AAV-NAbs Positive Patients
VTX-PID
The problem :
AAV vectors have emerged as a gene delivery platform with demonstrated safety and efficacy in a significant number of clinical trials for monogenic disorders, and a few AAV GT products have now been licensed such as Zolgensma, Elividys, Luxturna and Hemophilia A & B as Roactavian and Hemgenix.
However, circulating anti-AAV neutralizing antibodies (NAbs), secondary to either natural AAV or recombinant AAV gene therapy exposure, have been shown to inhibit AAV-mediated gene therapy. Regarding natural exposure, epidemiological surveys have estimated that approximately up to 80% of the adult population are seropositive to at least one AAV serotype (Huser 2017).
Such anti-AAV-vector NAbs pose a major problem for efficient AAV-mediated gene therapy. NAbs against AAV vectors, which are predominantly immunoglobulins G (IgG), are directed against the capsid and their presence may completely inhibit target tissue transduction and gene therapy efficacy, even at very low titers (Mingozzi 2011; Corden 2017; Nathwani 2017 and Fitzpatrick 2018).
Figure 1. Host Immune Responses against AAV Vectors
Prior to vector administration, humans are exposed to wild-type AAV and therefore can develop both humoral and T cell-mediated immunity to the vector. Exposure to wild-type AAV can occur years prior to gene transfer, and together with host-specific factors can determine the overall immunological context of AAV vector delivery. Immediately after vector delivery, the vector in its components can trigger innate immune recognition. While no evidence of severe systemic inflammation has been observed in AAV trials immediately after vector delivery, some episodes of pyrexia have been documented, as well as toxicities potentially associated with complement activation. Later after vector administration, anti-capsid antibodies are produced and persist for several years after gene transfer. Capsid T cell activation has also been documented in several trials, in some cases correlating directly with loss of transgene expression. Transgene immune responses are also a potential immune-related risk in gene therapy, although to date they have been documented only in isolated trials.
Source: Verdera et al., AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer, Molecular Therapy (2020), https://doi.org/10.1016/j.ymthe.2019.12.010
In particular, the humoral immunity to the AAV vector capsid constitutes a major limitation since it:
- Reduces the number of patients eligible for GT treatment to only patients with anti-AAV NAb levels below the inhibitory threshold (naturally immunized patients).
- Prevents the possibility of a subsequent administration of the same GT product, the first administration acting as an immunization and resulting in the generation of anti-AAV NAbs.
Expanding the population of patients eligible for AAV-based treatment especially in severe life-threatening disease or re-treating patients with AAV gene therapy products are important goals to achieve a long-term therapeutic effect and access to unique potential transformative or curing innovative products .
VTX-PID, a solution
VTX-PID is a recombinant streptococcal protease (IdeS) hydrolyzing specifically human IgG, temporarily reducing IgG and thus anti-AAV NAb titers below the inhibitory levels.
VTX-PID pre-treatment is intended to allow for AAV-based gene therapy in patients presenting with inhibitory levels of anti-AAV NAbs, either in the context of a first administration in patients with pre-existing natural immunity, or for re-administration purpose.
Treatment with IdeS was shown to be a promising tool to overcome pre-existing immunity with a complete, rapid but temporary removal of IgG in healthy subjects (Winstedt 2015) and also in nonclinical studies in the field of gene therapy (Leborgne 2020, Ros-Gañán 2022) ;
Vivet has extended these initial nonclinical findings and provides new important insights in the understanding of the action of IdeS as well as considerations for its potential application in a gene therapy setting. Preliminary proof-of-concept studies conducted in passively immunized mice with anti-AAV positive human serum and anti-AAV3B-NAb positive healthy NHP have shown that a single administration of VTX-PID, prior to treatment with an AAV-based gene therapy, led to efficacious liver transduction and transgene expression otherwise abrogated (Ros-Gañán 2022). Dose range findings pharmacology and GLP toxicology studies conducted in Beagle dogs confirmed the efficacy with rapid IgG cleavage and the good safety profile of VTX-PID.
Vivet Therapeutics has manufactured its own product with CDMOs, and acquired strong process development know-how covered by a patent.Various regulatory agencies have been consulted to define proper strategic plan for AAV-NAbs positive patients.
NAVIgATE, first-in-human VTX-PID clinical study
NAVIgATE (NAb AAV IgG Trial with Endopeptidase) is a single-dose, double-blind, randomized, placebo-controlled first-in-human clinical trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of ascending intravenous doses of VTX-PID in healthy adult male subjects has been completed mid-2025.
NAVIgATE results are key to determine a safe and efficacious VTX-PID dose, together with the time window for treatment with a GT product – Data will be published soon and presented at various Gene therapy conferences
Publications
Leborgne et al. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nature Medicine 2020 Jul;26(7):1096-1101.
Ros-Gañán et al. Optimising the IgG-degrading enzyme treatment regimen for enhanced adeno-associated virus transduction in the presence of neutralising antibodies Clinical & Translational Immunology 2022; e1375. doi: 10.1002/cti2.1375
Verdera et al., AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer, Molecular Therapy (2020), https://doi.org/10.1016/j.ymthe.2019.12.010
PRECLINICAL PROOF OF CONCEPT IN MICE & MONKEY
Results of a Phase | Clinical study demonstrate the strong efficacy of VTX-PID in NAbs+ AAV3B healthy subjects measured by the reduction of anti-AAV NAbs
VTX-PID offers access to a locked patient population, strong clinical data, and an attractive, tailored licensing model with high control over the technology
