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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: HM71224 single ascending dose
* Drug: HM71224 food effect
* Drug: HM71224 Multiple ascending dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gender : male Age : 18-65 years, inclusive BMI : 18.5 - 30.0 kg/m2 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 Medical history without major pathology Normal resting supine blood pressures and pulse rate, showing no clinically relevant deviations as judged by the MI Computerized (12-lead) electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the MI Willingness to use adequate contraception from the time of dosing until 90 days after the follow-up visit 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 Willingness to sign the written Informed Consent Form (ICF) Exclusion Criteria: Previous participation in the current study Evidence of clinically relevant pathology Mental handicap History of relevant drug and/or food allergies Regular/routine treatment with non-topical medications within 30 days prior to entry into the clinical research center Use of tobacco products within 60 days prior to drug administration History of alcohol abuse or drug addiction (including soft drugs like cannabis products) 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. 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). 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). Positive drug screen (opiates, methadone, cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines, and alcohol) 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) Positive screen on Hepatitis B Surface Antigen (HBsAg), anti-Hepatitis C Virus (HCV) or anti-Human Immunodeficiency Virus (HIV) 1/2 Illness within 5 days prior to the first drug administration Non-willingness to consume the FDA breakfast (Part B only)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis