AAV Company Series: Cardiac
gene therapy to address cardiovascular disease?
Following the last two AAV Company Series on Ophthalmology and the Central Nervous System is the final series on the cardiovascular system, specifically focusing the heart.
Before we get into it, let’s take a look at the updated list of FDA Approved AAV-based gene therapies as of May 2024:
LUXTURNA (AAV2) - Leber’s congenital amaurosis: 2017
ZOLGENSMA (AAV9) - Spinal muscular atrophy: 2019
HEMGENIX (AAV5) - Hemophilia B: 2022
ELEVIDYS (AAVrh74) - Duchenne muscular dystrophy: 2023
ROCTAVIAN (AAV5) - Hemophilia A: 2023
BEQVEZ (AAVRh74var) - Hemophilia B: 2024
Since the first FDA approval of Luxturna, we’ve had two approvals to treat neuromuscular disorders and three for blood disorders leading into a growing focus in other organ systems like the cardiovascular system.
Early approaches for gene therapy focused on regeneration or reversal of disease in ischaemic heart disease or heart failure. Here researchers were not focused on the underlying genetic defects but the pathophysiology which opened these technologies to huge potential indications. For example, initial attempts tried to address angiogenesis by delivering factors like VEGFs, PDGFs, FGFs, HIF-1a/b, HGF. However, these attempts led to unwanted vascular permeability, lesions in preclinical models and arrhythmias or ambiguous results or lack of efficacy. Recent results from a Phase 1 trial for KAT301, an intramyocardial adenovirus-mediated VEGF-D gene therapy in refractory angina, reported positive findings for symptom relief but imaging results suggested a strong placebo effect.
Many clinical trials investigating gene therapy for cardiac diseases have faced similar challenges or reported poor outcomes. Other examples include:
Adenylyl Cyclase 6 (AC6) Heart Failure Trial: This trial investigated the safety and efficacy of an AAV5-AC6 VECTOR in patients with heart failure. The trial failed to meet its primary endpoint of reducing heart failure-related events compared to placebo.
SERCA2a Gene Therapy for Heart Failure: Evaluated the safety and efficacy of an AAV1-SERCA2a vector in patients with heart failure. While the therapy appeared safe, it did not meet its primary endpoint of improving clinical outcomes compared to placebo.
These examples illustrate some of the challenges encountered, including issues related to safety, efficacy, and delivery technologies. Following these setbacks, we can see the lessons learned being applied to targeted gene therapies to address underlying the genetic disorders that cause cardiac disease.
The next wave of gene therapies for cardiac disease can be split into two categories: a systemic rare genetic disorder with a cardiomyopathy phenotype or inherited/familial cardiomyopathies.
Rare Genetic Disorders with a Cardiomyopathy phenotype:
X-linked LAMP2 deficiency (Danon disease)
AAV9 capsid containing the human LAMP2B in development by Rocket Pharmaceuticals
Fabry Disease:
Recombinant AAV2/6 vector containing functional GLA gene by Sangamo Therapeutics
4D-310 delivering the functional GLA gene by 4D Molecular Therapeutics
Other rare diseases with cardiomyopathy phenotypes: DMD, Friedrich’s ataxia, Pompe disease and more.
Genetic Targets for Inherited Cardiomyopathies:
MYH7: pathogenic variants cause HCM, a sarcomeric protein
MYBPC3: loss of function mutations lead to HCM, a sarcomeric protein
BAG3: truncation or pathogenic variants reducing expression leads to DCM
Myosin regulatory light chain (RLC): D166V mutation
Potential Challenges:
Delivery: the primary method to date has been AAV because of its affinity for cardiac tissue and recent improvements on cardiac tissue specificity (Tenaya Therapeutics). However, a non-immunogenic delivery method remains an unmet need.
Durability: As with all AAV-based therapies, durability of the therapeutic protein expression will be a question as well as potential requirements for re-dosing.
Timing of Treatment: timing of treatment will be essential to determine whether regeneration or reversal of the cardiomyopathy phenotype is possible or if treatment will simply halt disease progression.
Leading AAV Cardiac Gene Therapy Companies Today:
Rocket Pharmaceuticals RCKT 0.00%↑
Rocket Pharmaceuticals broadly focuses on rare genetic diseases with many of their pipeline programs having a cardiac phenotype. They leverage both lentivirus and AAV as their delivery technologies.
Cardiac Targets and Diseases
Danon Disease: X-linked mutations in LAMP2 leading to cardiomyopathy, affects prevalence of ~1:500 persons with 1-4% of those having a LAMP2 variant
PKP2-ACM: autosomal dominant mutations in PKP2 leading to arrhythmogenic cardiomyopathy, reported prevalence of 1/2,500 to 1/5,000 and 20% of patients have PKP2 mutations
BAG3-DCM: more than 60 genes have reported involvement in dilated cardiomyopathy, BAG3 is predominantly expressed in the heart, BA3 is reported to represent 2.3% and 3.6% of all DCM cases which has a prevalence rate of up to 1/2,500
Pipeline
RP-A501: AAV9.LAMP2B in Phase 2
RP-A601: AAVrh74.PKP2 in Phase 1
BAG3-DCM: AAV9-BAG3 acquired from Renovacor in Preclinical
Upcoming Milestones
Phase 2 pivotal study of RP-A501 for Danon Disease results in 2024
Phase 1 study of RP-A601 for PKP2-arrhythmogenic cardiomyopathy (ACM) in 2024
IND-enabling studies for BAG3-associated dilated cardiomyopathy (DCM)
Other program updates:
LV Therapy KRESLADI has a June 30, 2024 PDUFA date
RP-L102 for Fanconi Anemia BLA in 1H2024
Solid Biosciences SLDB 0.00%↑
Solid Biosciences has pipeline of AAV therapeutics with a larger focus on cardiac diseases.
Cardiac Targets and Diseases
RYR2 and CASQ2-Mediated CPVT: CPVT affects one in 10,000 people,
BAG3-Mediated DCM: company estimates 29K patients in the US and 33K in EU
TNNT2 DCM: represents 3-6% of DCM patients and 15% of familial hypertrophic cardiomyopathy HCM
RBM20: represents 2–6% of the cases of familial DCM
Pipeline
SGT-501: AAV.CASQ2-mediated over-expression to treat both RYR2 and CASQ2 patients in Preclinical
AVB-401: AAVrh74.BAG3 in Preclinical
SGT-601: TNNT2 DCM vector in Research/Discovery Stage
SGT-701: RBM20 vector in Research/Discovery Stage
Upcoming Clinical Milestones
IND for SGT-501 for the treatment of CPVT in 1Q2025
Ongoing preclinical studies in BAG3, TNNT2 and RBM20
Other program updates:
Initiate dosing in the Phase 1/2 trial of SGT-003 in pediatric patients with DMD in 2Q2024
Lexeo Therapeutics LXEO 0.00%↑
Lexeo Therapeutics is a gene therapy company targeting CNS and cardiac diseases.
Cardiac Targets and Diseases
Friedreich’s Ataxia: prevalence is 1 in 40,000 worldwide, company estimates approximately 5K patients in the United States
PKP2-ACM: company estimates approximately 6K patients in the United States
DSP (Desmoplakin) cardiomyopathy (CX43): company estimates approximately 35K patients in the United States
Hypertrophic cardiomyopathy (TNNI3): company estimates 1 in 500 people in the United States
Pipeline
LX2006: AAVrh10 delivering frataxin
LX2020: AAVrh10 delivering PKP2
LX2021: AAVrh10 delivering Cx43
LX2022: AAVrh10 delivering TNNI3
Upcoming Clinical Milestones
LX2006: Mid 2024 interim data readout
LX2020: 2H2024 interim data readout (Cohort 1)
LX2021: IND enabling studies
Other program updates:
LX1001: APOE4 2H2024 interim Phase 1/2 data readout
Tenaya Therapeutics TNYA 0.00%↑
Cardiac Targets and Diseases
MYBPC3 HCM: most prevalent form of genetic HCM, 115K patients in the United States estimated by the company
PKP2 ARVC: 70K patients in the United States estimated by the company
Pipeline
TN-201: AAV9.MYBPC3
TN-401: AAV9.PKP2
Upcoming Clinical Milestones
TN-201: initial safety, biopsy and biomarker data in 2H2024
TN-401: begin dosing adult patients in the second 2H2024
All 4 of these companies are nearing significant platform and pipeline validation moments in 2024, it will be exciting to see how it all plays out.