Mydicar (AAV1/SERCA2a) / Eiger, Armata, Theragene - LARVOL DELTA

Medera Receives DSMB Clearance to Initiate Phase 2 Portion of MUSIC-HFrEF Phase 1b/2 Trial for SRD-001 Gene Therapy in Heart Failure with Reduced Ejection Fraction (GlobeNewswire) - "Medera Inc...today announced that the independent Data and Safety Monitoring Board (DSMB) has completed its planned review of the MUSIC-HFrEF Phase 1b/2 clinical trial data, recommending the completion of the Phase 1b portion and clearance to initiate the Phase 2 portion of the trial evaluating the gene therapy candidate SRD-001 in patients with heart failure with reduced ejection fraction (HFrEF)...The DSMB recommendation is based on the review of data from all nine patients in the Phase 1 portion of the MUSIC-HFrEF trial, an open-label study investigating SRD-001...The trial is expected to commence patient enrollment in the second quarter of 2025."

DSMB • Enrollment status • Heart Failure

Medera Completes Patient Dosing in Phase 1/2a MUSIC-HFrEF Trial of SRD-001 Gene Therapy for Heart Failure with Reduced Ejection Fraction (GlobeNewswire) - "Medera Inc...announced that patient dosing has been completed in its MUSIC-HFrEF Phase 1/2a clinical trial of the gene therapy candidate SRD-001 in patients with heart failure with reduced ejection fraction (HErEF)....The MUSIC-HFrEF trial is an open-label, uncontrolled study investigating SRD-001 across two cohorts with six patients dosed with SRD-001 in Cohort A (low-dose 3x10¹³ vg per patient) and three patients dosed in Cohort B (high-dose 4.5x10¹³ vg per patient)."

Trial status • Heart Failure

MUSIC-DMD: Modulation of SERCA2a of Intra-Myocytic Calcium Trafficking in Cardiomyopathy Secondary to Duchenne Muscular Dystrophy (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Sardocor Corp. | Not yet recruiting ➔ Recruiting | Trial completion date: Feb 2030 ➔ Oct 2030 | Trial primary completion date: Feb 2027 ➔ Oct 2027

Enrollment open • Trial completion date • Trial primary completion date • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

A Phase 1 Clinical Trial of High Dose AAV1.SERCA2a in Patients with Heart Failure: Modulation of SERCA2a of Intra-myocytic Calcium trafficking in Heart Failure with Reduced Ejection Fraction (MUSIC-HFrEF) (ASGCT 2024) - "The early clinical efficacy at a dose of 3E13vg/patient of AAV1.SERCA2a will be followed by enrollment of patients at a higher dose at 4.5E13 vg/patient. These encouraging results of high dose AAV1.SERCA2a in patients with HFrEF not observed previously may offer alternative treatments to patients with severe heart failure where a large unmet need remains."

Clinical • Late-breaking abstract • P1 data • Cardiovascular • Congestive Heart Failure • Gene Therapies • Heart Failure

MUSIC-DMD: Modulation of SERCA2a of Intra-Myocytic Calcium Trafficking in Cardiomyopathy Secondary to Duchenne Muscular Dystrophy (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Sardocor Corp.

New P1 trial • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

MUSIC-HFrEF1: Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P1/2 | N=57 | Recruiting | Sponsor: Sardocor Corp. | Trial primary completion date: Dec 2023 ➔ Dec 2025

Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

MUSIC-HFpEF: Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Preserved Ejection Fraction (clinicaltrials.gov) - P1b | N=10 | Recruiting | Sponsor: Sardocor Corp.

New P1 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

AAV.Cas9 and AAV.SERCA2a strategies to mitigate heart failure in DMD pigs (ESC 2023) - "Compared to ubiquitous excision of exon 51 (DMDdelta51-52) or postnatal AAV.Cas9-gE51 treatment of a DMDdelta52 pig model, which both improved ejection fraction EF and almost normalized action potential amplitudes, a moderate dose of AAV1.SERCA2a sufficed to normalize left ventricular function, but did not affect electrical vulnerability of the heart. Hence, AAV.SERCA2a combined with antitachycardic pacemaker protection may serve as a safe treatment option for DMD cardiomyopathy, whereas Cas9-mediated gene editing may provide additional therapy of electrical vulnerability. Further translational studies will establish novel gene therapeutic options for DMD patients."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

AAV1.SERCA2a gene therapy for treating pulmonary hypertension in a pig model: efficacy of endo-bronchial versus intra-tracheal aerosolization to address the lung delivery bottleneck (ESC 2022) - "SERCA2a gene therapy delivered via endo-bronchial aerosolization ameliorate PH in diseased pigs. A direct comparison between endo-bronchial and intra-tracheal aerosolization revealed that the endo-bronchial delivery is a more efficient delivery method for AAV based PH gene therapy."

