WASKYRA Suspension for solution for infusion Ref.[116110] Active ingredients: Etuvetidigene autotemcel

No dedicated clinical pharmacology studies have been conducted to study pharmacodynamics. The presence of gene-corrected HSPCs in BM and peripheral blood has been assessed at different time points after treatment with WASKYRA:

Engraftment of gene corrected cells was observed from 1 month post-WASKYRA administration and throughout post-treatment follow-up, in all evaluated participants up to 9 years after GT, as indicated by VCN values in bone marrow and peripheral blood cell lineages above the protocol-defined target of 4% in BM-derived CD34+ cells and 10% in PB derived CD3+ cells.

The presence of the WAS transgene resulted in the restoration of WASP expression in the hematopoietic compartment of all subjects, with a >65% at 1 year of follow up in lymphocytes and >74% at 30 days follow up in platelets stably expressing WASP. Reconstitution of WASP expression in turn led to improved platelet counts, ultrastructure and activation profile, as well as restored immune cell functions in treated subjects.

WASKYRA is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. The nature of WASKYRA is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

No mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have been performed with WASKYRA.

In vitro immortalization (IVIM) experiments with WAS lentiviral vector (LVV) transduced mouse Lin-BM cells, vector insertion site analyses (VISA) with WAS patient and healthy donor HSPCs in vitro and in vivo after engraftment in immunodeficient Rag2^−/− γc^−/− mice and a vector integration tag analysis (VITA) study in disease model mice showed no evidence for clonal proliferation and no genotoxic potential.

Toxicity studies were performed in vivo in two different WAS knock-out mouse models transplanted with Lin-BM cells transduced with WAS LVV. Investigations included follow-up for at least 12 months post-transplant in one model and serial transplant studies in the second model covered a cumulative period of 10 months (4+6). These studies demonstrated normal engraftment, differentiation and seeding of lymphoid tissues with no adverse clinical signs, mortalities and no pathologic changes related to the integration of WAS LVV. No toxicity and no increase in tumorigenesis occurred in either model. The WAS protein was not overexpressed, even at high VCNs, and no toxicity due to protein overexpression has been observed.

Additional studies with human CD34+ cells transduced with WAS LVV administered to immunodeficient, myeloablated mice demonstrated no toxicity, no replication competent lentivirus (RCL), no vector mobilization and no secondary transduction of bystander cells, including male gonads.

The efficacy of WASKYRA was evaluated in two clinical studies, Study 1 (201228; NCT01515462) and Study 2 (OTL-103-4; NCT03837483) as well as in patients from an expanded access program (EAP). Study 1 was a prospective, open-label, single-arm, single-center study (n=8) that evaluated the safety and efficacy of WASKYRA fresh formulation compared to 12-month pre-treatment outcomes. Study 2 is an ongoing, open-label, single-arm, multicenter study (n=10) evaluating the efficacy of WASKYRA cryopreserved formulation compared to 12-month pre-treatment outcomes. The expanded access program included Hospital Exemption (HE) 205030 (n=3), and Compassionate Use Program (CUP) 206257 (n=6) which provided WASKYRA treatment to patients with Wiskott-Aldrich syndrome (WAS).

The studies and the expanded access program enrolled patients who had a diagnosis of WAS confirmed by genetic mutation and at least one of the following criteria: 1) severe clinical score (Zhu clinical score ≥ 3), 2) severe WAS mutation, or 3) absent WASP expression. All patients lacked a suitable human leukocyte antigen (HLA)-matched donor. Patients with prior allogeneic hematopoietic stem-cell transplantation (HSCT) within 6 months or evidence of residual cells of donor origin, prior gene therapy, human immunodeficiency virus (HIV) infection and cytogenetic alterations were excluded.

Patients underwent hematopoietic stem-cell (HSC) collection by bone marrow collection (n=5), from apheresis following the administration of HSC mobilizing agents (n=21), or from both sources (n=1). Prior to treatment, patients received rituximab and a conditioning regimen with busulfan, and fludarabine. Rituximab was administered as a single dose of 375 mg/m² on Day –22 ( + / - 1). Busulfan was given in eight doses every 6 hours from Days -4 to -2, with dosing adjusted based on pharmacokinetic monitoring to achieve a target cumulative AUC of 48,000 ± 10% ng/mL per hour. Fludarabine was given at a total dose of 60 mg/m², split into two doses on Days -4 and -3. Patient then received a single infusion of WASKYRA through a central venous access at a dose range of 7–31×10⁶/kg CD34+ cells (median dose: 16.90×10⁶/kg).

The demographic characteristics were as follows: median age was 2.6 years (range 1 to 35 years), all patients (100%) were male, 20 patients (74%) were White, 4 patients (15%) were Asian, 2 patients (7%) were African American, and 1 patient was American Indian or Alaska Native. Three patients (11%) were Hispanic or Latino. Twenty-six out of 27 patients were included in efficacy evaluation. One patient did not receive WASKYRA treatment due to mobilization failure and was excluded from the analyses.

The major efficacy outcomes were the rate of severe infections during the 6 to 18 month period after WASKYRA infusion compared with the 12-month pre-treatment period, and the rate of moderate or severe bleeding episodes during the 12-month period after WASKYRA infusion compared with the 12-month pre-treatment period.

The rate of severe infections decreased from 2.0 (95% CI: 1.50, 2.61) infections per patient year observation (PYO) in the 12 months pre-treatment period to 0.2 (95% CI: 0.04, 0.40) per PYO infections in 6-18 months post-gene therapy.

The rate of moderate and severe bleeding events decreased from 2.0 (95% CI: 1.50, 2.61) events per PYO in the 12 months pre-treatment to 0.8 (95% CI: 0.49, 1.22) events per PYO in the 12 months after WASKYRA treatment.