Leucettinib-21 First-in-Human Phase 1 in Healthy Volunteers and Subjects With Down Syndrome and Alzheimer's Disease (LEUCETTA)

Randomized, Double-Blind, Placebo-Controlled Phase 1 Study to Evaluate Safety, Tolerability, PK/PD of SAD, MAD and Food Effect of Leucettinib-21 in Healthy Male Subjects, and Single Dose in Subjects With Down Syndrome or Alzheimer's Disease

Leucettinib-21 First-in-Human Phase 1 Study in 4 Parts: Single (Part 1) and Multiple (Part 3) Ascending Doses, and Food-Effect (Part 2) in Healthy Subjects, and Single Dose (Part 4) in People with Down Syndrome (DS) and Alzheimer's Disease (AD).

For Parts 1, 3 and 4, safety and tolerability of an oral administration of Leucettinib-21 will be assessed as primary objectives. Pharmacokinetics and pharmacodynamic biomarkers will be investigated as secondary objectives.

For Part 2, the effect of high fat meal will be evaluated on the pharmacokinetics parameters after an oral administration of Leucettinib-21.

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers; Down Syndrome; Alzheimer's Disease
• Intervention / Treatment: Drug: Leucettinib-21

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Laurent MEIJER, Dr; Phone Number: +33(0)608605834; Email: meijer@perha-pharma.com
• Study Contact Backup: Name: Emilie CHRETIEN, Dr; Phone Number: +33(0)222554572; Email: chretien@perha-pharma.com

Study Locations

• France
  • Gières, France, 38610
    • Recruiting
    • Eurofins Optimed
    • Contact: Yves DONAZOLLO, MD, MSc; Phone Number: +33(0)438374750; Email: YvesDonazzolo@eurofins.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria for Parts 1, 2 & 3:

1. Healthy male aged to 18-45 years inclusive;
2. Must agree to adhere to the contraception requirements: use of condom by the male subject plus an effective method of contraception for the subject partner of childbearing potential from the time of informed consent signature up to 4 months after last IMP administration. Highly effective method of birth control such as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intra uterine devices (IUDs), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle);
3. Non-smoker subject or smoker of not more than 5 cigarettes a day;
4. Body Mass Index (BMI) between 18.5 and 28,0 (kg/m2) inclusive, with body weight between 60 and 100 kg inclusive, at Screening and Day -1;
5. Considered as healthy after a comprehensive clinical assessment (detailed medical history and complete physical examination);

6. Normal Blood Pressure (BP), oxygen saturation and Heart Rate (HR) at the screening visit after 10 minutes in supine position:

   • 95 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg,
   • 50 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg,
   • 45 bpm ≤ HR ≤ 90 bpm,
   • Or considered NCs by investigators;

7. Normal ECG recording on a 12-lead ECG at the screening visit:

   • 120 ≤ PR < 210 ms,
   • QRS < 120 ms,
   • QTcf ≤ 430 ms for male,
   • No sign of any trouble of sinusal automatism,
   • Or considered NCs by investigators;
8. Laboratory parameters within the normal range of the laboratory (hematology, hemostasis and blood biochemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non-relevant by the Investigator;
9. Normal dietary habits;
10. Signing a written informed consent prior to selection;
11. Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

Non-inclusion criteria for Parts 1, 2 & 3:

1. Any history or presence of cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, hematological, neurologic, psychiatric, systemic, infectious disease, endocrine, immunologic, dermatologic or/and any relevant disease;
2. Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician;
3. Symptomatic hypotension whatever the decrease of the blood pressure or asymptomatic postural hypotension defined by a decrease in SBP equal to or greater than 20 mmHg or DBP equal to or greater than 10 mmHg within two minutes of changing from supine to standing position;
4. Positive urine drug testing or alcohol testing at Screening or Day -1;
5. Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C Virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV) 1 or 2 tests;
6. Clinical symptoms suspected of acute infectious disease within 2 weeks before the first study drug administration;
7. Any drug intake (except paracetamol) during the month prior to the first administration;
8. History or presence of drug or alcohol abuse (alcohol consumption > 40 grams / day);
9. Blood donation (including as part of a clinical trial) in the 2 months before administration;
10. General anaesthesia in the 3 months before administration;
11. Inability to abstain from intense muscular effort;
12. No possibility of contact in case of emergency;
13. Excessive consumption of beverages with xanthine bases (>4cups or glasses/day);
14. Subject who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development;
15. Persons deprived of their liberty by judicial or administrative decision; persons under coercive psychiatric care; adults under legal protection (guardianship/trusteeship); persons under court protection;
16. Subject in the exclusion period of a previous study and within less than 4 weeks or 5 half-lives of the last administration of an experimental drug;
17. Administrative or legal supervision;
18. Subject who would receive more than 6000 euros as indemnities for his participation in biomedical research within the 12 last months, including the indemnities for the present study.

