LX2006 / Lexeo Therap, Adverum Biotech - LARVOL DELTA

SUNRISE-FA 2: Study of LX2006 Gene Therapy in Friedreich Ataxia Cardiomyopathy (clinicaltrials.gov) - P2 | N=26 | Recruiting | Sponsor: Lexeo Therapeutics

New P2 trial • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Movement Disorders

AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial. (PubMed, JAMA Cardiol) - P1, P1/2 | "There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Findings of this nonrandomized clinical trial suggest that intravenous administration of AAVrh.10hFXN was well tolerated and may be a potential treatment for FA cardiomyopathy, as evidenced by preliminary improvement in exploratory efficacy end points. ClinicalTrials.gov Identifiers: NCT05302271 and NCT05445323."

Clinical • Journal • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Inflammation • Movement Disorders • FXN

Gene therapy for the neurologic manifestations of Friedreich's ataxia by delivery of therapeutic AAV vectors to the cerebellum: comparison of direct cerebellar delivery to cerebral spinal fluid administration via the cisterna magna (ASGCT 2026) - "Methods To identify the optimal route of delivery of an AAV vector to the cerebellum, we administered AAVrh.10hFXN-HA, a rh.10 serotype coding for the normal human FXN coding sequence with a hemagglutinin tag to nonhuman primates (NHP), directly to the cerebellum (n=6) compared to administration to the cerebral spinal fluid (CSF) via the cisterna magna (n=2)...All NHP were immunosuppressed throughout the study with prednisolone and sirolimus...In the immune NHP, while the systemic anti-AAVrh.10 antibodies had no effect on the cerebellar vector genome copies following CSF administration (p>0.4), the systemic immunity, despite immunosuppression, reduced cerebellar vector genome copies following direct delivery to the cerebellum (p<0.03). Conclusion These observations have several important conclusions for strategizing AAV gene therapy for the cerebellar disease associated with FA, including: (1) direct intraparenchymal and intracisternal administration of gene..."

Gene therapy • Ataxia • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Movement Disorders • FXN

Gene therapy for Friedreich ataxia cardiomyopathy: safety and preliminary assessment of efficacy (ASGCT 2026) - "Interestingly, comparison of the most recent mFARS neurologic scale to pre-therapy demonstrated improvement in 47%, stabilization in 47% and worsening in 6%. Conclusion This interim data suggests that a single intravenous administration of AAVrh.10hFXN to individuals with FA cardiomyopathy is generally safe and biologically active, increasing cardiac FXN expression, improving a key marker of cardiac structure, reducing a serum biomarker relevant to cardiomyocyte integrity and improving or stabilizing neurologic function."

Clinical • Gene therapy • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Inflammation • Movement Disorders • FXN

Safety And Preliminary Efficacy Of AAVrh.10hFXN (LX2006) Gene Therapy In Friedreich Ataxia Cardiomyopathy (ACC 2026) - "Abstract is embargoed at this time."

Clinical • Gene therapy • Late-breaking abstract • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Movement Disorders

Lexeo Therapeutics Announces Progress in FDA Discussions for Accelerated Approval Pathway and Positive Interim Clinical Data for LX2006 in Friedreich Ataxia Cardiomyopathy (The Manila Times) - "U.S. Food and Drug Administration (FDA) open to pooling data from ongoing Phase I/II studies of LX2006 with pivotal data to support a Biologics License Application (BLA) for Accelerated Approval...Interim clinical data show sustained or deepening improvements in the majority of participants across both cardiac and neurologic measures of Friedreich ataxia; Participants with abnormal left ventricular mass index (LVMI) at baseline achieved 18% mean reduction in LVMI at 6 months and 23% mean reduction at 12 months, exceeding FDA-aligned target threshold of 10% reduction"

FDA event • P2 data • Friedreich ataxia

Lexeo Therapeutics Announces FDA Breakthrough Therapy Designation for LX2006 in Friedreich Ataxia (GlobeNewswire) - "Lexeo Therapeutics, Inc...announced that the U.S. Food and Drug administration (FDA) has granted Breakthrough Therapy designation to LX2006 based on clinical evidence generated on both cardiac and neurologic measures of Friedreich ataxia...The FDA decision was based on interim clinical data demonstrating that treatment with LX2006 was associated with clinically significant improvements in cardiac biomarkers and in cardiac and neurologic functional measures, with increased frataxin expression observed in all participants with cardiac biopsies at three months post treatment."

Breakthrough therapy • Friedreich ataxia

SUNRISE-FA: Gene Therapy for Cardiomyopathy Associated With Friedreich's Ataxia (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: Lexeo Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Gene therapy • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Movement Disorders

Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: Weill Medical College of Cornell University | N=10 ➔ 25

Enrollment change • Gene therapy • Ataxia • Cardiomyopathy • Cardiovascular • Fibrosis • Friedreich ataxia • Gene Therapies • Immunology • Movement Disorders • AFP

First In Human Gene Therapy For The Cardiomyopathy Of Friedreich Ataxia (HFSA 2024) - P1, P1/2 | "Baseline characteristics of the 11 dosed participants with FA-CM included 4 males, 7 females, mean age was 27.2±5.7 years, and all had GAA repeats in the shortest allele >700. Cardiac MRI showed concentric remodeling/hypertrophy (left ventricular (LV) mass 139.2±39.2 g; LV mass index 75.0±18.7 g/m2, relative wall mass 1.24±0.30 g/ml), with preserved LV ejection fraction (66.7±4.5%) and elevated serum high sensitivity troponin I (420.7±626.1 pg/ml). There were no serious adverse events related to therapy."

Gene therapy • Late-breaking abstract • P1 data • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Hypertrophic Cardiomyopathy • Movement Disorders • FXN

Study Design And Rationale Of SUNRISE-FA, A Phase 1/2 StUdy Of The Safety ANd Efficacy Of LX2006 Gene TheRapy In ParticipantS With Cardiomyopathy AssociatEd With Friedreich's Ataxia (HFSA 2024) - P1/2 | "SUNRISE-FA is evaluating the safety and preliminary efficacy of LX2006 for the treatment of FA-CM. Successful outcomes from this trial may provide a life-saving therapy for patients with FA and have the potential to serve as a milestone in gene therapy development for other elements of clinical illness and burden for patients with FA."

Clinical • Gene therapy • P1/2 data • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Hypertrophic Cardiomyopathy • Movement Disorders • FXN

Lexeo Therapeutics Reports Second Quarter 2024 Financial Results and Operational Highlights (GlobeNewswire) - "Expected Upcoming Milestones: LX2006 for the treatment of Friedreich ataxia cardiomyopathy: Previously disclosed data, and one additional cardiac biopsy from Cohort 2, will be shared at a scientific conference in Fall 2024; Update on ongoing regulatory engagements expected by end of 2024; LX2020 for the treatment of PKP2-ACM: Interim data readout (Cohort 1) in 2H 2024; LX1001 for the treatment of APOE4-associated Alzheimer’s disease: Interim Phase 1/2 data readout (all cohorts) in 2H 2024; LX2021 for the treatment of DSP cardiomyopathy: Initiate IND-enabling studies in 2024."

P1/2 data • Preclinical • Regulatory • Alzheimer's Disease • Cardiomyopathy • CNS Disorders • Friedreich ataxia

Lexeo Therapeutics Granted FDA Fast Track Designation for LX2006, an AAV-Based Gene Therapy Candidate for the Treatment of Friedreich’s Ataxia Cardiomyopathy (GlobeNewswire) - "Lexeo Therapeutics, Inc...announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to LX2006, the company’s AAVrh.10hFXN-based gene therapy candidate for the treatment of Friedreich’s ataxia (FA) cardiomyopathy. LX2006 is designed to deliver a functional frataxin gene to promote frataxin protein expression and restore mitochondrial function in myocardial cells."

Fast track designation • Cardiomyopathy • Cardiovascular • Friedreich ataxia

Expression and processing of mature human frataxin after gene therapy in mice. (PubMed, Sci Rep) - "AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice."

Gene therapy • Journal • Preclinical • Ataxia • Friedreich ataxia • Gene Therapies • Metabolic Disorders • Movement Disorders • FXN

Study Design And Rationale Of SUNRISE-FA, A Phase 1/2 StUdy Of The Safety ANd Efficacy Of LX2006 Gene TheRapy In ParticipantS With Cardiomyopathy AssociatEd With Friedreich's Ataxia (HFSA 2023) - "SUNRISE-FA will evaluate the safety and preliminary efficacy of gene therapy for cardiomyopathy associated with FA. Successful outcomes from This trial may provide a life-saving therapy for patients with FA and have the potential to serve as a milestone in gene therapy development for other elements of clinical illness and burden for patients with FA."

Clinical • Gene therapy • P1/2 data • Ataxia • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Friedreich ataxia • Gene Therapies • Heart Failure • Hypertrophic Cardiomyopathy • Immunology • Movement Disorders

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. (PubMed, Hum Gene Ther) - "After 12 weeks, the vector expressed FXN in the heart was 17.8±4.9 ng/mg, comparable to the target human levels. These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA."

Journal • Ataxia • Cardiovascular • Congestive Heart Failure • Friedreich ataxia • Heart Failure • Movement Disorders

Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia (ASGCT 2023) - "On average, the increase in cardiac FXN expression after AAVrh.10hFXN administration with 5.7x1011 and 1.8x1012 gc/kg doses was 6.5 and 37%, respectively, over the PBS-treated controls. Together, these data identify the safe doses of AAVrh.10hFXN relevant for the treatment of the cardiac manifestations of FA."

Clinical • Ataxia • Friedreich ataxia • Gastrointestinal Cancer • Heart Failure • Hepatocellular Cancer • Hepatology • Movement Disorders • Oncology • Solid Tumor

Dose-Dependent Cardiac Responses to Intravenous AAVrh.10hFXN Treatment of the MCK Murine Model of Friedreich's Ataxia (ASGCT 2023) - "In summary, there is a substantial survival and cardiac benefit in AAV-mediated expression of frataxin above the normal physiological level achieved at the 10X reference dose in the MCK mouse model of Friedrich's ataxia, but toxicity at high doses. This provides a rationale for ascending the dose in human clinical studies, but with caution regarding toxicity."

Preclinical • Ataxia • Friedreich ataxia • Gene Therapies • Movement Disorders

Gene Therapy for Cardiomyopathy Associated With Friedreich's Ataxia (clinicaltrials.gov) - P1/2 | N=10 | Recruiting | Sponsor: Lexeo Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Movement Disorders

Gene Therapy for Cardiomyopathy Associated With Friedreich's Ataxia (clinicaltrials.gov) - P1/2 | N=10 | Not yet recruiting | Sponsor: Lexeo Therapeutics

New P1/2 trial • Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Movement Disorders

Identification of the Therapeutically Beneficial Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friederichs's Ataxia (ASGCT 2022) - "After 12 weeks, the levels in the heart were 21.9 ± 4.9 ng/kg, comparable to levels in the range estimated necessary to convert the FA homozygote to an FA heterozygote. Together these data identify a therapeutically effective dose that has a potential to be clinically relevant for the treatment of the cardiac manifestations of Friedreich’s ataxia."

Ataxia • Cardiomyopathy • Cardiovascular • Friedreich ataxia • Gene Therapies • Heart Failure • Movement Disorders