Abecma idecabtagene vicleucel 300000000 1/1 Suspension, 1 suspension — NDC 59572-515-02 (Billing 59572-0515-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action ABECMA is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

12.2Pharmacodynamics Following ABECMA infusion, pharmacodynamic responses of CAR activation and anti-tumor efficacy were evaluated. Peak elevation of plasma cytokines, chemokines, and soluble immune mediators occurred within 14 days of ABECMA infusion and returned to baseline levels within one month. Rapid decreases in tumor markers associated with clinical response, including serum levels of soluble BCMA, and bone marrow CD138+ cells, as well as minimal residual disease (MRD) negative responses, were observed within the first month following ABECMA infusion.

12.3Pharmacokinetics Following ABECMA infusion, the CAR-positive T cells proliferate and undergo rapid multi-log expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood (T max ) occurred 11 days after infusion. ABECMA can persist in peripheral blood for up to 1 year post-infusion.

A summary of T max , AUC 0-28days , and C max from Study 1 and Study 2 is provided in Table 7. Table 7: Pharmacokinetic Parameters of ABECMA in Patients with Relapsed/Refractory Multiple Myeloma AUC 0-28days =area under the curve of the transgene level from time of dose to 28 days post-infusion; C max =the maximum transgene level; ddPCR=droplet digital polymerase chain reaction; qPCR=quantitative polymerase chain reaction; PK=pharmacokinetics; T max =time of maximum observed transgene level. a The PK parameters of Study 1 were determined by time course of transgene copies per microgram of DNA extracted from whole blood as quantified by droplet digital PCR (ddPCR). b The PK parameters of Study 2 were determined by time course of transgene copies per microgram of DNA extracted from CD3+ sorted cells as quantified by quantitative polymerase chain reaction (qPCR).

Note: The PK parameters should not be directly compared between Study 1 and Study 2 due to different primary PK assays used in these two studies. Pharmacokinetic Parameter Summary Statistic Study 1 Total [300 to 510 × 10 6 ] CAR-Positive T Cells (Quantified by ddPCR) a Study 2 Total [300 to 460 × 10 6 ] CAR-Positive T Cells (Quantified by qPCR) b T max (days) Median (Range) 11 (4-31) N=207 11 (7-28) N=99 C max (copies/mcg) Geometric mean (geometric CV%) 117,557 (215) N=207 256,333 (165) N=99 AUC 0-28days (days* copies/mcg) Geometric mean (geometric CV%) 1,098,862 (228) N=205 3,088,455 (190) N=98 ABECMA transgene levels were positively associated with objective tumor response (partial response or better).

Among patients who received ABECMA in Study 1, the median C max levels in responders (N=172) were approximately 6.5-fold higher compared to the corresponding levels in non-responders (N=35). Median AUC 0-28days in responders (N=172) was approximately 6.1-fold higher than non-responders (N=33). Among patients who received ABECMA in Study 2, the median C max levels in responders (N=72) were approximately 4.6-fold higher than the corresponding levels in non-responders (N=27).

Median AUC 0-28days in responders (N=72) was approximately 5.6-fold higher than non-responders (N=26). Tocilizumab or Siltuximab and Corticosteroid Use Some patients required tocilizumab or siltuximab and/or corticosteroid for the management of CRS. ABECMA can continue to expand and persist following tocilizumab or siltuximab or corticosteroid administration [see Warnings and Precautions (5.2) ] .

In Study 2, patients with CRS treated with tocilizumab h… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action ABECMA is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

12.3Pharmacokinetics Following ABECMA infusion, the CAR-positive T cells proliferate and undergo rapid multi-log expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood (T max ) occurred 11 days after infusion. ABECMA can persist in peripheral blood for up to 1 year post-infusion.

