The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK Study Number: AD Title: ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of ADA-SCID. Rationale: GSK is an innovative gene therapy. The present document describes the third trial conducted with GSK in subjects with severe combined immunodeficiencies due to adenosine deaminase deficiency (ADA- SCID). This document presents the results of the first 3 years post-treatment for the 12 subjects enrolled in this study. Phase: I/II Study Period: 12 June 2002 to 06 July Study Design: This was a prospective, sequential, open-label, non-randomised, single centre, controlled study (comparison with historical control data). Subjects underwent screening, discontinuation of polyethylene glycolmodified adenosine deaminase (PEG-ADA) and baseline evaluation ( Pre-Treatment phase); bone marrow extraction and transduction, non-myeloablative conditioning and bone marrow re-infusion ( Treatment phase); and posttreatment follow-up (for the purposes of adverse event reporting, divided into an initial 3 Month Hospitalisation phase [0 to 3 months post-treatment] and a 3 Year phase [post-3 months to 3 years post-treatment]). Centre: Hospital San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy. Indication: SCID due to ADA deficiency. Treatment: Following busulfan preconditioning between 2 and 20 x 10 6 transduced autologous CD34+ cells/kg were infused through an intravenous catheter over approximately 20 minutes. The exact dose received by each subject was dependent upon the number of CD34+ cells available following bone marrow extraction, their growth during the manufacturing process, and the % CD34+ cells present at the end of the transduction procedure. Objectives: Evaluation of the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy. Evaluation of biological activity (engraftment, ADA expression) of ADA-transduced CD34+ cells and their haematopoietic progeny. Evaluation of immunological reconstitution and purine metabolism after gene therapy. Primary Outcome (Endpoints)/Efficacy: The primary efficacy endpoint was survival at 3 years post-gene therapy. Secondary Outcome (Endpoints)/Efficacy: Secondary efficacy endpoints were as follows: 1.1) Change in the rate of severe infections (defined as infections requiring hospitalisation or prolonging hospitalisation). 1.2) Change in T-lymphocyte counts. 1.3) Modification of the "systemic" metabolic defect, analysed by levels of purine metabolites in red blood cells (RBCs). 2.1) Change in the proliferative response to polyclonal stimuli. 2.2) Change in thymic activity (T-cell receptor excision circles; TREC). 2.3) Presence of genetically modified cells in the bone marrow compartment and presence of >10% genetically modified cells in peripheral blood lymphocytes. 2.4) Lymphocyte ADA enzyme activity. 2.5) Change in lymphocyte counts. 3.1) Recovery of physical growth. 3.2) Need for reintroduction of PEG-ADA (in subjects previously treated with PEG-ADA). 3.3) Antibody response to vaccination. All efficacy endpoints were evaluated at 1, 2 and 3 years. Safety endpoints were adverse events (AEs) and serious adverse events (SAEs). Statistical Methods: The sample size was 12 subjects, which provided approximately 90% power to detect a 35% advantage in overall survival at 3 years following treatment with gene therapy (alpha=0.05) over bone marrow transplant from matched unrelated donor (MUD). Efficacy Analyses: The primary analysis population was the Intent-to-Treat (ITT) Population. Analyses for the Per- Protocol (PP) Population were also performed for the primary endpoint and selected secondary endpoints. The primary efficacy endpoint was subject survival. Overall survival at 3 years was estimated using the Kaplan-Meier product limit method. A Poisson regression model was used to compare the pre- and post-treatment rate of severe infections. The continuous secondary efficacy endpoints were analysed using a repeated measures model to compare the mean change from baseline at 1, 2 and 3 years using a mixed model. Continuous variables were examined for the 1

2 normality assumption. If necessary, log-transformation was applied to improve compliance with the normality assumption. A small positive number was added to zero to enable log-transformation if the original observed value was zero. Other secondary efficacy endpoints that were characterised as categorical were compared with the reference using a 1-sample proportion test. Summary statistics and 95% confidence intervals were also presented. Unless otherwise stated, all statistical analyses were 2-sided and performed at the 5% level of significance. Safety analyses: Safety was evaluated in the ITT Population. Study Population: Subjects aged <18 years who had SCID with ADA deficiency, as assessed by ADA enzymatic activity and/or genetic analysis, and for whom a human leukocyte antigen (HLA)-identical healthy sibling was not available as a suitable bone marrow donor, were enrolled. In addition, subjects had to fulfil at least 1 of the following criteria: - Subjects who had received enzyme replacement therapy (PEG-ADA) for at least 6 months before enrolment and had at least 2 of the following: absolute lymphopenia (<1500 cells/ul); absolute T lymphopenia (<1000 cells/ul); requirement for intravenous immunoglobulin (IVIG) infusion; deficit of serum immunoglobulins (IgM or IgA or subclasses of IgG) or lack of antibody response to vaccination. -Subjects who had received PEG-ADA, and in whom the drug had been discontinued due to intolerance, allergy, or autoimmune manifestations. -Subjects for whom PEG-ADA was not a life-long therapeutic option (e.g., from countries in which the drug is not available). Subjects infected with human immunodeficiency virus and those with a current malignancy or a history of malignancy, or who received a previous gene therapy treatment in the 12 months preceding enrolment were excluded from the study. Number of Subjects: Enrolled, N 12 Completed, n (%) 11 (92) Total Number Subjects Withdrawn, n (%) 1 (8) Withdrawn due to Adverse Events, n (%) 0 Withdrawn due to Lack of Efficacy, n (%) 0 Withdrawn for other reasons (investigator discretion), n (%) 1 (8) Demographics N (ITT) 12 Females: Males 5: 7 Mean Age, years (SD) 2.38 (1.722) Mean height, cm (SD) 83.4 (15.56) Mean weight, kg (SD) 10.3 (4.16) White White/Caucasian/European Heritage, n (%) 10 (83) Lansky performance status index, n (%) Fully active, normal 9 (75) Minor restrictions in strenuous physical activity 3 (25) Primary Efficacy Results: The summary below presents results for the ITT analysis population. The results for the PP analysis population were consistent with the ITT analysis results for the primary endpoint and the 3 key secondary endpoints. The primary efficacy endpoint was subject survival at 3 years follow-up post-gene therapy. There were no deaths during the study, i.e., 100% survival in both the ITT and PP Populations. This was numerically greater than the postulated alternate hypothesis of 85% survival. Survival time data was censored for 1 subject who was withdrawn at 2.1 years for BMT when an HLA-identical sibling/family member became available. Secondary Outcome Results: Severe Infections ITT Population Before gene therapy (N=12) After gene therapy (N=12) Number (%) of subjects with events 10 (83) 7 (58) Number of events Total months to 1 year - 8 Year 1 to Year 2-6 Year 2 to Year 3-0 Person-years of observation (free from infection) Rate of infection