Clinical • Preclinical • Cardiovascular • Hypertension

MUSIC-HFrEF1: Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Sardocor Corp. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Endo-bronchial aerosolized AAV1.SERCA2a gene therapy in a pulmonary hypertension pig model: addressing the lung delivery bottleneck. (PubMed, Hum Gene Ther) - "In part two of the study, we directly compared the endo-bronchial aerosolization gene delivery to the intra-tracheal aerosolization in PH pigs. Endo-bronchial delivery demonstrated higher viral expression (6,719 ± 927 vs 1,444 ± 402 vg copy/100ng DNA, p=0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH."

Journal • Preclinical • Gene Therapies • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

CUPID-3: Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (clinicaltrials.gov) - P1/2; N=56; Not yet recruiting; Sponsor: Sardocor Corp.; Initiation date: Jun 2021 ➔ Oct 2021

Clinical • Trial initiation date • Cardiovascular • Congestive Heart Failure • Gene Therapies • Heart Failure

CUPID-3: Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (clinicaltrials.gov) - P1/2; N=56; Not yet recruiting; Sponsor: Sardocor Corp.

Clinical • New P1/2 trial • Cardiovascular • Congestive Heart Failure • Gene Therapies • Heart Failure

[VIRTUAL] SERCA2a gene therapy ameliorates pulmonary hypertension in a pig model: comparison of different delivery methods and therapeutic effect (ERS 2020) - "Objective: a) compare two different airway delivery bronchoscopic vs intratracheal sprayer, b) efficacy/safety of bronchoscopic delivered AAV1-SERCA2a Gene Therapy for treating PH... Gene delivery using a bronchoscope is an efficient method for PH gene therapy. AAV1SERCA2 gene therapy using this delivery method ameliorates PH in a large animal model."

Gene Therapies • Hypertension • Pulmonary Arterial Hypertension

[VIRTUAL] Impact of pulmonary hypertension on the left ventricular stiffness: a large animal study (ERS 2020) - "2 months after surgery adeno-associated virus serotype 1(AAV1) SERCA2a or saline were intratracheally delivered... RV failure associated with PH impairs LV diastolic function through increased LV stiffness. SERCA2a gene therapy exhibits a beneficial effect on LV stiffness in a pig model of chronic PH."

Preclinical • Cardiovascular • Gene Therapies • Hypertension • Pulmonary Arterial Hypertension

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL. (PubMed, Gene Ther) - "There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Transplantation

Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism. (PubMed) - Int J Cardiol - "Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism."

Journal • Biosimilar • Depression • Heart Failure

Celladon Corporation receives patent from United States Patent and Trademark Office (PRNewswire) - Celladon Corporation announced today that the USPTO issued US patent with claims that cover the administration of Mydicar, Celladon's first in class drug under clinical evaluation for advanced HF

Patent • Cardiovascular

Evaluation of the long-term effects of AAV1/SERCA2a gene therapy on clinical events in heart failure patients using a novel statistical model: Results and implications for future trials (HFSA 2012) - P2, N=39; CUPID; High-dose AAV1/SERCA2a decreased the frequency of pre-specified clinical events relative to PBO in advanced HF pts; CUPID-ll, scheduled to begin in Q4 2012, will assess efficacy based on a reduction in the frequency &/or delayed recurrence of HF-related hospitalizations in NYHA Class III/IV systolic HF pts using the joint frailty model

Anticipated new P2 trial • P2 data • Heart Failure

A Phase 1/2 Study of High-dose Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure (clinicaltrials.gov) - P1/2; N=36; Not yet recruiting; Sponsor: Celladon Corporation

New P1/2 trial • Acute Coronary Syndrome • Biosimilar • Heart Failure • Myositis • Reperfusion Injury

Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR-1 expression via up-regulation of the homeobox gene Nkx2.5. (PubMed) - "Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells."

Journal • Biosimilar

SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery (Gene Ther) - SERCA2a gene transfer prevented vascular remodeling & significantly (p<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07 ± 0.01 vs. 0.40 ± 0.03 in β-gal-infected arteries); Findings could have potential implications for treatment of pathological in-stent restenosis

Preclinical • Cardiovascular

Effect of TRIAC Treatment in Mct8-deficiency: a Word of Caution. (PubMed) - Thyroid - "The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content."

Journal • Biosimilar

The molecular interaction of heart LIM protein (HLP) with RyR2 and caveolin-3 is essential for Ca(2+)-induced Ca(2+) release in the heart. (PubMed) - "siRNA and adenovirus-mediated KD of HLP decreased the electrically evoked Ca(2+) release from the sarcoplasmic reticulum without directly affecting SERCA2 and RyR2 activities. Collectively, the HLP-RyR2 interaction in the cell surface caveolae region may be essential for efficient excitation-contraction coupling in the heart."

Journal • Biosimilar

Fast-twitch skeletal muscle fiber adaptation to SERCA1 deficiency in a Dutch Improved Red and White calf pseudomyotonia case. (PubMed) - "By contrast, pathological muscles are characterized by a broad distribution of mitochondrial markers in all fiber types, not related to intrinsic features of double muscle phenotype and by an increased expression of sarcolemmal calcium extrusion pump. Calcium removal mechanisms, operating in muscle fibers as compensatory response aimed at lowering excessive cytoplasmic calcium concentration caused by SERCA1 deficiency, could explain the difference in severity of clinical signs."

Journal • Biosimilar