A summary of T max , AUC 0-28days , and C max from Study 1 and Study 2 is provided in Table 7. Table 7: Pharmacokinetic Parameters of ABECMA in Patients with Relapsed/Refractory Multiple Myeloma AUC 0-28days =area under the curve of the transgene level from time of dose to 28 days post-infusion; C max =the maximum transgene level; ddPCR=droplet digital polymerase chain reaction; qPCR=quantitative polymerase chain reaction; PK=pharmacokinetics; T max =time of maximum observed transgene level. a The PK parameters of Study 1 were determined by time course of transgene copies per microgram of DNA extracted from whole blood as quantified by droplet digital PCR (ddPCR). b The PK parameters of Study 2 were determined by time course of transgene copies per microgram of DNA extracted from CD3+ sorted cells as quantified by quantitative polymerase chain reaction (qPCR).

Note: The PK parameters should not be directly compared between Study 1 and Study 2 due to different primary PK assays used in these two studies. Pharmacokinetic Parameter Summary Statistic Study 1 Total [300 to 510 × 10 6 ] CAR-Positive T Cells (Quantified by ddPCR) a Study 2 Total [300 to 460 × 10 6 ] CAR-Positive T Cells (Quantified by qPCR) b T max (days) Median (Range) 11 (4-31) N=207 11 (7-28) N=99 C max (copies/mcg) Geometric mean (geometric CV%) 117,557 (215) N=207 256,333 (165) N=99 AUC 0-28days (days* copies/mcg) Geometric mean (geometric CV%) 1,098,862 (228) N=205 3,088,455 (190) N=98 ABECMA transgene levels were positively associated with objective tumor response (partial response or better).

Among patients who received ABECMA in Study 1, the median C max levels in responders (N=172) were approximately 6.5-fold higher compared to the corresponding levels in non-responders (N=35). Median AUC 0-28days in responders (N=172) was approximately 6.1-fold higher than non-responders (N=33). Among patients who received ABECMA in Study 2, the median C max levels in responders (N=72) were approximately 4.6-fold higher than the corresponding levels in non-responders (N=27).

Median AUC 0-28days in responders (N=72) was approximately 5.6-fold higher than non-responders (N=26). Tocilizumab or Siltuximab and Corticosteroid Use Some patients required tocilizumab or siltuximab and/or corticosteroid for the management of CRS. ABECMA can continue to expand and persist following tocilizumab or siltuximab or corticosteroid administration [see Warnings and Precautions (5.2) ] .

In Study 2, patients with CRS treated with tocilizumab had higher ABECMA cellular expansion levels, as measured by 1.3‑fold and 1.6-fold higher median C max (N=67) and AUC 0‑28days (N=66), respectively, compared to patients who did not receive tocilizumab (N=59 for C max and N=58 for AUC 0‑28days ). Patients with CRS treated with corticosteroids had higher ABECMA cellular expansion levels, as measured by 1.7-fold and 2.2-fold higher median C max (N=18) and AUC 0‑28days (N=18), respectively, compared to patients who did not receive corticosteroids (N=108 for C max and N=106 for AUC 0‑28days ).

Similar trend was observed in Study 1. Specific Populations Geriatric Age (range: 30 to 81 years) had no significant impact on expansion parameters [see Use in Special Populations (8.5) ] . Pediatric The pharmacokinetics of ABECMA in patients less than 18 years of age have not been evaluated.

Patients with Hepatic/Renal Impairment Hepatic and renal impairment studies of ABECMA were not conducted. Patients with Other Intrinsic Factors Gender, race, and ethnicity had no significant impact on ABECMA expansion parameters. Patients with lower body weight had higher expansion.

Due to high variability… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Following ABECMA infusion, pharmacodynamic responses of CAR activation and anti-tumor efficacy were evaluated. Peak elevation of plasma cytokines, chemokines, and soluble immune mediators occurred within 14 days of ABECMA infusion and returned to baseline levels within one month. Rapid decreases in tumor markers associated with clinical response, including serum levels of soluble BCMA, and bone marrow CD138+ cells, as well as minimal residual disease (MRD) negative responses, were observed within the first month following ABECMA infusion.

14 CLINICAL STUDIES The efficacy of ABECMA was evaluated in two studies, Study 1 (Study BB2121-MM-003; NCT03651128) and Study 2 (Study BB2121-MM-001; NCT03361748) as described below. Study 1 (Relapsed/Refractory Multiple Myeloma After Two to Four Prior Lines of Therapy) Study 1 was an open-label, multicenter, randomized, controlled study in adult patients with relapsed and refractory multiple myeloma who had received two to four prior antimyeloma therapies including an immunomodulatory agent, a proteasome inhibitor and daratumumab, and were refractory to the most recent prior antimyeloma regimen.

The study included patients who achieved a response (minimal response or better) to at least 1 prior treatment regimen and had ECOG performance status of 0 or 1. The study excluded patients with serum creatinine clearance <45 mL/min, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal, and left ventricular ejection fraction (LVEF) <45%. Patients were also excluded if absolute neutrophil count <1000/µL and platelet count <75,000/μL in patients in whom <50% of bone marrow nucleated cells are plasma cells and platelet count <50,000/μL in patients in whom ≥50% of bone marrow nucleated cells are plasma cells.

In total, 386 patients were randomized 2:1 to receive either ABECMA (N=254) or standard regimens (N=132). The standard regimens consisted of daratumumab, pomalidomide, dexamethasone [DPd], daratumumab, bortezomib, dexamethasone [DVd], ixazomib, lenalidomide, dexamethasone [IRd], carfilzomib, dexamethasone [Kd], or elotuzumab, pomalidomide, dexamethasone [EPd]), selected by Investigator prior to randomization contingent upon the patient’s most recent antimyeloma treatment. Randomization was stratified by age, number of prior antimyeloma regimens, and presence of high-risk cytogenetics abnormalities.

Patients randomized to ABECMA were to receive lymphodepleting chemotherapy consisting of cyclophosphamide (300 mg/m 2 IV infusion daily for 3 days) and fludarabine (30 mg/m 2 IV infusion daily for 3 days) starting 5 days prior to the target infusion date of ABECMA. Up to 1 cycle of DPd, DVd, IRd, Kd or EPd bridging therapy, dependent on the patient’s most recent antimyeloma treatment regimen, was permitted for disease control between apheresis and until 14 days before the start of lymphodepleting chemotherapy. Of the 254 patients randomized to receive ABECMA, 249 (98%) patients underwent leukapheresis: • Five (2%) patients did not receive leukapheresis due to patient withdrawal (n=2), adverse event (n=1) or failure to meet lymphodepleting chemotherapy treatment criteria (n=2). • Twenty-four (10%) patients did not receive ABECMA either due to death (n=4), adverse event (n=4), physician decision (n=7), failure to meet lymphodepleting chemotherapy treatment criteria (n=6) or inability to manufacture product (n=3). • Three (1.2%) patients received CAR-positive T cells that did not meet product release specifications for ABECMA (non-conforming product; n=3).

The overall manufacturing failure rate for patients who underwent leukapheresis was 2.4% (6 out of 249 patients). Of these six patients, three received CAR positive T cells that did not meet product release specifications for ABECMA, and in three patients there was an inability to manufacture ABECMA. Most patients (85%) treated with ABECMA received bridging therapy for control of their multiple myeloma during the manufacturing process.

The median time from leukapheresis to product availability was 35 days (range: 24 to 102 days). In overall study population, the median age was 63 years (range: 30 to 83 years), 61% were male, 65% were white, 9.3% were black and 3.1% were Asian. Most patients (80%) were Revised International Staging System (R-ISS) Stage I or II.

High-risk cytogenetics [presence of t(4:14), (14:16), and 17p13 del] were present in 42% of patients. Twenty-four percent of patients had presence of extramedullary disease. The med… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Genotoxicity assays and carcinogenicity studies in rodents were not performed for ABECMA. In vitro expansion studies with CAR-positive T cells (ABECMA) from five patients and two healthy donor drug product lots showed no evidence for transformation and/or immortalization of T cells. A genomic insertion site analysis of the lentiviral vector was performed on ABECMA samples from twenty (20) individual patient donors.

There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harboring integration sites of concern. No studies on the effects of ABECMA on fertility have been conducted.