3 Lymphocytes and Naïve T-Cell Data (Log-Transformed Data) ITT Population Biomarker (cell counts) Time point n Mean GM ratio vs. baseline (SE) 95% CI CD3+ (10 6 /L) Year (0.37) 1.45, 6.19 Year (0.37) 2.63, Year (0.38) 3.08, CD3+CD8+ (10 6 /L) Year (0.44) 1.80, Year (0.44) 3.54, Year (0.45) 4.35, CD3+CD4+ (10 6 /L) Year (0.34) 1.26, 4.76 Year (0.34) 2.07, 7.85 Year (0.34) 2.26, 8.83 CD4+CD45RA+ (10 6 /L) Year (0.50) 1.01, 7.54 Year (0.52) 1.51, Year (0.52) 1.76, GM=geometric mean; SE=standard error; CI=confidence interval. Lymphocyte Data (Untransformed Data) ITT Population Biomarker (cell counts) Time point n Mean difference vs. baseline (SE) 95% CI CD19+ (10 6 /L) Year (32.65) , Year (32.65) , Year (33.42) , CD16+CD56+ (10 6 /L) Year (16.36) , 3.67 Year (16.36) , Year (16.74) , Summary of Subjects with Metabolic Detoxification Findings ITT Population Time point Detoxification: n/n (%) 95% CI Bone marrow aspirate Year 1 10/11 (91) 59%, 100% Year 2 11/11 (100) 72%, 100% Year 3 10/10 (100) 69%, 100% Peripheral venous whole blood Year 1 11/12 (92) 62%, 100% Year 2 11/11 (100) 72%, 100% Year 3 11/11 (100) 72%, 100% Purine Metabolites and ADA Activity (Log-Transformed Data) ITT Population Biomarker Time point n Mean GM ratio vs. baseline (SE) 95% CI Bone marrow RBC daxp (nmol/ml) Year (0.73) 0.48, 9.10 Year (0.72) 0.23, 4.23 Year (0.74) 0.22, 4.31 Plasma ADA activity (umol/h/ml) RBC ADA activity (umol/h/ml) Year (0.60) 0.00, 0.03 Year (0.59) 0.01, 0.11 Year (0.61) 0.01, 0.08 Year (0.46) 0.70, 4.51 Year (0.45) 1.37, 8.54 Year (0.47) 1.90, Peripheral venous whole blood RBC daxp (nmol/ml) Year (0.53) 1.32, Year (0.54) 0.65, 5.57 Year (0.54) 0.79, 6.87 Plasma ADA activity (umol/h/ml) RBC ADA activity (umol/h/ml) Year (0.50) 0.00, 0.02 Year (0.51) 0.01, 0.05 Year (0.52) 0.01, 0.05 Year (0.55) 0.93, 8.05 Year (0.56) 1.65, Year (0.56) 1.79,

4 Lymphocyte Proliferative Response Data ITT Population 3 H Thymidine Time point n Mean difference vs. baseline (SE) 95% CI incorporation CD3 antibody (counts per Year ( ) , minute) Year ( ) , Phytohaemagglutinin (counts per minute) Year ( ) , Year ( ) , Year ( ) , Year ( ) , Thymic Activity (TREC) Data (Log-Transformed) ITT Population Biomarker Time point n Mean GM ratio vs. baseline (SE) 95% CI TREC (copies/ 100 ng DNA) Year (0.83) 0.44, Year (0.75) 0.65, Year (0.83) 0.68, Summary Statistics of Genetically Modified Cells (Log-Transformed Data) ITT Population Biomarker Year 1 Year 2 Year 3 n Geometric mean (95% CI) n Geometric mean (95% CI) n Geometric mean (95% CI) Bone marrow CD15+ (%) (0.39, 2.88) (0.42, 4.10) (0.45, 1.93) CD19+ (%) (0.90, 8.42) (1.07, 7.08) (2.51, 11.00) CD3+ (%) (17.00, 70.99) (16.99, 75.29) (29.88, 75.31) CD34+ (%) (0.53, 3.10) (0.56, 5.20) (0.78, 2.56) CD56+ (%) (6.57, 41.28) (11.68, 33.39) (4.34, 22.46) Glycophorin A+ (%) (0.26, 2.07) (0.62, 3.56) (0.54, 3.20) Peripheral blood CD15+ (%) (0.26, 1.56) (0.25, 1.26) (0.32, 1.42) CD19+ (%) (17.03, 55.51) (12.74, 40.46) (15.88, 41.17) CD3+ (%) (20.91, 91.46) (48.92, 81.16) (46.66, 73.10) CD4+ (%) (39.92, 91.04) (41.83, 98.21) (46.95, 66.67) CD56+ (%) (11.57, 88.12) (11.30, 38.68) (14.55, ) CD8+ (%) (35.04, ) (67.61, 96.65) (45.04, 80.12) CD16+CD56+ (%) Summary of Subjects