scAAV2/8-LP1-hFIXco / REGENXBIO - LARVOL DELTA

Stable Therapeutic Transgenic FIX Levels for More Than 10 Years in Subjects with Severe Hemophilia B Who Received scAAV2/8-LP1-Hfixco Adeno-Associated Virus Gene Therapy (ASH 2023) - P1 | "Expression of transgenic FIX has remained stable over a period of 10 years following systemic administration of scAAV2/8-LP1-hFIXco resulting in sustained clinical benefit, with substantial reduction in ABR and FIX concentrate use."

Clinical • Gene therapy • Cardiovascular • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Rare Diseases • Respiratory Diseases • Solid Tumor • Thrombosis

Long-Term Persistence of Antibodies to Adeno-Associated Viral Vectors Following Gene Therapy with scAAV8-LP1-Fixco (ASH 2023) - P1 | "We report a longitudinal analysis of anti-AAV antibody response over a 10-year period in severe HB participants following systemic administration of scAAV2/8-LP1-hFIXco from the St Jude-UCL Phase I/II, gene therapy trial (AGT4HB ClinicalTrials.gov:NCT00979238)...AAV5 NAB titres were lower than other serotypes declining to levels below a threshold required for efficient gene transfer in the low and mid dose cohort within 10 years. This suggests that, should FIX levels fall below therapeutic levels in this cohort, successful re-administration of an alternative vector may be possible."

Gene therapy • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Infectious Disease • Rare Diseases

Anti-AAV antibody persistence following gene therapy with scAAV8-LP1 hFIXco in participants with haemophilia B: A 10 year follow up (ESGCT 2024) - P1 | "This study presents a 10-year longitudinal analysis of anti-AAV antibody response in severe HB participants following systemic administration of scAAV2/8-LP1-hFIXco from the St Jude-UCL Phase I/II gene therapy trial (AGT4HB ClinicalTrials.gov:NCT00979238)...There is a dose-dependent rise in anti-AAV8 antibody levels that decline over time but preclude re-administration of the same serotype. Cross-reactive antibodies to other serotypes initially increase but also decline with time, potentially permitting subsequent re-administration."

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Infectious Disease • Rare Diseases

Mirroring AAV gene therapy for haemophilia B: insights from an in vitro stably transduced humanised liver cell model (ESGCT 2024) - P1 | "Here, we present an in vitro model using human hepatocytes stably expressing human factor IX (hFIX) after transduction with scAAV2/8-LP1-hFIXco, the same vector used in the St Jude/UCL AGT4HB clinical trial for haemophilia B (NCT00979238)...This stable human in vitro model of liver transduction exhibits variability in AAV transgene transcription and translation, mirroring observations from human liver biopsy studies following gene therapy. These clones offer a valuable opportunity to study and understand the AAV life cycle in a context that closely resembles in vivo gene transfer to the human liver."

Gene therapy • Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Infectious Disease • Rare Diseases

Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Dec 2032 ➔ Dec 2025 | Trial primary completion date: Jun 2032 ➔ Dec 2025

Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B. (PubMed, N Engl J Med) - P1 | "A single administration of scAAV2/8-LP1-hFIXco gene therapy resulted in durable factor IX expression, sustained clinical benefit, and no late-onset safety concerns over a period of 13 years. These data support the long-term efficacy and safety of AAV gene therapy for severe hemophilia B. (Funded by the U.K. Medical Research Council and others; ClinicalTrials.gov number, NCT00979238; EudraCT number, 2005-005711-17.)."

Journal • Cardiovascular • Fibrosis • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatology • Immunology • Liver Failure • Oncology • Rare Diseases • Thrombosis

Adeno-Associated Mediated Gene Transfer for Hemophilia B:8 Year Follow up and Impact of Removing "Empty Viral Particles" on Safety and Efficacy of Gene Transfer (ASH 2018) - P1; "Conclusion : This is the first report to demonstrate stable therapeutic expression of FIX in patients with severe HB over a period of 8 years following systemic administration of scAAV2/8-LP1-hFIXco without late toxicities. We show for the first time that reducing the capsid load by removing empty AAV capsids does not appear to reduce the incidence of hepatotoxicity in patients with severe HB suggesting that other factors are involved in the aetiology of this process."

Clinical • Biosimilar • Gene Therapies • Hematological Disorders • Hemophilia

Interspecies normalization of dose response relationship for adeno-associated virus-mediated hemophilia gene therapy - application to human dose prediction. (PubMed, Br J Clin Pharmacol) - "This study first demonstrated that it is feasible to normalize dose-response relationship of AAV-mediated hemophilia gene therapy in multiple species to a species-invariant scale. The normalized dose response relationship from preclinical species was successfully extrapolated to patients for FIH dose prediction."

Journal • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

A Novel Self-Complementary AAV Vector Enhances Transgene Expression (ASGCT 2022) - "For new scAAV-EGFP-TelN and scAAV-Gluc-TelN, the transgene expression was not obviously affected by MRN inhibitor KU55933 or Mirin. In vivo assay showed that hFIX expression was significantly different between scAAV-hFIX and scAAV-hFIX-TelN, the later showed a higher hFIX expression level in the long term. In conclusion, this new scAAV vector shows more efficient transduction efficacy in vitro and in vivo, without sacrificing productivity."

Gene Therapies • Pediatrics • MRE11A

Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-induced Osteoporosis Mouse Model. (PubMed) - "These results demonstrate that hAAT gene therapy by rAAV vector efficiently mitigates bone loss possibly through inhibition of proinflammatory cytokine IL-6 and RANK gene expression. Considering the safety profile of hAAT and rAAV vector in humans, our results provide new alternative for the treatment of osteoporosis."

Biomarker • Journal • Biosimilar

Long-term follow-up of liver-directed, adeno-associated, vector-mediated gene therapy in the canine model of hemophilia A (WFH 2012) - At 5–7 years post–gene transfer, FVIII levels ranged between 13% and 24% and now, at 8->10 years follow-up, FVIII levels are between 10% and 17%; These values are consistent with whole blood clot times that prior to therapy were between 14 and 18 min and post–gene transfer have remained below 7 min

Preclinical-animal • Hemophilia

Gene Supplementation Therapy for CNGA3-Linked Achromatopsia (ASGCT 2017) - P1/2; "So far, the treatment has proven to be safe, was well tolerated and did not result in any clinically apparent inflammation or test item related events. Preliminary clinical data will be discussed."

Biosimilar • Gene Therapies • Immunology • Oncology • Ophthalmology

Developing immunologically inert adeno-associated virus (AAV) vectors for gene therapy: possibilities and limitations (Curr Pharm Biotechnol) - "Several strategies, that aim targeted disruption of antigenic sites or those that chemically modify the vectors have been proposed for host immune evasion. While these approaches have been successful in the pre-clinical model systems, this continues to be a field of intense experimentation and constant improvisation due to limited information available on vector immunology or data from human studies."

Review • Hemophilia

ReGenX Biosciences: Annual Report 2015 (Regenxbio) - Anticipated expiry of patents related to AAV8 vectors and uses in US from 2022 to 2026; Anticipated patent expiry in Europe related to AAV8 vectors in 2022

Anticipated patent expiry • Hemophilia

Stable factor IX activity following AAV-mediated gene transfer in patients with severe hemophilia B (ASH 2012) - P1, N=8; NCT00979238; "Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration"

P1 data • Hemophilia

Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: St. Jude Children's Research Hospital; Trial primary completion date: Dec 2018 ➔ Jun 2032

Clinical • Trial primary completion date