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adverse reactions
6 ADVERSE REACTIONS The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 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 most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD. All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia and lymphopenia. Sickle Cell Disease The safety of CASGEVY in patients with SCD was evaluated in two open-label, single-arm trials (Trial 1 and Trial 4) and a long-term follow-up trial that included patients with SCD and TDT (Trial 3). Trial 1 included 44 patients 12 years and older and Trial 4 included 11 patients 5 years to less than 12 years of age. Patients were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. Trial 1 (patients 12 years and older) The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY. Trial 4 (patients 5 years to less than 12 years of age) The median (min, max) duration of follow-up after being administered CASGEVY was 16.9 (7.6, 24.3) months [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 46% of patients with SCD. The most common serious adverse reactions (all in 1 patient each) were enterococcal sepsis, platelet count decreased, and viral abdominal infection. Table 2 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1 with corresponding incidences for Trial 4. Table 3 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 2: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1 with corresponding incidences in Trial 4: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. System organ class, preferred term Trial 1 (N=44) n (%) Trial 4 (N=11) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) 8 (73) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) 8 (73) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) 0 Hepatobiliary disorders Cholelithiasis 5 (11) 0 Metabolism and nutrition disorders Decreased appetite 18 (41) 3 (27) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity. , 6 (14) 0 Skin and subcutaneous tissue disorders Pruritus 5 (11) 0 In Trial 1, other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Hepatobiliary disorders : Veno-occlusive liver disease (1 [2%] patient). Infusion-related reactions : 6 (14%) patients, including preferred terms of abdominal pain in 3 (7%) patients; and infusion-related reaction, nausea, non-cardiac chest pain, pruritus, sinus tachycardia, and vomiting in 1 (2%) patient each. Table 3: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1 with corresponding incidences in Trial 4: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormality Trial 1 N=44 The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis. (%) Trial 4 N=11 (%) Neutropenia 100 100 Thrombocytopenia 100 100 Leukopenia 98 100 Anemia 84 100 Lymphopenia 50 64 CD4 lymphocytes decreased 23 0 Activated partial thromboplastin time prolonged 16 9 Hyperbilirubinemia 14 18 Platelet engraftment in patients with SCD (Trial 1 and Trial 4) Platelet engraftment in patients with SCD is defined as 3 consecutive measurements of platelet counts ≥ 50 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. One patient in Trial 4 received a thrombopoietin (TPO) mimetic which was initiated on Day 52 and continued through Day 151. The median time to platelet engraftment for patients with SCD by age sub-group is provided in Table 4. Table 4: Median (min, max) time to platelet engraftment in patients with SCD Age Number of patients Median (min, max) Time (days) to Platelet Engraftment 5 to < 12 years 11 47 (24, 78) 12 to < 17 years 9 40 (23, 64) 17 years and older 34 32.5 (23, 126) In both Trials 1 and 4, there was no association observed between bleeding events and time to platelet engraftment. Neutrophil engraftment in patients with SCD ( Trial 1 and Trial 4) Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/μL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. All patients achieved neutrophil engraftment in Trials 1 and 4. The median time to neutrophil engraftment for patients with SCD by age sub-group is provided in Table 5. Table 5: Median (min, max) time to neutrophil engraftment in patients with SCD Age Number of patients Median (min, max) Time (days) to Neutrophil Engraftment 5 to < 12 years 11 28 (20, 37) 12 to < 17 years 9 29 (26, 40) 17 years and older 35 26 (15, 38) In Trial 1, 19 out of 44 (43%) and in Trial 4, 8 out of 11 patients (73%) received G-CSF beginning on or after Day 21, post-infusion. Transfusion-dependent β-thalassemia The safety of CASGEVY in patients with TDT was evaluated in two open-label, single-arm trials (Trial 2 and Trial 5) and a long-term follow-up trial that included patients with SCD and TDT (Trial 3). Trial 2 included 52 patients 12 years and older and Trial 5 included 15 patients 5 years to less than 12 years of age. Patients