with Lymphocyte ADA Enzyme Activity >210 nmol/h/mg ITT Population Time point ADA Activity: n/n (%) 95% CI Year 1 4/10 (40) (12%, 74%) Year 2 5/10 (50) (19%, 81%) Year 3 8/11 (73) (39%, 94%) Lymphocytes in Peripheral Blood Data (Log-Transformed Data) ITT Population Biomarker Time point n Mean GM ratio vs. baseline (SE) 95% CI Lymphocytes (10 6 /L) Year (0.26) 0.59, 1.62 Year (0.26) 0.94, 2.59 Year (0.26) 1.20, 3.39 Summary of Time-To-PEG-ADA Reintroduction Endpoint ITT Population Endpoint Gene therapy (N=12) PEG-ADA reintroduction 2 Censored, follow-up ended 0 Censored, follow-up ongoing 10 Event summary in years n 2 Mean (standard deviation) (1.1965) Median (range) ( ) While generally remaining below the 50 th percentile, boys and girls showed increases in height and weight over the period for which data were collected. 4

5 Eleven of 12 subjects no longer required long-term enzyme replacement therapy after gene therapy. Two subjects required PEG-ADA, with a mean time to reintroduction of 1.2 years; however, 1 of these subjects was treated with PEG-ADA for only 1 month in total. All 12 subjects were receiving IVIG at screening, and 7 were able to discontinue maintenance IVIG during the 0 3 year follow-up. Six of 7 subjects who were able to discontinue IVIG had vaccination records. Three of these had detectable antibodies to pertussis, diphtheria, tetanus toxoid, and Haemophilus B at 1 or more time points. For the remaining 3 subjects post-vaccination antibody response data was not available. Safety Results: All AEs occurring in more than 1 subject are summarised below. Most Frequent Adverse Events Pre- and Post-Therapy Pre-treatment phase Treatment phase 3 Months hospitalisation 3 Month 3 Years follow-up (N=12) (N=12) (N=12) (N=12) (N=12) n (%) n (%) n (%) n (%) n (%) Subjects with any AE(s) 12 (100) 5 (42) 12 (100) 12 (100) 12 (100) Total 5

6 Failure to thrive 8 (67) (67) Rhinitis 2 (17) (67) 8 (67) Device-related infection (25) 4 (33) 6 (50) Diarrhoea 3 (25) 0 3 (25) 4 (33) 6 (50) Upper respiratory tract infection 1 (8) 0 2 (17) 4 (33) 6 (50) Anaemia 1 (8) 0 2 (17) 2 (17) 5 (42) Computerised tomogram thorax abnormal 3 (25) (25) 5 (42) Cough 1 (8) (33) 5 (42) Gastroenteritis 1 (8) (33) 5 (42) Hepatic enzyme increased (33) 2 (17) 5 (42) Hypothyroidism 3 (25) (17) 5 (42) Oral candidiasis 3 (25) 0 4 (33) 1 (8) 5 (42) Pyrexia 3 (25) 1 (8) 1 (8) 4 (33) 5 (42) Hepatomegaly 3 (25) (8) 4 (33) Hypertension 1 (8) 0 3 (25) 0 4 (33) Neutropenia (25) 2 (17) 4 (33) Phimosis 2 (17) (17) 4 (33) Skin lesion 1 (8) 0 1 (8) 2 (17) 4 (33) Atrial septal defect 3 (25) (25) Blood immunoglobulin E increased 1 (8) (17) 3 (25) Bronchitis (8) 3 (25) 3 (25) Candida infection 1 (8) 0 1 (8) 1 (8) 3 (25) Deafness bilateral 1 (8) (17) 3 (25) Ear infection 1 (8) 0 1 (8) 1 (8) 3 (25) Electrophoresis protein abnormal 1 (8) 0 1 (8) 1 (8) 3 (25) Eosinophilia 1 (8) (17) 3 (25) Escherichia urinary tract infection (8) 3 (25) 3 (25) Hypertrichosis 3 (25) (25) Nasopharyngitis 1 (8) 0 2 (17) 2 (17) 3 (25) Pneumonitis 2 (17) 0 1 (8) 0 3 (25) Psychomotor retardation 3 (25) (25) Rash (8) 2 (17) 3 (25) Upper respiratory tract infection bacterial (17) 1 (8) 3 (25) Urinary tract infection pseudomonal 1 (8) 1 (8) 3 (25) 0 3 (25) Varicella (25) 3 (25) Vomiting 2 (17) 0 1 (8) 0 3 (25) Acquired phimosis (17) 2 (17) Blood alkaline phosphatase increased 1 (8) 0 1 (8) 1 (8) 2 (17) Bone development abnormal (17) 2 (17) Cryptorchism 2 (17) (8) 2 (17) Decreased appetite (17) 0 2 (17) Dermatitis (17) 0 2 (17) Dermatitis atopic (17) 2 (17) Developmental delay 1 (8) (8) 2 (17) Enteritis (8) 1 (8) 2 (17) Febrile neutropenia (17) 0 2 (17) Food aversion 2 (17) (8) 2 (17) Gastroesophageal reflux disease 1 (8) (8) 2 (17) Haemophilus infection (17) 2 (17) Hypothalamo-pituitary disorder 2 (17) (17) Interstitial lung disease 1 (8) 0 1 (8) 0 2 (17) Iron deficiency anaemia (8) 1 (8) 2 (17) 6

