A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy
- Conditions
- Dilated Cardiomyopathy
- Interventions
- Drug: AZD4063
- Registration Number
- NCT07241104
- Lead Sponsor
- AstraZeneca
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 31
- Participants must be 18 to 80 years of age inclusive, at the time of Screening
- Participants with pre-existing positive screening for R14 del PLN mutation
- Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography
- Participants with New York Heart Association (NYHA) function class I-III
- Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure
- Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D)
- Participants with Body mass index (BMI) within the range 18-35 kg/m2
- Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception
- All females must have a negative pregnancy test at the Screening Visit.
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Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
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Known to have tested positive for Human immunodeficiency virus (HIV)
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Any known genetic mutation associated with hereditary electrical or structural disease
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Congenital long QT syndrome
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QTcF < 350 ms
-
Known Short QT syndrome (SQTS) or family history of SQTS
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Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months
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Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator
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History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% > stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting)
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Routinely scheduled outpatient intravenous infusions for heart failure
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Uncontrolled hypertension
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Significant primary valvular disease
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Congenital heart disease
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Left ventricular wall thickness of > 13 mm or with any relative with hypertrophic cardiomyopathy (HCM)
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Recent acute presentation of myocarditis
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Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis)
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Alcohol consumption in excess
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Any laboratory values with the following deviations:
- Alanine Transaminase >2 upper normal limit (ULN)
- Aspartate Transaminase >2 ULN
- Total bilirubin > 2 x ULN
- Estimated GFR < 30 mL/min/1.73 m2
- Hemoglobin <10g/dL
-
Any vital sign values with the following deviations at Screening
- Systolic blood pressure > 160 mmHg
- Diastolic blood pressure > 100 mmHg
- Pulse rate > 100 beats per minute
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Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM)
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History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity
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Any history of cardiotoxic drug exposure with documented cardiomyopathy
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Noncardiac condition that limits expected lifespan to less than 1 year
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Participation in another clinical study with a study intervention administered in the last 3 months
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Participants with a known hypersensitivity to AZD4063
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Participants who are part of a gene therapy trial
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1 (SAD): Dose 1 of AZD4063 AZD4063 Participants will receive Dose 1 of AZD4063 via SC injection in Cohort 1 of SAD. Cohort 2 (SAD): Dose 2 of AZD4063 AZD4063 Participants will receive Dose 2 of AZD4063 via SC injection in Cohort 2 of SAD. Cohort 3 (MAD): Dose 6 of AZD4063 AZD4063 Participants will receive Dose 6 of AZD4063 via SC injection in Cohort 3 of MAD. Cohort 3 (SAD): Dose 3 of AZD4063 AZD4063 Participants will receive Dose 3 of AZD4063 via SC injection in Cohort 3 of SAD. Optional Cohort 1 (SAD): Dose 7 of AZD4063 AZD4063 Participants will receive Dose 7 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings. Cohort 1 (MAD): Dose 4 of AZD4063 AZD4063 Participants will receive Dose 4 of AZD4063 via SC injection in Cohort 1 of MAD. Cohort 2 (MAD): Dose 5 of AZD4063 AZD4063 Participants will receive Dose 5 of AZD4063 via SC injection in Cohort 2 of MAD. Optional Cohort 2 (SAD): Dose 8 of AZD4063 AZD4063 Participants will receive Dose 8 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings. Optional Cohort 1 (MAD): Dose 9 of AZD4063 AZD4063 Participants will receive Dose 9 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings. Optional Cohort 2 (MAD): Dose 10 of AZD4063 AZD4063 Participants will receive Dose 10 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings.
- Primary Outcome Measures
Name Time Method Number of participants with adverse events (AEs) 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 The safety and tolerability of AZD4063 following the SC administration of single and repeated doses in participants with PLN R14del dilated cardiomyopathy
- Secondary Outcome Measures
Name Time Method Renal clearance (CLR) 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 The CLR of the single and repeated dose of AZD4063 following SC administration will be evaluated.
Cumulative amount of analyte excreted (Ae) 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 The Ae of single and repeated dose of AZD4063 following SC administration will be evaluated
Fraction of dose excreted unchanged in urine (Fe) 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 The Fe of single and repeated dose of AZD4063 following SC administration will be evaluated
Area under plasma concentration-time curve from 0 to infinity (AUCinf) 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 The AUCinf of single and repeated dose of AZD4063 following SC administration will be evaluated.
Area under the plasma concentration-curve from 0 to the last quantifiable concentration (AUClast) 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 The AUClast of single and repeated dose of AZD4063 following SC administration will be evaluated.
Maximum plasma drug concentration (Cmax) 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 The Cmax of single and repeated dose of AZD4063 following SC administration will be evaluated.
Change in endomyocardial biopsy PLN messenger ribonucleic acid (mRNA levels) from baseline to estimated peak knockdown and estimated return-to-baseline 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 The effects of single and repeated doses of AZD4063 on knockdown of PLN mRNA will be evaluated.