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WASKYRA (etuvetidigene autotemcel) is an autologous hematopoietic stem cell-based gene therapy for intravenous infusion.
WASKYRA is prepared from the patient’s own hematopoetic stem cells (HSCs), which are collected using apheresis procedure(s). The autologous cells are enriched for CD34+ cell and then transduced ex vivo with a replication incompetent self-inactivating (SIN) human immunodeficiency virus-1 (HIV1)-based lentiviral vector (LVV) that has been modified to carry the WAS gene sequence under the control of the human WAS promoter. The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved.
WASKYRA is manufactured for each individual patient into infusion bags, which are cryopreserved before being thawed prior to administration [see Dosage and Administration (2.3), How Supplied/Storage and Handling (16)].
The formulation contains 7% (w/v) human serum albumin (HSA) and 5% (v/v) dimethyl sulfoxide (DMSO). Each 1mL of WASKYRA suspension for IV infusion contains 3.5 mg of sodium.
WASKYRA is indicated for the treatment of pediatric patients aged 6 months and older and adults with Wiskott-Aldrich Syndrome (WAS) who have a mutation in the WAS gene and for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available.
For autologous use only. For single-dose intravenous use only.
The minimum recommended dose of WASKYRA is 7 × 106 CD34+ cells/kg based on patient’s body weight at the time of infusion.
The maximum volume of WASKYRA to be administered should remain < 20% of the patient’s estimated plasma volume.
Administer intravenous chlorpheniramine (0.2 mg/kg, max. dose 10 mg), or an equivalent 15-30 minutes before the infusion of WASKYRA to reduce the possibility of an allergic reaction to the infusion.
WASKYRA is shipped in the vapor phase of liquid nitrogen (<-130°C) from the manufacturing site to the qualified treatment center for the infusion. The Lot Information Sheet and the Chain of Custody documentation travels with the cryoshipper.
Upon arrival check the temperature on the display of the cryoshipper, open it using the proper DPI, and confirm the patient code, batch number and number of bags against product label(s).
Transfer WASKYRA from the vapor phase of liquid nitrogen at less than -130°C (-202°F) to the treatment center vapor phase of liquic nitrogen storage (<-130°C) until ready for thaw and administration.
In the event of issues, contact Fondazione Telethon ETS at: 1-888-212-6928.
WASKYRA contains human blood cells that are genetically modified with a replication-incompetent, self-inactivating lentiviral vector (LVV). Follow universal precautions and local biosafety guidelines for handling and disposal of WASKYRA to avoid potential transmission of infectious diseases.
Note: Do not sample, alter, irradiate or refreeze WASKYRA.
Prior to WASKYRA infusion, confirm that the patient’s identity matches the essential unique patient information on the infusion bag(s) labels.
Administer WASKYRA as an intravenous infusion using a central venous catheter, per the qualified treatment site’s standard procedures for cell therapy products.
When more than one bag of WASKYRA is needed, prior to infusion ensure that the volume of WASKYRA to be infused is compatible with the recommended limit of DMSO, i.e., the total volume of DMSO administered should remain < 1% of the patient’s estimated plasma volume. The maximum volume of WASKYRA to be administered should therefore remain < 20% of the patient’s estimated plasma volume.
Monitor vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptom prior to the start of the infusion, approximately every ten minutes during the infusion and every hour, for 3 hours, after the infusion.
WASKYRA is a single-dose cell suspension for intravenous infusion.
WASKYRA is provided in one to eight infusion bags which contain 2–11.4 x 106 cells/mL (1.9–11.4 x 106 CD34+ cells/mL) [see How Supplied/Storage and Handling (16)]. Each infusion bag contains 10 to 20 mL of WASKYRA. The thawed product is colorless to yellow or pink and may be cloudy to clear.
See the Lot Information Sheet for actual dose.
WASKYRA is supplied in 1 to 8 infusion bags containing a frozen suspension of genetically modified autologous cells enriched for CD34+ cells. Each bag contains 10 to 20 mL of suspension.
Infusion bags consist of a 50 mL ethylene vinyl acetate (EVA) bag(s) with two available spike ports, packed in an EVA overwrap bag placed inside a metal cassette.
WASKYRA is shipped from the manufacturing facility to the treatment centre storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal cassette contains one infusion bag with WASKYRA. A Lot Information Sheet and the Chain of Custody/Chain of Identity is included with the cryoshipper.
Manufactured for: Fondazione Telethon ETS Via Varese 16/B 00185 Rome Italy
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data described in this section reflects exposure to WASKYRA in two clinical studies, Study 1 (201228) and Study 2 (OTL-103-4) as well as patients in expanded access program (EAP). A total of 27 patients received a single infusion of WASKYRA at a dose range of 7 to 31×106 CD34+ cells/kg (median dose: 16.90×106 CD34+ cells/kg). The median duration of the follow up was 5.67 years (range: 0.37–13.26 years) [see Clinical Studies (14)].
