A Study of the Safety, Tolerability, Pharmacokinetics and Food Effect After Single and Multiple Ascending Oral Doses

A Randomised, Double-blind, Placebo-controlled, Study of the Safety, Tolerability, and Pharmacokinetics of AX-158 Following Administration of Single and, Multiple Ascending Oral Doses and Food Effect Sub-study in Healthy Male Volunteers

This is a Phase I Healthy volunteer study with the primary objective to evaluate the safety and pharmacokinetics profile of AX-158. The first part will evaluate single ascending dose administrations. A substudy will be performed as well to evaluate possible impact of food on drug exposure if administered under fasted or fed state. The second part will evaluate multiple ascending dose over 10 days of dosing in fed or fast state depending on the results of the substudy food effect on AX-158.

Study Overview

• Status: Completed
• Conditions: Autoimmune Diseases
• Intervention / Treatment: Drug: AX-158

Detailed Description

This is a phase I, randomised, double-blind , placebo controlled study to investigate the safety, tolerability, and PK of AX-158 in healthy male participants following single (Part A) and multiple (Part C) ascending doses including food effect (Part B).The study will be conducted in three parts (Part A, Part B and Part C). Part A will enrol 8 participants per cohort randomised (3 :1) to receive AX-158 (6 participants) or placebo (2 participants). Part A will follow a single ascending dose (SAD) design with all participants receiving one dose of AX-158 (or placebo) in the fasted state. Part B (Food Effect) will be conducted in 8 participants in a cross-over manner; each participant will receive AX-158 in the fed and fasted state. Part C will enrol 8 participants per cohort randomised to (3 :1) to receive AX-158 (6 participants) or placebo (2 participants). Part C will follow a multiple ascending dose (MAD) design with participants receiving AX-158 (or placebo) once daily for 10 consecutive days, in a fed or fasted state (depending on the outcome of the Part B (Food Effect).

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Merthyr Tydfil, United Kingdom
    • Simbec-Orion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy Male participant, between 18 and 50 years of age, inclusive.
2. Male participant (and partner of childbearing potential) willing to use a highly effective method of contraception in addition to a condom, if applicable (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the participant) from first dose until 4 months after last dose of Investigational Medicinal Product (IMP).
3. Participant with a body mass index (BMI) of 18-30kg/m2. BMI = body weight (kg) / [height (m)]2.
4. Total serum bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN). If total bilirubin is above the upper limit of normal and is then fractionated, direct bilirubin must be within normal limits.
5. Total serum Testosterone levels 2 x above the lower limit of the normal range within 28 days before the first dose administration of the IMP.
6. Participant with a negative urinary drugs of abuse (DOA) screen (including alcohol) test results, determined within 28 days before the first dose administration of the IMP (N.B.: A positive test result may be repeated at the Investigator's discretion).
7. Participant with negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg)) and hepatitis C virus antibody (HCV Ab) test results at Screening.
8. No clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 28 days before first dose of IMP including a QRS interval > 120ms, PR interval > 220ms and QTcF > 450ms.
9. No clinically significant abnormalities in vital signs (e.g., blood pressure/pulse rate, respiration rate and oral temperature) determined within 28 days before first dose of IMP.
10. Participant must be available to complete the study (including all follow-up visits).
11. Participant must satisfy an Investigator about his fitness to participate in the study.
12. Participant must provide written informed consent to participate in the study.
13. Participants with a negative COVID-19 PCR test on admission.

Exclusion Criteria:

