WASKYRA Dispersion for infusion Ref.[116230] Active ingredients: Etuvetidigene autotemcel

Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned

Mechanism of action

Etuvetidigene autotemcel is an ex vivo genetically modified autologous CD34+ haematopoietic stem and progenitor cell gene therapy. Autologous CD34+ haematopoietic stem and progenitor cells (HSPCs) are enriched from patient mobilised peripheral blood and transduced with a lentiviral vector (LVV), which inserts one or more copies of the human Wiskott-Aldrich Syndrome (WAS) complementary deoxyribonucleic acid (cDNA) into the cell's genome making the genetically modified cells capable of expressing the functional WAS protein. Following administration, the genetically modified cells engraft and repopulate the haematopoietic compartment. These genetically modified cells containing the corrected WAS protein (WASP) differentiate and produce biologically active lymphoid and myeloid progenitors whose progeny express WAS protein.

Clinical efficacy

The efficacy of Waskyra has been assessed in a clinical development program that includes data from a total of 27 subjects treated in a clinical trial with a fresh formulation (n=8), a clinical trial with a cryopreserved formulation (n=10) and patients treated with the fresh formulation under a compassionate use program (CUP) and Hospital Exemptions (HE), collectively referred as Expanded Access Program (EAP) (HE, n=3; and CUP, n=6).

Study OTL-103-4

The main evidence of efficacy comes from this clinical trial, in which 10 patients were treated with etuvetidigene autotemcel. All the 10 participants completed at least 2 years of follow-up, with eight participants completing 3 years of follow-up. Six participants had completed the 5-year follow-up visit.

Patients were eligible if they had a diagnosis of WAS defined by genetic mutation and at least one of the following criteria: a) Severe WAS mutation, b) Absent Wiskott-Aldrich syndrome protein (WASP) expression, c) Severe clinical score (Zhu clinical score ≥3) and no human leukocyte antigen-identical related donor available for hematopoietic stem cell transplantation (HSCT).

The WAS gene mutation was classified as severe in all but one participant, for whom severity of the mutation was not known. All participants had a history of bleeding events, recurrent infection, and skin disorders.

Patients who had end-organ dysfunction, severe active infection not responsive to treatment or other severe disease or clinical condition, malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome; myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukemia, or other serious hematological disorders were excluded from the studies. Patients who had prior allogeneic HSCT, with evidence of residual cells of donor origin or previous GT, as well as patients with documented human immunodeficiency virus (HIV) infection (positive HIV RNA and/or anti-p24 antibodies) were excluded from the studies.

Results

Primary endpoint:

The primary endpoints were annualized rate of severe infections from 6 to 18 months after GT compared with 1 year prior to GT and annualized rate of moderate and severe bleeding episodes up to 1 year after GT compared with 1 year prior to GT. Rate of events was estimated as number of events over person-years of observation.

Severe infections: The annualized rate of severe infections decreased from 2.40 per person-year of observation (PYO) in the 12 months before Waskyra infusion to 0.20 per PYO in the 6–18 months post-Waskyra. All severe infections were Grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE).

Moderate and severe bleeding episodes: The combined annualized rate of moderate and severe bleeding events decreased from 0.90 events per PYO in the 12 months before Waskyra infusion to 0.30 events per PYO in the first 12 months following Waskyra. One severe bleeding event (diarrhea hemorrhagic) was reported in the >3-year period in one patient.

Main Secondary efficacy endpoints:

Overall survival: All 10 participants were alive with a median follow up duration of 5.02 years (range 2.32-5.43 years).

Annualized rate of severe infections and moderate and severe bleeding episodes at 2 and 3 years post treatment

The annualized rate of severe infections decreased from 2.40 per person-year of observation (PYO) in the 12 months before infusion to 0.10 per PYO in the 1-2 years post-infusion and to 0 in the 2-3 years post Waskyra.

The combined annualized rate of moderate and severe bleeding events decreased from 0.90 events per PYO in the 12 months before infusion to 0.20 events per PYO in the 1-2 years following Waskyra and 0 events per PYO in the 2-3 years post-Waskyra.

Integrated analysis of all treated patients

An integrated analysis of data from the two clinical trials (TIGET-WAS and OTL-103-4) and patients treated in the EAP has been performed in order to assess the overall clinical efficacy of Waskyra. The population for this analysis includes all the 27 participants who were enrolled and treated with Waskyra.

Patient characteristics

In the total population for the integrated analysis, the subjects' age at the time of GT ranged from 1.0 year to 35.1 years. Eighteen participants were aged <5 years and nine were ≥5 years, of which two adults, both enrolled in the EAP. By study, the age range was 1.1 – 12.4 years in study Tiget-WAS, 1-9 years in OTL-103-4, and 1.4 – 35.1 years in the EAP.

The WAS gene mutation was classified as severe in 22 participants and of unknown severity in the other five participants. Twenty-six participants had severe clinical features of WAS with a Zhu score ≥3.0 at baseline and one participant with milder clinical features (Zhu score of 2.0) was identified as having a severe WAS mutation.

Waskyra administration

The doses administered ranged between 7.0 and 31.0 CD34+ cells 10 6 /kg. The median dose in the trial TIGET-WAS was lower than in the OTL-103-4 trial and EAP. In 5 participants of TIGET-WAS the cellular source for the GT drug product was obtained from bone marrow harvest. Mobilized peripheral blood, yielding a larger number of cells, was the CD34+ cell source in the remaining patients in TIGET-WAS and in the OTL-103-4 trial and EAP.

Results

Primary endpoints:

The primary endpoints for the integrated analysis were overall survival and rate of severe infections and rate of moderate and severe bleeding events.

Overall survival: Overall, the follow-up duration in all 26 surviving participants ranges from 2.31 to 13.26 years. An overall 96% survival rate (95% CI: 82-99%) was observed following treatment with Waskyra. One adult participant treated in the EAP died as a result of a fatal SAE unrelated to Waskyra.

Severe infections: The annualized rate of severe infections decreased from 2.00 events per person-year of observation (PYO) in the 12 months before Waskyra infusion to 0.12 in the 2-3 years post Waskyra.

Moderate and severe bleeding events: The combined annualized rate of moderate and severe bleeding events decreased from 2.00 events per Person-year(s) of observation (PYO) in the 12 months before GT to 0.16 events per PYO in the 2-3 years post-Waskyra

Table 3. Integrated analysis: Annualized rate of severe infections and rate of moderate/severe bleeding events:

Secondary endpoints:

Durable and stable engraftment of gene corrected cells was observed from 1 month after the single administration of Waskyra and throughout post-treatment follow-up, in all evaluated participants (n=26) with a follow-up period ranging between 2 and 9 years after gene therapy (GT). All participants showed a marked increase in WASP expression in platelets and lymphocytes, and an increase in platelet count and improved T-cell functionality.