During the above-mentioned clinical trials no adverse reactions attributable to the gene therapy were reported. There were 45 serious adverse reactions reported in 21 patients including catheter-related infections (n=11), bacterial and viral infections (n=10), pyrexia (n=3), prolonged neutropenia (n=2), vomiting (n=2), veno-occlusive disease (n=1), aspergillus infection (n=1). One patient died approximately 4.5 months after WASKYRA infusion due to neurological decompensation.
Table 1: Adverse Reactions Occurring in ≥10% of Patients (N=27)
| Adverse Reactions | Any Grade n (%) |
Grade 3 or higher n (%) |
||
| Infections and Infestations | - | - | ||
| Catheter related infection | 16 (59) | 14 (52) | ||
| Respiratory tract infection* | 18 (67) | 4 (15) | ||
| Conjunctivitis* | 10 (37) | 0 | ||
| Cytomegalovirus infection* | 8 (30) | 4 (15) | ||
| Epstein-Barr virus infection | 5 (19) | 1 (4) | ||
| Gastroenteritis | 5 (19) | 2 (7) | ||
| Ear infection | 4 (15) | 0 | ||
| Oral candidiasis | 4 (15) | 0 | ||
| Urinary tract infection* | 5 (19) | 3 (11) | ||
| Balanoposthitis | 3(11) | 0 | ||
| Gastrointestinal disorders | - | - | ||
| Diarrhea* | 16 (59) | 3 (11) | ||
| Vomiting | 12 (44) | 5 (19) | ||
| Liver injury* | 16 (59) | 3 (11) | ||
| Stomatitis | 6 (22) | 3 (11) | ||
| Hematochezia | 5 (19) | 0 | ||
| Abdominal pain | 3 (11) | 0 | ||
| Constipation | 3 (11) | 0 | ||
| Nervous System disorders | - | - | ||
| Head Injury* | 10 (37) | 1 (4) | ||
| Headache | 4 (15) | 2 (7) | ||
| Respiratory, thoracic and mediastinal disorders | - | - | ||
| Rhinitis | 9 (33) | 0 | ||
| Cough* | 8 (30) | 0 | ||
| Wheezing | 4 (15) | 0 | ||
| Oropharyngeal pain | 3 (11) | 1 (4) | ||
| Skin and subcutaneous tissue disorders | - | - | ||
| Rash** | 23 (85) | 9 (33) | ||
| Petechiae | 16 (59) | 1 (4) | ||
| Immune system disorders | - | - | ||
| Hypersensitivity* | 6 (22) | 4 (15) | ||
| Lymphadenopathy | 4 (15) | 1 (4) | ||
| Blood and lymphatic system disorders | - | - | ||
| Anemia* | 11 (41) | 4 (15) | ||
| Immune thrombocytopenia | 4 (15) | 4 (15) | ||
| Febrile neutropenia | 7 (26) | 6 (22) | ||
| Epistaxis | 9 (33) | 0 | ||
| Mouth hemorrhage | 3 (11) | 0 | ||
| Traumatic hematoma* | 4 (15) | 0 | ||
| General disorders and administration site conditions | - | - | ||
| Pyrexia | 11 (41) | 6 (22) | ||
| Catheter site complications*** | 10 (37) | 1 (4) | ||
|
Note: Adverse reactions are defined as adverse events occurred during conditioning and year 1 following WASKYRA administration. * Is a composite that includes multiple related terms. ** Rash includes eczema, rash, urticaria, dermatitis, dry skin, erythema. *** Catheter site complications includes Catheter site inflammation, Catheter site hemorrhage, Unintentional medical device removal. |
||||
Other clinically significant adverse reactions that occurred in < 20% patients include papillary thyroid cancer diagnosed in one patient with a familial history of Graves’ disease at 5-years post treatment. The tumor cells did not contain viral vector gene sequences.
Table 2. Laboratory Abnormalities that Worsened from Baseline in ≥ 10% of Patients (N=27)
| Laboratory Abnormality | All Grade n (%) |
Grade 3 or 4 n (%) |
||
| Neutrophils decreased | 10 (37) | 9 (33) | ||
| Eosinophils increased | 7 (26) | 1 (4) | ||
| Electrolyte imbalance* | 11 (41) | 6 (22) | ||
| Creatinine increased | 3 (11) | 0 | ||
| Calcium decreased | 3 (11) | 0 | ||
|
* Electrolyte imbalance includes hypokalemia, hyperkalemia, hyponatremia, hypomagnesemia |
||||
No formal drug interaction studies have been performed. WASKYRA is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.
The safety and effectiveness of vaccination during or following WASKYRA treatment have not been studied. Vaccination with live virus vaccines is not recommended until immune reconstitution is completed following treatment with WASKYRA.