1. A clinically significant history of gastrointestinal disorder likely to influence IMP absorption.
2. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 28 days or 5 half-lives (whichever is longer) prior to the first dose of IMP. Occasional use of paracetamol will be allowed.
3. Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular, or metabolic dysfunction.
4. Clinically significant history of previous allergy / sensitivity to AX-158 or any of the excipients contained within the IMP.
5. Participant with history of autoimmune disease, cardiac disease, kidney disease or any food intolerance.
6. Participants with clinically significant abnormal test results for serum biochemistry, haematology and/or urine analyses within 28 days before the first dose administration of the IMP
7. A clinically significant history of drug or alcohol abuse (defined as the consumption of more than 14 units [for male and female participants] of alcohol a week) within the past two years.
8. Inability to communicate well with the Investigators (i.e., language problem, poor mental development, or impaired cerebral function).
9. Participation in a New Chemical Entity (NCE) clinical study within the previous 3 months or five half-lives, whichever is longer, or a marketed drug clinical study within the 30 days or five half-lives, whichever is longer, before the first dose of IMP. (Washout period between studies is defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study).
10. Donation of 450 milliliters or more blood within the 3 months before the first dose of IMP.
11. Vegans, vegetarians, or other dietary restrictions (e.g., restrictions for medical, religious, or cultural reasons, etc), which would prevent participants from consuming a high-fat breakfast or standardised meal.
12. Users of nicotine products i.e., current smokers or ex-smokers who have smoked within the 6 months prior to screening or users of cigarette replacements (i.e., e-cigarettes, nicotine patches or gums).
13. Participants who have received a COVID-19 vaccine injection within 28 days prior to the first dose of IMP.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A - 5mg AX-158; AX-158 oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part A - 10mg AX-158; AX-158 oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part A - 15mg AX-158 or Placebo; AX-158 oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part A - 25mg AX-158; AX-158 oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part A -50mg AX-158; AX-158 oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part B - 15mg AX-158 Fed state; AX-158 oral single dose with food	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part B - 15mg AX-158 Fasted; AX-158 oral single dose without food	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part C - 5mg AX-158; AX-158 oral daily dose for 10 days (Multiple Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part C - 10mg AX-158; AX-158 oral daily dose for 10 days (Multiple Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part C - 15mg AX-158; AX-158 oral daily dose for 10 days (Multiple Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part A - Placebo; Placebo oral Single (Single Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo
Experimental: Part C - Placebo; Placebo oral daily dose for 10 days (Multiple Ascending Dose)	Drug: AX-158; Oral administrations of AX-158; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events	The number of participants with recorded treatment emergent adverse events following single and multiple doses of AX-158.	Up to 10 days of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Plasma Concentration (Cmax)	Values calculated for derived PK parameters following samples obtained at the following timepoints: Part A & B: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, Day 2: 24 hr, 36 hr, Day 3: 48 hr & Day 4: 72 hr post-Day 1 dose Part C: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 1 dose Day 2: 24 hr, 36 hr post-Day 1 dose Day 3: 48 hr post-Day 1 dose Day 4: 72 hr post-Day 1 dose Day 5: prior to dose Day 10: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 10 dose Day 11: 24 hr, 36 hr post-Day 10 dose Day 12: 48 hr post-Day 10 dose Day 13: 72 hr post-Day 10 dose	Up to 13 days following dose administration
Total Plasma Drug Exposure (AUC0-t)	Values calculated for derived PK parameters following samples obtained at the following timepoints: Part A & B: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, Day 2: 24 hr, 36 hr, Day 3: 48 hr & Day 4: 72 hr post-Day 1 dose Part C: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 1 dose Day 2: 24 hr, 36 hr post-Day 1 dose Day 3: 48 hr post-Day 1 dose Day 4: 72 hr post-Day 1 dose Day 5: prior to dose Day 10: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 10 dose Day 11: 24 hr, 36 hr post-Day 10 dose Day 12: 48 hr post-Day 10 dose Day 13: 72 hr post-Day 10 dose	Up to 13 days following dose administration
Terminal Half Life (t1/2)	Values calculated for derived PK parameters following samples obtained at the following timepoints: Part A & B: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, Day 2: 24 hr, 36 hr, Day 3: 48 hr & Day 4: 72 hr post-Day 1 dose Part C: Day 1: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 1 dose Day 2: 24 hr, 36 hr post-Day 1 dose Day 3: 48 hr post-Day 1 dose Day 4: 72 hr post-Day 1 dose Day 5: prior to dose Day 10: pre-dose, 30 mins, 45 mins, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr post-Day 10 dose Day 11: 24 hr, 36 hr post-Day 10 dose Day 12: 48 hr post-Day 10 dose Day 13: 72 hr post-Day 10 dose	Up to 13 days following dose administration

Collaborators and Investigators

• Sponsor: Artax Biopharma Inc
• Collaborators: Simbec-Orion Group
• Investigators: Principal Investigator: Dr Annelize Koch, Simbec-Orion Merthyr Tydfil CF48 4DR, United Kingdom

