The purpose of the study is to assess the safety, tolerability and the pharmacokinetics (PK) of AZD4063 after single and multiple dose administration in participants with phospholamban (PLN) R14del dilated cardiomyopathy.
This is a Phase 1, first in human, unblinded, ascending dose study which will be comprised of: 3 single ascending dose (SAD) cohorts, 3 multiple ascending dose (MAD) cohorts and optional cohorts. The SAD part of the study will assess the single doses of AZD4063 across 3 cohorts. It will consist of: * A screening period * A treatment period: The participants will receive a single dose of AZD4063 by subcutaneous (SC) injection * A follow-up period The MAD part of the study will initiate on receiving the data from SAD cohort with available safety, PK and pharmacodynamics (PD) data from all cohorts. This part of the study will consist of: * A screening period * A treatment period: The participants will receive multiple doses of AZD4063 by SC injection * A follow-up period Optional cohorts may be added based on emerging safety, PK and PD data of the SAD and MAD cohorts.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
AZD4063 will be administered in the SAD and MAD part of the study as solution for injection via subcutaneous route of administration.
Research Site
Amsterdam, Netherlands
NOT_YET_RECRUITINGResearch Site
Groningen, Netherlands
RECRUITINGResearch Site
Rotterdam, Netherlands
RECRUITINGNumber of participants with adverse events (AEs)
The safety and tolerability of AZD4063 following the SC administration of single and repeated doses in participants with PLN R14del dilated cardiomyopathy
Time frame: Cohort 1 (SAD): From Day 1 to Day 109, Cohorts 2 and 3 (SAD) From Day 1 to Day 99; For Cohorts 1,2 and 3 (MAD): Day 1 to Day 155
Area under plasma concentration-time curve from 0 to infinity (AUCinf)
The AUCinf of single and repeated dose of AZD4063 following SC administration will be evaluated.
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Area under the plasma concentration-curve from 0 to the last quantifiable concentration (AUClast)
The AUClast of single and repeated dose of AZD4063 following SC administration will be evaluated.
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Maximum plasma drug concentration (Cmax)
The Cmax of single and repeated dose of AZD4063 following SC administration will be evaluated.
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Renal clearance (CLR)
The CLR of the single and repeated dose of AZD4063 following SC administration will be evaluated.
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Cumulative amount of analyte excreted (Ae)
The Ae of single and repeated dose of AZD4063 following SC administration will be evaluated
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Research Site
Utrecht, Netherlands
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Fraction of dose excreted unchanged in urine (Fe)
The Fe of single and repeated dose of AZD4063 following SC administration will be evaluated
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141
Change in endomyocardial biopsy PLN messenger ribonucleic acid (mRNA levels) from baseline to estimated peak knockdown and estimated return-to-baseline
The effects of single and repeated doses of AZD4063 on knockdown of PLN mRNA will be evaluated.
Time frame: Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141