were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. Trial 2 (patients 12 years and older) The median (min, max) duration of follow-up for 52 patients with TDT after being administered CASGEVY was 20.4 (2.1, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reactions (≥ 2 patients) were veno-occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection. Trial 5 (patients 5 years to less than 12 years of age) The median (min, max) duration of follow-up after CASGEVY infusion was 16.0 (2.2, 24.3) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reaction was veno-occlusive liver disease, which occurred in two patients. One patient who received busulfan conditioning and CASGEVY developed veno-occlusive disease (VOD) and hemophagocytic lymphohistiocytosis (HLH) and died due to pneumonia and subsequent multi-organ failure [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . Table 6 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 2 with the corresponding incidences in Trial 5. Table 7 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT. Table 6: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2 with corresponding incidences in Trial 5: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. System organ class, preferred term Trial 2 (N=52) n (%) Trial 5 (N=15) n (%) Blood and lymphatic system disorders Febrile neutropenia 28 (54) 13 (87) Gastrointestinal disorders Mucositis Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 37 (71) 12 (80) Hepatobiliary disorders Veno-occlusive liver disease 5 (10) 2 (13) Metabolism and nutrition disorders Decreased appetite 12 (23) 2 (13) Respiratory, thoracic and mediastinal disorders Epistaxis 7 (13) 1 (7) In Trial 2 or Trial 5, other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Immune system disorders : Hemophagocytic lymphohistiocytosis (Trial 2: 1 [2%] patient; Trial 5: 1 [7%] patient). Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (Trial 2: 1 [2%] patient). Infusion-related reactions: In Trial 2, 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each. In Trial 5, 2 (13%) patients, with preferred term of abdominal pain. Table 7: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2 with corresponding incidences in Trial 5: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormality Trial 2 N=52 The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis. (%) Trial 5 N=15 The denominator for CD4 lymphocytes decreased is 13 and the denominator for all other laboratory data is 15, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 100 Thrombocytopenia 100 100 Leukopenia 98 100 Anemia 92 93 Lymphopenia 79 67 CD4 lymphocytes decreased 23 8 Hyperbilirubinemia 23 27 Alanine aminotransferase increased 19 33 Hypokalemia 19 13 Gamma-glutamyltransferase increased 17 7 Activated partial thromboplastin time prolonged 13 27 Hypocalcemia 12 7 Platelet engraftment in patients with TDT (Trial 2 and Trial 5) Platelet engraftment in patients with TDT is defined as 3 consecutive measurements of platelet counts ≥ 20 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. The median time to platelet engraftment for patients with TDT by age sub-group is provided in Table 8. Table 8: Median (min, max) time to platelet engraftment in patients with TDT Age Number of patients Median (min, max) Time (days) to Platelet Engraftment 5 to < 12 years 14 51 (22, 82) 12 to < 17 years 13 46 (20, 199) 17 years and older 39 40 (24, 200) In both Trials 2 and 5, there was no association observed between bleeding events and time to platelet engraftment. In Trial 2, patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 47.5 (27, 200) days in patients with an intact spleen. 13 of the 14 patients achieving platelet engraftment in Trial 5 had an intact spleen. While the use of TPO mimetics was not specified in the Trial 2 protocol, five patients (10%) received a TPO mimetic at the time of platelet engraftment. All 5 patients continued TPO mimetic use for thrombocytopenia beyond engraftment. The total duration of TPO mimetic use was 98-457 days. Neutrophil engraftment in patients with TDT (Trial 2 and Trial 5) Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. All patients achieved neutrophil engraftment in Trials 2 and 5. The median time to neutrophil engraftment for patients with TDT by age sub-group is provided in Table 9. Table 9: Median (min, max) time to neutrophil engraftment in patients with TDT Age Number of patients Median (min, max) Time (days) to Neutrophil Engraftment 5 to < 12 years 15 30 (19, 38) 12 to < 17 years 13 31 (19, 56) 17 years and older 39 29 (12, 40) In Trial 2, one patient had neutrophil engraftment on Day 56. In Trial 2, 33 out of 52 (63%) patients and in Trial 5, 12 out of 15 patients (80%) received G-CSF beginning on or after Day 21 post-infusion.