A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of KYN-5356 in Healthy Subjects Aged 18 to 55 Years

A First in Human Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of KYN-5356 in Adult, Healthy Subjects

This first-in-human clinical trial with a randomized, double-blind, placebo-controlled, dose-escalation study design is regarded as standard to test the safety, tolerability, and pharmacokinetics of KYN-5356.

The study comprises 3 parts:

Part 1: Single Ascending Dose study Part 2: Multiple Ascending Dose study Part 3: Food Effect study

The aim of Parts 1 and 2 of the study is to evaluate the safety and tolerability following single and multiple ascending doses of KYN-5356.

The secondary aim is to evaluate the pharmacokinetics (PK) of escalating single and multiple doses of KYN-5356. In Part 2, cerebrospinal fluid will be sampled to explore PK and pharmacodynamic effects of KYN-5356.

The potential effect of food intake on the disposition of KYN-5356 following a single oral dose will be evaluated in Part 3. Part 3 is an open-label, randomized, 2 period, 2 sequence design.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Cognitive Dysfunction
• Intervention / Treatment: Drug: KYN-5356; Drug: placebo

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Hakop Gevorkyan, MD, MBA; Phone Number: +1 818-254-1600; Email: Mike.Proshyan@parexel.com

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Recruiting
      • Parexel Los Angeles Early Phase Clinical Unit
      • Contact: Hakop Gevorkyan, MD, MBA
      • Principal Investigator: Hakop Gevorkyan, MD, MBA

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subject understands the study procedures and agrees to participate by providing written informed consent prior to any study procedures.
• Subject is between 18 and 55 years of age (inclusive), on the date of signing the informed consent form.
• Subject has a body mass index between 18 and 30 kg/m2, inclusive.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential or a woman of childbearing potential who agrees to follow the contraceptive guidance (highly effective birth control method) from Screening until end of the study. Note: Males should use appropriate contraceptive method from Screening until end of the study.
• Subject is judged to be in good health by the Principal Investigator based upon the results of a medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory safety tests.
• Subject is willing to adhere to the study requirements and restrictions.

Exclusion Criteria:

• Subject has positive serology for HBsAg, HCV, or HIV, or history of hepatitis from any cause with the exception of hepatitis A that was resolved at least 3 months prior to first dosing of the Investigational Medicinal Product.
• Subject has any illness judged by the Principal Investigator as clinically significant, in the 3 months prior to first dosing of the Investigational Medicinal Product.
• Subject has a suicidality score of "yes" on item 4 or item 5 of the suicidal ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the suicidal behavior section, except for the "Non-Suicidal Self-Injurious Behavior" (item also included in the suicidal behavior section), if this behavior occurred in the past 2 years.
• Subject has a history or current sign or symptom of psychiatric or neurologic disease.
• Subject has a history of head trauma in the past year and/or current seizures.
• Subject is a smoker (use of tobacco products in the previous 3 months from Screening) or uses nicotine or nicotine-containing products and has a positive urine cotinine test at Screening or Admission.
• Subject has a history of alcohol and/or illicit drug abuse within 2 years of entry or has a positive screening test for alcohol and/or drugs of abuse at Screening or Admission.
• Subject consumes caffeine containing beverages exceeding 500 mg caffeine per day (5 cups of coffee) during the off-site days during the study.
• Subject has regular excessive consumption of alcohol within 6 months prior to Screening (7 drinks/week for females, 14 drinks/week for males where 1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor).
• Subject has a history or current sign or symptom of a cardiovascular, renal, or metabolic bone disease or disease of bone remodeling, or any history of endocrine disease, including an abnormal laboratory result for pre-specified clinical laboratory safety parameters related to these conditions.
• Subject has a history or presence of clinically significant abnormalities detected on 12-lead ECG of either rhythm or conduction. A first-degree atrioventricular block will not be considered as a significant abnormality. Subject has QTcF > 450 ms (mean values per parameter will be considered) detected on the 12-lead ECG at Screening or Admission.
• Presence or sequelae of gastrointestinal, liver, kidney (creatinine clearance <85 mL/min, using the Cockcroft-Gault formula), or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs at Screening or Admission.
• Subject has a history of malignancy within the past 5 years prior to Screening with the exception of excised and curatively treated non-metastatic cell carcinoma of the skin which is considered cured with minimal risk of recurrence.
• Subject tests positive for SARS-CoV-2 at Admission.
• Additional exclusion criteria for subjects in the MAD Part in view of lumbar puncture for cerebrospinal fluid (CSF) sampling and the ERP assessment.
• Subject uses any prescription drugs, herbal supplements, within 4 weeks prior to initial dosing, and/or over-the-counter medication, dietary supplements (vitamins included) within 2 weeks prior to initial dosing, other than what is allowed per protocol.
• Subject received vaccination 1 month before admission or plans to receive vaccination during the study.
• Use of other investigational drugs/devices within 5 half-lives of the drug from enrollment (time of the subject signing the informed consent form), or within 30 days, whichever is longer.
• Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing.
• Plasma donation (> 200 mL) within 7 days prior to first dosing.
• Resting vital signs at Screening (blood pressure > 140/90 mmHg, heart rate > 90 beats per minute, respiratory rate > 20 breaths per minute, and clinically significant elevated body temperature), or any clinically significant abnormalities in vital signs requiring intervention in the opinion of the Investigator. Up to 2 repeat measurements are permitted to confirm eligibility.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAD Cohort 1; Single-Ascending Dose Cohort 1. Intervention: KYN-5356 A mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: SAD Cohort 2; Single-Ascending Dose Cohort 2. Intervention: KYN-5356 B mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: SAD Cohort 3; Single-Ascending Dose Cohort 3. Intervention: KYN-5356 C mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: SAD Cohort 4; Single-Ascending Dose Cohort 4. Intervention: KYN-5356 D mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: SAD Cohort 5; Single-Ascending Dose Cohort 5. Intervention: KYN-5356 E mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: SAD Cohort 6; Single-Ascending Dose Cohort 6. Intervention: KYN-5356 F mg or placebo, single dose, oral tablet	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: MAD Cohort 1; Multiple-Ascending Dose Cohort 1. Intervention: KYN-5356 G mg or placebo, oral tablets for 7 days	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: MAD Cohort 2; Multiple-Ascending Dose Cohort 2. Intervention: KYN-5356 H mg or placebo, oral tablets for 7 days	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: MAD Cohort 3; Multiple-Ascending Dose Cohort 3. Intervention: KYN-5356 I mg or placebo, oral tablets for 7 days	Drug: KYN-5356; KYN-5356, oral tablet; Drug: placebo; placebo, oral tablet
Experimental: Food Effect Cohort; Intervention: KYN-5356 J mg, single dose, oral tablets in fasted or fed state.	Drug: KYN-5356; KYN-5356, oral tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events	All cohorts	Initiation of dosing through the last follow-up visit after the last dose, approximately 8 days in the MAD and 5 days after dosing in the SAD and the Food Effect parts of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameters: Cmax [SAD]	Maximum plasma concentration determined directly from the concentration-time profile. For each dose in SAD part.	Baseline (predose) through 72 hours post dosing
PK parameters: tmax [SAD]	Time of maximum plasma concentration determined directly from the concentration-time profile. For each dose in SAD part.	Baseline (predose) through 72 hours post dosing
PK parameters: AUCinf [SAD]	Area under the concentration-time curve from pre-dose (time 0) extrapolated to infinite time calculated using the linear-log trapezoidal rule. For each dose in SAD part.	Baseline (predose) through 72 hours post dosing
PK parameters: Cmax on Day 1 [MAD]	Maximum plasma concentration determined directly from the concentration-time profile. For each dose in MAD part	Baseline (predose) through 24 hours post first dosing
PK parameters: tmax on Day 1 [MAD]	Time of maximum plasma concentration determined directly from the concentration-time profile. For each dose in MAD part.	Baseline (predose) through 24 hours post first dosing
PK parameters: Cmax,ss [MAD]	Maximum observed plasma concentration during a dosing interval at steady state. For each dose in MAD part.	Baseline (predose) through 72 hours post dosing on Day 7.
PK parameters: tmax,ss [MAD]	Time of maximum plasma concentration determined directly from the concentration-time profile at steady state. For each dose in MAD part.	Baseline (predose) through 72 hours post dosing on Day 7.
PK parameters: AUCinf [MAD]	Area under the concentration-time curve from pre-dose (time 0) extrapolated to infinite time calculated using the linear-log trapezoidal rule. For each dose in MAD part.	Baseline (predose) through 72 hours post dosing on Day 7.
PK parameters: AUCtau on Days 1 and 7 [MAD]	Area under the concentration-time curve over the dosing interval. For each dose in MAD part	Baseline (predose) through 72 hours post dosing on Day 7.

Collaborators and Investigators

• Sponsor: Kynexis B.V.
• Collaborators: Parexel
• Investigators: Principal Investigator: Hakop Gevorkyan, MD, MBA, Parexel

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2023
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: December 20, 2023
• First Submitted That Met QC Criteria: January 16, 2024
• First Posted (Actual): January 25, 2024

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Cognition Disorders; Schizophrenia; Cognitive Dysfunction
• Other Study ID Numbers: KYN5356-CL-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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