7 Lymphadenopathy 2 (17) (17) Nuclear magnetic resonance 2 (17) (17) imaging brain abnormal Otitis media (17) 2 (17) Productive cough 1 (8) (8) 2 (17) Pseudomonas test positive 1 (8) 0 1 (8) 0 2 (17) Respiratory tract infection (8) 2 (17) 2 (17) Respiratory tract infection bacterial 1 (8) (8) 2 (17) Rhinorrhoea 1 (8) (8) 2 (17) Sinusitis 1 (8) (8) 2 (17) Skin ulcer 1 (8) 0 1 (8) 0 2 (17) Staphylococcal sepsis 1 (8) 0 1 (8) 0 2 (17) Tympanometry abnormal (17) 2 (17) Urinary tract infection bacterial (8) 1 (8) 2 (17) Visual evoked potentials abnormal 2 (17) (17) Weight decreased (17) 2 (17) 1 Central venous catheter Serious Adverse Events - Post-Therapy [Number of events considered by the investigator to be related to study medication] Treatment 3 Months 3 Month Total phase 1 hospitalisation 3 Years follow-up (N=12) (N=12) (N=12) (N=12) n (%) n (%) n (%) n (%) Subjects with non-fatal SAEs NR 4 (33) [0] 9 (75) [0] 10 (83) [0] Device-related infection NR 2 (17) [0] 4 (33) [0] 5 (42) [0] Gastroenteritis NR 0 2 (17) [0] 2 (17) [0] Neutropenia NR 2 (17) [0] 0 2 (17) [0] Aplastic anaemia NR 0 1 (8) [0] 1 (8) [0] Autoimmune hepatitis NR 0 1 (8) [0] 1 (8) [0] Autoimmune thrombocytopenia NR 1 (8) [0] 1 (8) [0] 1 (8) [0] Diarrhoea NR 0 1 (8) [0] 1 (8) [0] Epstein-Barr virus infection NR 1 (8) [0] 0 1 (8) [0] Guillain-Barre syndrome NR 0 1 (8) [0] 1 (8) [0] Hypertension NR 1 (8) [0] 0 1 (8) [0] Lipofibroma NR 0 1 (8) [0] 1 (8) [0] Pyrexia NR 0 1 (8) [0] 1 (8) [0] Respiratory tract infection NR 0 1 (8) [0] 1 (8) [0] Upper respiratory tract infection bacterial NR 0 1 (8) [0] 1 (8) [0] Urinary tract infection NR 0 1 (8) [0] 1 (8) [0] Varicella NR 0 1 (8) [0] 1 (8) [0] Subjects with fatal SAEs NR The formal reporting of SAEs by the investigator began from gene therapy onwards, i.e. the end of the treatment phase. Conclusion: This study demonstrated the engraftment of transduced stem cells as evidenced by the presence of genetically modified lymphocytes. This led to metabolic reconstitution with reference to ADA enzyme activity and systemic detoxification following gene therapy, and immune reconstitution with regard to lymphocyte numbers and functions. All 12 subjects were alive at the end of the follow-up period, with a concomitant decrease in the number of severe infections; 11 of 12 subjects remained free from the need to receive long-term enzyme replacement therapy. With respect to the safety of the treatment observed during the 3-year follow-up period, this was in keeping with a population of patients with primary immunodeficiency treated with non-myeloablative chemotherapy prior to autologous bone marrow transplantation. All 12 subjects reported AEs. The most frequently reported post-treatment AEs were rhinitis (8 subjects, 67%) and device-related infection (6 subjects, 50%). None of the AEs were attributed to study medication by the Investigator. There were no AEs leading to withdrawal from the study. 7

8 Ten subjects (83%) reported a total of 26 SAEs during the 0 3 years follow-up period, most frequently device-related infection (8 events in 5 subjects; 42%). None of the SAEs were fatal, none were attributed to study medication by the investigator and none led to withdrawal. The events resolved with intervention. 8