weeks once they received the dose of study medication, including follow-up visits. Participants underwent three PET (positron emission tomography) scans during the study (one before and two after taking the oral study medication). During study visits, participants gave blood to help determine how long the study medication stays in the body.
Participants remained at the study center from one day before their first (baseline) PET scan until roughly 12 hours after their second on-treatment PET scan and returned to the clinic approximately seven days after their final dose of study medication for a follow-up visit. The study was conducted at HMR research site in the United Kingdom in the Fall of 2021. The doctors and support staff of HMR, London and Imanova Limited (trading as Invicro) organized the study. The doctors at HMR and Invicro have no financial interest in Pipeline Therapeutics, Inc.
The study medicine is an experimental new medicine that may promote remyelination (regeneration of the myelin sheath that covers nerve cells) for treating multiple sclerosis (MS) by binding to a receptor in the brain referred to as M1AChR. MS is a chronic brain and nervous system disease that degrades the myelin sheath that covers nerve cells (also referred to as demyelination), and results in the disruption of nerve cell transmission and causes progressive disability. Effective treatments for the nerve cell damage in MS is one of the largest unmet needs for the nearly 1 million US patients (in the United States) and 2.5 million (globally) patients living with this disorder (Fillippi, 2018). While current treatments focus on suppressing the immune system to limit inflammation and further loss of the myelin sheath, there are no approved therapies that effectively promote remyelination to mitigate the related progressive disability associated with chronic demyelination (Bove and Green, 2017) (Stankoff, 2016).
This study was done in healthy volunteers to find out how much of the study medicine gets into the brain, and to help determine the correct doses when the drug is tested in patients. To measure how much study medicine gets into the brain, a PET scan was used to take images which showed how much of the study drug bound to the appropriate receptors in the brain. A small dose of an intravenous radioactive tracer (Carbon-11-PIPE-307) was injected, and this tracer bound to the M1AChR receptor in the brain, revealing the relationship between study drug dose and activity within the brain. The amount of binding of the study drug after different oral dosing was the main objective of the study.
A total of six subjects (2 subjects per dose level) were enrolled in the study, and single 10, 20 and 40 mg doses of the study drug were administered. The results of the study showed that a single oral dose of the study medication was well tolerated in healthy volunteers for all three tested dose levels; half of the subjects experienced mild symptoms of dizziness, needle injection site irritation, or muscle soreness.
The relationship between the receptor occupancy in the brain and the amount of the drug in the bloodstream was successfully analyzed. The concentration of the study drug in the blood (plasma) correlated with the dose administered, and maximum plasma concentrations were achieved within 1.00 to 1.42 hours after dosing across all 6 subjects. A positive relationship was observed between the amount of study medicine that bound to the key receptor in the brain (M1AChR) and the study drug concentration in the bloodstream over 24 hours after dosing. Based on the results of this Phase 1 study in healthy volunteeers, the estimated human half-maximal effective concentration (also referred to as the EC50) after a single oral dose of PIPE-307 was 29.1 ng/mL.REC name
London - Surrey Borders Research Ethics Committee
REC reference
21/FT/0088
Date of REC Opinion
27 Jul 2021
REC opinion
Further Information Favourable Opinion