Publications and helpful links

General Publications

• Borroto A, Reyes-Garau D, Jimenez MA, Carrasco E, Moreno B, Martinez-Pasamar S, Cortes JR, Perona A, Abia D, Blanco S, Fuentes M, Arellano I, Lobo J, Heidarieh H, Rueda J, Esteve P, Cibrian D, Martinez-Riano A, Mendoza P, Prieto C, Calleja E, Oeste CL, Orfao A, Fresno M, Sanchez-Madrid F, Alcami A, Bovolenta P, Martin P, Villoslada P, Morreale A, Messeguer A, Alarcon B. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. Sci Transl Med. 2016 Dec 21;8(370):370ra184. doi: 10.1126/scitranslmed.aaf2140.
• Roy E, Togbe D, Holdorf AD, Trubetskoy D, Nabti S, Kublbeck G, Klevenz A, Kopp-Schneider A, Leithauser F, Moller P, Bladt F, Hammerling G, Arnold B, Pawson T, Tafuri A. Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15529-34. doi: 10.1073/pnas.1009743107. Epub 2010 Aug 13.
• Roy E, Togbe D, Holdorf A, Trubetskoy D, Nabti S, Kublbeck G, Schmitt S, Kopp-Schneider A, Leithauser F, Moller P, Bladt F, Hammerling GJ, Arnold B, Pawson T, Tafuri A. Fine tuning of the threshold of T cell selection by the Nck adapters. J Immunol. 2010 Dec 15;185(12):7518-26. doi: 10.4049/jimmunol.1000008. Epub 2010 Nov 15.
• Gil D, Schamel WW, Montoya M, Sanchez-Madrid F, Alarcon B. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002 Jun 28;109(7):901-12. doi: 10.1016/s0092-8674(02)00799-7.
• Juraske C, Wipa P, Morath A, Hidalgo JV, Hartl FA, Raute K, Oberg HH, Wesch D, Fisch P, Minguet S, Pongcharoen S, Schamel WW. Anti-CD3 Fab Fragments Enhance Tumor Killing by Human gammadelta T Cells Independent of Nck Recruitment to the gammadelta T Cell Antigen Receptor. Front Immunol. 2018 Jul 9;9:1579. doi: 10.3389/fimmu.2018.01579. eCollection 2018.
• Borroto A, Arellano I, Blanco R, Fuentes M, Orfao A, Dopfer EP, Prouza M, Suchanek M, Schamel WW, Alarcon B. Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. J Immunol. 2014 Mar 1;192(5):2042-53. doi: 10.4049/jimmunol.1203414. Epub 2014 Jan 27.
• Borroto A, Arellano I, Dopfer EP, Prouza M, Suchanek M, Fuentes M, Orfao A, Schamel WW, Alarcon B. Nck recruitment to the TCR required for ZAP70 activation during thymic development. J Immunol. 2013 Feb 1;190(3):1103-12. doi: 10.4049/jimmunol.1202055. Epub 2012 Dec 24.
• Lettau M, Pieper J, Gerneth A, Lengl-Janssen B, Voss M, Linkermann A, Schmidt H, Gelhaus C, Leippe M, Kabelitz D, Janssen O. The adapter protein Nck: role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes. Protein Sci. 2010 Apr;19(4):658-69. doi: 10.1002/pro.334.
• Yiemwattana I, Ngoenkam J, Paensuwan P, Kriangkrai R, Chuenjitkuntaworn B, Pongcharoen S. Essential role of the adaptor protein Nck1 in Jurkat T cell activation and function. Clin Exp Immunol. 2012 Jan;167(1):99-107. doi: 10.1111/j.1365-2249.2011.04494.x.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2021
• Primary Completion (Actual): November 16, 2022
• Study Completion (Actual): December 3, 2022

Study Registration Dates

• First Submitted: December 2, 2021
• First Submitted That Met QC Criteria: January 17, 2022
• First Posted (Actual): February 1, 2022

Study Record Updates

• Last Update Posted (Actual): August 23, 2024
• Last Update Submitted That Met QC Criteria: August 21, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases
• Other Study ID Numbers: AX-158-101

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