Etuvetidigene Autotemcel

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. WASKYRA ® is an autologous hematopoietic stem cell-based gene therapy 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 for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available. ( 1 )

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 10 6 cells/mL (1.9–11.4 x 10 6 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 packaged in one to eight infusion bags overall containing a suspension of 2–11.4 x 10 6 cells /mL (1.9–11.4 x 10 6 CD34 + cells/mL) in a cryopreservative solution. ( 3 )

Hypersensitivity to the active substance or to any of the excipients [see Hypersensitivity and Infusion Related Reactions (5.1) ]. Previous treatment with HSCT within 6 months prior to treatment or HSCT with evidence of residual donor cells. Previous treatment with hematopoietic stem cell gene therapy. Contraindications to the mobilization and the conditioning regimen. Hypersensitivity to the active substance or to any of the excipients. ( 4 ) Previous treatment with HSCT within 6 months prior to screening or HSCT with evidence of residual donor cell. ( 4 ) Previous treatment with hematopoietic stem cell gene therapy. ( 4 ) Contraindications to the mobilization and the conditioning regimen. ( 4 )

Hypersensitivity and infusion-related reactions : Monitor patients for hypersensitivity and infusion-related reactions during and after infusion. ( 5.1 ) Engraftment failure : 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. ( 5.2 ) Cytopenias : Severe cytopenias, including anemia, neutropenia, and thrombocytopenia have occurred for several weeks following reduced intensity conditioning and WASKYRA ® infusion. Monitor patients for signs and symptoms of cytopenia for at least 8 weeks after treatment with WASKYRA and manage accordingly. ( 5.3 ) Serious infections : Serious infections have occurred with WASKYRA ® administration. Increased susceptibility to infections may occur due to concomitant administration of rituximab and conditioning regimen. Monitor patients for signs and symptoms of infection before and after WASKYRA infusion and treat appropriately. ( 5.4 ) Transmission of an infectious agent : All infections thought to be transmitted by WASKYRA ® should be reported to Fondazione Telethon ETS at 1- 888- 212- 6928. ( 5.5 ) Hepatic veno-occlusive disease : Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests for one month after WASKYRA ® infusion ( 5.6 ) Risk of oncogenesis : There is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancy after treatment with WASKYRA ® . Monitor patients after treatment with WASKYRA ® for the development of malignancies. ( 5.7 ) Interference with HIV 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. ( 5.8 ) Blood, organ, tissue and cell donation : Patients treated with WASKYRA ® should not donate blood, organs, tissues and cells for transplantation at any time in the future. ( 5.9 )

5.1 Hypersensitivity and Infusion Related Reactions Hypersensitivity and infusion related reactions, including anaphylaxis may occur with WASKYRA ® infusion due to 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.

5.2 Engraftment failure 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.

5.3 Cytopenias 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.

5.4 Serious Infections 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 hypogammaglobinemia, resulting from disease – related immune deficiency, rituximab administration and conditioning. Any blood products required after WASKYRA ® infusion should be irradiated.

5.5 Transmission of an infectious agent 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.

5.6 Hepatic veno-occlusive disease 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.

5.7 Risk of oncogenesis 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.

5.8 Interference with HIV 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.

5.9 Blood, organ, tissue and cell donation 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.

The most common adverse reactions (incidence ≥ 20%) are catheter related infections, bacterial and viral infections, diarrhea, vomiting, stomatitis, liver injury, head injury, rhinitis, cough, rash, petechiae, hypersensitivity, anemia, febrile neutropenia, epistaxis, pyrexia, catheter site complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fondazione Telethon ETS at toll-free phone 1-888-212-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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 31×10 6 CD34 + cells/kg (median dose: 16.90×10 6 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 Is a composite that includes multiple related terms. 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 Rash includes eczema, rash, urticaria, dermatitis, dry skin, erythema. 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 Catheter site complications includes Catheter site inflammation, Catheter site hemorrhage, Unintentional medical device removal. 10 (37) 1 (4) Note: Adverse reactions are defined as adverse events occurred during conditioning and year 1 following WASKYRA ® administration. 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 Electrolyte imbalance includes hypokalemia, hyperkalemia, hyponatremia, hypomagnesemia 11 (41) 6 (22) Creatinine increased 3 (11) 0 Calcium decreased 3 (11) 0

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.

7.1 Effect of Vaccines on WASKYRA ® 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 ® .

7.2 Effect of Anti-retrovirals on 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. 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.

8.1 Pregnancy Risk Summary There are no clinical data from the use of WASKYRA ® in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with WASKYRA to assess whether it can cause fetal harm when administered to a pregnant woman. WASKYRA ® must not be administered during pregnancy because of the risk associated with conditioning. Pregnancy after WASKYRA ® infusion should be discussed with the treating physician. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of WASKYRA ® in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with conditioning, breast-feeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WASKYRA ® and any potential adverse effects on the breastfed child from WASKYRA ® or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential The safety of WASKYRA ® was only evaluated in male patients. Pregnancy Testing A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before administration of WASKYRA ® in females of childbearing potential. Contraception Males capable of fathering a child and females of childbearing age should use an effective method of contraception from start of mobilization through at least 6 months after administration of WASKYRA ® . Infertility There is no data on the effects of WASKYRA ® on fertility. Consult the Prescription Information of the conditioning medicinal products. It should be noted that the treating physician should inform the patients or the patient’s parents/carers in case of minors about options for cryopreservation of spermatogonial stem cells or ovarian tissue prior to application of conditioning.

8.4 Pediatric Use The safety and efficacy of WASKYRA ® for the treatment of WAS have been established in pediatric patients aged 6 months and older. The use of WASKYRA ® in pediatric patients is supported by evidence from Study 1, Study 2, and patients in expanded access program which included 25 pediatric patients 1 to 16 years of age [see Adverse Reactions (6) and Clinical Studies (14) ]. The safety and effectiveness of WASKYRA ® have not been established in pediatric patients younger than 6 months of age.

WASKYRA ® adds full-length copies of the human 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.