Safety,PK/PD, Food Effect Study of Orally Administered HM71224 in Healthy Adult Male Volunteers

A Phase1 Study, to Determine the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of Single and Multiple Doses of Orally Administered HM71224 in Healthy, Adult Male Volunteers

HM71224 is a potent small molecule inhibitor of Bruton's tyrosine kinase (BTK). BTK is a member of the Tec family of non-receptor protein tyrosine kinases. BTK is mostly expressed in hematopoietic cells such as B cells, mast cells and macrophages. BTK plays key roles in multiple cell signaling pathways including B-Cell Receptor (BCR) and Fc receptor (FcR) signaling cascades and is an essential mediator not only in B-cell dependent but also in myeloid cell dependent inflammatory arthritis. HM71224 has been selected as a novel therapeutic agent for the treatment of autoimmune diseases such as rheumatoid arthritis (RA).

In view of the above, further development of HM71224 for the treatment of RA is warranted. In this first-in-man (FIM) study, a single and multiple dose escalation design will be employed, in which the primary objective is to evaluate the safety and tolerability of the compound. The biomarkers included as pharmacodynamic (PD) variables are chosen as they are indicators for any effects of HM71224 on the expected mode of action (pBTK, pPLCγ, and pERK).

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: HM71224 single ascending dose; Drug: HM71224 food effect; Drug: HM71224 Multiple ascending dose

Detailed Description

Primary objective

• To evaluate the safety and tolerability, and if possible maximum tolerated dose (MTD) of HM71224 after single and multiple ascending dose administration in healthy subjects.

Secondary objective

• To determine the PK of HM71224 and selected metabolites (M1 and M2) following single and multiple oral dose administration of HM71224.
• To assess the PD effects of HM71224 on the biomarkers pBTK, pPLCγ, and pERK.
• To assess whether the PK of HM71224 is affected by food.

• Study Type: Interventional
• Enrollment (Anticipated): 62
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands
    • PRA Clinical research center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Gender : male
2. Age : 18-65 years, inclusive
3. BMI : 18.5 - 30.0 kg/m2
4. Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks), and grapefruit (juice) from 48 h prior to entry in the clinical research center until discharge
5. Medical history without major pathology
6. Normal resting supine blood pressures and pulse rate, showing no clinically relevant deviations as judged by the MI
7. Computerized (12-lead) electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the MI
8. Willingness to use adequate contraception from the time of dosing until 90 days after the follow-up visit
9. All values for hematology and for clinical chemistry tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the MI
10. Willingness to sign the written Informed Consent Form (ICF)

Exclusion Criteria:

1. Previous participation in the current study
2. Evidence of clinically relevant pathology
3. Mental handicap
4. History of relevant drug and/or food allergies
5. Regular/routine treatment with non-topical medications within 30 days prior to entry into the clinical research center
6. Use of tobacco products within 60 days prior to drug administration
7. History of alcohol abuse or drug addiction (including soft drugs like cannabis products)
8. Use of concomitant medication, except for acetaminophen (paracetamol), which is allowed up to 3 days before entry into the clinical research center. Multivitamins and vitamin C are allowed up to 7 days before entry into the clinical research center. All other medication (including over the counter medication, health supplements, and herbal remedies such as St. John's Wort extract) must have been stopped at least 14 days prior to entry into the clinical research center. The use of a limited amount of acetaminophen during the study is permitted.
9. Participation in a drug study within 60 days prior to drug administration. Participation in more than 3 other drug studies in the 10 months preceding the start of this study (this is the first administration of study drug).
10. Donation of more than 50 mL of blood within 60 days prior to drug administration. Donation of more than 1.5 liters of blood in the 10 months preceding the start of this study (this is the first administration of study drug).
11. Positive drug screen (opiates, methadone, cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines, and alcohol)
12. Intake of more than 24 units of alcohol per week (one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits)
13. Positive screen on Hepatitis B Surface Antigen (HBsAg), anti-Hepatitis C Virus (HCV) or anti-Human Immunodeficiency Virus (HIV) 1/2
14. Illness within 5 days prior to the first drug administration
15. Non-willingness to consume the FDA breakfast (Part B only)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A Period 2; 40mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: Treatment B Period1; 20mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: Treatment A Period1; 10mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: Treatment B Period2; 80mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: TreatmentA Period3; 160mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: TreatmentB Period3; 200mg HM71224 single dose	Drug: HM71224 single ascending dose
EXPERIMENTAL: Food effect period1; active 4subjects + placebo 4subjects	Drug: HM71224 food effect
EXPERIMENTAL: Food effect period2; active 4subjects + placebo 4subjects	Drug: HM71224 food effect
EXPERIMENTAL: TreatmentC; HM71224 Xmg multiple dose for 14days	Drug: HM71224 Multiple ascending dose
EXPERIMENTAL: TreatmentD; HM71224 Ymg 14days multiple dose	Drug: HM71224 Multiple ascending dose
EXPERIMENTAL: TreatmentE; HM71224 Zmg 14days multiple dose	Drug: HM71224 Multiple ascending dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate safety and tolerability	Number of participants with AE occurrence, clinically significant clinical lab,vital sign, and/or ECG change.	3days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine plasma PK parameters	Cmax, C trough, tmax, kel, t1/2, AUC, CL/F, Vz, Rac, Ae, CLr, Fe% of HM71224 and selected metabolites M1, M2 following single and multiple oral dose administration of HM71224	3days
To determine urine PK parameters	Cmax, C trough, tmax, kel, t1/2, AUC, %AUC, CL/F, Vz, Rac, Ae, CLr, Fe% of of HM71224 and selected metabolites M1, M2 following single and multiple oral dose administration of HM71224	3days

Collaborators and Investigators

• Sponsor: Hanmi Pharmaceutical Company Limited
• Investigators: Principal Investigator: Salah Hadi, MD MSc, PRA Health Sciences

Publications and helpful links

General Publications

• Byun JY, Koh YT, Jang SY, Witcher JW, Chan JR, Pustilnik A, Daniels MJ, Kim YH, Suh KH, Linnik MD, Lee YM. Target modulation and pharmacokinetics/pharmacodynamics translation of the BTK inhibitor poseltinib for model-informed phase II dose selection. Sci Rep. 2021 Sep 21;11(1):18671. doi: 10.1038/s41598-021-98255-7.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): November 1, 2014
• Study Completion (ACTUAL): November 1, 2014

Study Registration Dates

• First Submitted: January 7, 2013
• First Submitted That Met QC Criteria: January 9, 2013
• First Posted (ESTIMATE): January 10, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): May 18, 2015
• Last Update Submitted That Met QC Criteria: May 15, 2015
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: 12-HM71224-101