Anti-retroviral medications may interfere with the manufacturing of WASKYRA. Patients should not take anti-retroviral medications for at least one month prior to mobilization until at least 7 days after WASKYRA infusion [see Warnings and Precautions (5.87)]. If a patient requires anti-retroviral treatment following exposure to HIV/HTLV, initiation of WASKYRA treatment should be delayed until an HIV/HTLV western blot and viral load assay have been performed at 6 months post-exposure.
Included as part of the PRECAUTIONS section.
Hypersensitivity and infusion related reactions, including anaphylaxis may occur with WASKYRA infusion due to dimethylsulfoxide (DMSO) as an excipient in WASKYRA. Monitor patients for signs and symptoms of hypersensitivity and infusion-related reactions during and after the WASKYRA infusion.
When more than one bag of WASKYRA is needed, prior to infusion it should be ensured that the volume of product to be infused is compatible with the recommended limit of DMSO, i.e., the total volume of DMSO administered should remain < 1% of the patient’s estimated plasma volume. The maximum volume of WASKYRA to be administered should therefore remain < 20% of the patient’s estimated plasma volume. Also, when more than one bag of WASKYRA is needed, only one bag of medicinal product should be infused at a time.
Engraftment failure defined as failure to reach an absolute neutrophil count (ANC) > 500 cells/μL associated with no evidence of bone marrow recovery (i.e., hypocellular marrow) by day 60 may potentially occur after WASKYRA infusion. Monitor patients for signs and symptoms of engraftment failure. In case of engraftment failure, infuse the non-transduced back-up hematopoietic stem cells according to local standards.
Severe cytopenias, including anemia, neutropenia, and thrombocytopenia have occured for several weeks following reduced intensity conditioning and WASKYRA infusion [see Adverse Reactions (6.1)].
Monitor patients for signs and symptoms of cytopenia for at least 8 weeks after treatment with WASKYRA. Manage patients with supportive transfusion according to clinical practice.
If neutropenia persists beyond six to seven weeks after WASKYRA infusion, despite the use of granulocyte colony – stimulating factor, consider administration of the non-transduced back up stem cells or alternative treatments.
Serious infections have occurred with WASKYRA administration [see Adverse Reactions (6.1)]. Increased susceptibility to infections may occur to concomitant administration of rituximab and conditioning regimen.
Monitor patients for signs and symptoms of infection before and after WASKYRA infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Maintain immunoglobulin G serum level above 5 g/l to prevent potential infections associated with severe hypogammaglobinaemia, resulting from disease – related immune deficiency, rituximab administration and conditioning.
Any blood products required after WASKYRA infusion should be irradiated.
Transmission of infectious disease or agents may occur with WASKYRA treatment because it is manufactured using human and bovine-derived reagents, which are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use. Additionally, WASKYRA is tested for sterility and mycoplasma at release. These measures do not eliminate the risk of transmitting these or other infectious diseases or agents.
All infections thought to be transmitted by WASKYRA should be reported to Fondazione Telethon ETS at 1-888-212-6928.
Hepatic veno-occlusive disease has occurred with WASKYRA treatment [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests during the first month after WASKYRA infusion.
There is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancy after treatment with WASKYRA [see Adverse Reactions (6.1)]. Monitor patients after treatment with WASKYRA for the development of malignancies. In the event that a malignancy occurs, contact Fondazione Telethon ETS at 1-888-212-6928 to obtain instructions on collecting patient samples for testing.
Patients who have received WASKYRA may test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV. Do not screen patients who have received WASKYRA for HIV infection using a PCR-based assay.
Patients treated with WASKYRA should not donate blood, organs, tissues and cells for transplantation at any time in the future. This information is provided in the Patient Alert Card which should be given to the patient after treatment.
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.
No information provided
WASKYRA adds full-length copies of the human Wiskott-Aldrich Syndrome (WAS) complementary deoxyribonucleic acid (cDNA) into patients’ hematopoietic stem cells (HSCs) through transduction with WAS lentiviral vector (LVV). After infusion, the genetically modified cells engraft in the bone marrow, repopulate the hematopoietic compartment, and produce biologically active lymphoid and myeloid progenitors whose progeny express WAS protein (WASP). WASP regulates the structural protein actin in blood cells.
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.
Ensure that patients and/or caregivers understand the risk of manufacturing failure. A collection of unmanipulated back-up CD34+ cells is required in case of manufacturing failure. These cells must be collected from the patient and be cryopreserved prior to conditioning.
Prior to treatment, discuss following with the patients and/or caregivers:
Advise patients and/or caregivers to:
Advise patients and/or caregivers that patients should not donate blood, organs, tissues, or cells at any time in the future [see Dosage and Administration (2.3)].
Advise patients and/or caregivers that treatment with WASKYRA may cause a false-positive human immunodeficiency virus (HIV) test result if tested using a PCR assay [see Warnings and Precautions (5.10)].