Main inclusion criteria for Part 4:

1. Down Syndrome and Alzheimer's disease male individuals
2. Must agree to adhere to the contraception requirements
3. Non-smoker subject or smoker of not more than 5 cigarettes a day;
4. Patient and/or their legal representatives (if applicable) are able to understand and provide written informed consent before starting any study-related activity according investigator judgment;
5. Patient is able to participate fully in the study, be sufficiently proficient in the official language of the country in which they live, and be able to carry out study evaluations reliably;
6. Blood Pressure (BP), oxygen saturation and Heart Rate (HR) at the screening visit after 10 minutes in supine position considered normal according the population or judged clinically non-relevant by investigators;
7. ECG recording on a 12-lead ECG at the screening visit considered normal according the population or judged clinically non-relevant by investigators;
8. Laboratory parameters within the normal range of the laboratory (hematology, hemostasis and blood biochemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non-relevant by the Investigator according the population;
9. Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research;
10. Presence of an accompanying caregiver at the end of the study.

Main exclusion criteria for Part 4: :

1. Any relevant history or presence of significant diseases that would interfere with the assessment according the population except stabilized pathology with associated treatment for more than 3 months and known in the medical history;
2. Patients considered unable to complete study assessments, according the investigator judgment;
3. History of cancer in the past 5 years;
4. History of inflammatory disease with potential for central nervous system involvement;
5. Positive urine drug testing or alcohol testing at Screening or Day -1;
6. Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C Virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV) 1 or 2 tests;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 : Single Ascending Doses in Healthy Volunteers; A total of 48 healthy male volunteers will be randomized into six consecutive single ascending dose cohorts of 8 subjects, 6 receiving one dose of Leucettinib-21 and 2 receiving placebo.	Drug: Leucettinib-21; See arm's description.
Experimental: Part 2 : Food-Effect in Healthy Volunteers; A total of 12 healthy male volunteers will be randomly assigned to one of two sequences in this cross over study part. All subjects will receive the same one dose of Leucettinib-21 in each sequence.	Drug: Leucettinib-21; See arm's description.
Experimental: Part 3 : Multiple Ascending Doses over 14 days in Healthy Volunteers; A total of 36 healthy male volunteers will be randomized into three consecutive multiple ascending doses cohorts of 12 subjects, 9 receiving one dose of Leucettinib-21 and 3 receiving placebo everyday for 14 days.	Drug: Leucettinib-21; See arm's description.
Experimental: Part 4 : Single Dose in People with Down Syndrome and Alzheimer's Disease; A total of 12 people with Down Syndrome and 12 people with Alzheimer's Disease will receive the same one dose of Leucettinib-21.	Drug: Leucettinib-21; See arm's description.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 : Safety and tolerability of Leucettinib-21 after single administration at 6 increasing doses in healthy male subjects.	Assessment of systemic tolerability and safety:	Part 1 : Up to 8 days following administration
Part 2 : Effect of food on the PK parameters after an oral administration of Leucettinib-21 in healthy male subjects in high fat breakfast condition vs. under fasted conditions.	Plasma PK assessments	Part 2 : Up to 8 days following administration
Part 3 : Safety and tolerability of Leucettinib-21 after multiple administration at 3 increasing doses in healthy male subjects	Assessment of systemic tolerability and safety	Part 3 : Up to 21 days following administration
Part 4 : Safety and tolerability of Leucettinib-21 after single administration at 1 dose in Down Syndrome individuals and patients with Alzheimer's disease	Assessment of systemic tolerability and safety	Part 4 : Up to 8 days following administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK of Leucettinib-21	Assessment of the plasmatic PK of Leucettinib-21	Up to 24 hours following Leucettinib-21 administration
PD of Leucettinib-21	Change in the proteome following Leucettinib-21 administration assessed by phosphoproteomics	Up to 4 hours following Leucettinib-21 administration
Activity of DYRK1A	Change in DYRK1A activity following Leucettinib-21 administration assessed in Peripheral Blood Mononuclear Cells	Up to 8 hours following Leucettinib-21 administration

Collaborators and Investigators

• Sponsor: Perha Pharmaceuticals
• Collaborators: Fondation Jérôme Lejeune; European Innovation Council; France 2030 program

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2024
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: December 20, 2023
• First Submitted That Met QC Criteria: January 4, 2024
• First Posted (Actual): January 16, 2024

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Intellectual Disability; Dementia; Tauopathies; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Alzheimer Disease; Down Syndrome
• Other Study ID Numbers: OP112522; 2023-507075-22 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No