Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Autolus GmbH, Im Schwarzenbach 4, 79576 Weil am Rhein, Germany
Pharmacotherapeutic group: Antineoplastic agents, Antineoplastic cell and gene therapy
ATC code: L01XL12
Obecabtagene autoleucel is an autologous immunotherapy consisting of the patient's own T cells engineered to express a CAR that recognises CD19 on-target cells via the murine CAT13.1E10 hybridoma (CAT) binding domain. Engagement of anti-CD19 (CAT) CAR-positive T cells with CD19-expressed on-target cells, such as cancer cells and normal B cells, leads to activation of the anti-CD19 (CAT) CAR-positive T cells and downstream signalling through the CD3-zeta domain. Proliferation and persistence by the anti-CD19 (CAT) CAR-positive T cells following activation are enhanced by the presence of the 4-1BB co-stimulatory domain. This binding to CD19 results in anti-tumour activity and killing of CD19-expressing target cells.
Studies demonstrate obecabtagene autoleucel has a fast off-rate of 3.1 × 10-3s-1 of its CD19 binding domain.
Serum levels of cytokines such as IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and granulocyte macrophage colony-stimulating factors were evaluated pre- and up to 3 months post-obecabtagene autoleucel infusion. Peak elevation of plasma cytokines was observed at day 28 of obecabtagene autoleucel infusion and levels returned to baseline by month 3.
Due to the on-target effect of obecabtagene autoleucel, a period of B cell aplasia is expected.
The efficacy and safety of obecabtagene autoleucel is based on the results of the FELIX study (EU CT number 2024-512903-38-00), an open-label, multi-centre, single arm Phase Ib/II study of obecabtagene autoleucel in adult patients with r/r B ALL.
The primary outcome of Cohort IIA was overall complete remission rate defined as proportion of patients achieving complete remission (CR) or complete remission with incomplete haematologic recovery (CRi) as assessed by an Independent Response Review Committee (IRRC) and the secondary outcomes included duration of remission (DOR), complete remission rate (CRR) and proportion of patients achieving minimal residual disease (MRD)-negative response.
Patients in the pivotal study were adults (≥18 years) with r/r CD19+ B ALL, presence of ≥5% blasts in BM at screening and confirmed CD19 expression after blinatumomab therapy. Relapsed or refractory status was defined as follows: primary refractory disease, first relapse following a remission lasting ≤12 months, r/r acute lymphoblastic leukaemia (ALL) after 2 or more prior lines of systemic therapy, or r/r ALL at least greater than 3 months after allogeneic HSCT. Patients with Philadelphia chromosome positive ALL were eligible if they were intolerant to or have failed 2 lines of any tyrosine kinase inhibitor (TKI) or one line of second-generation TKI, or if TKI therapy was contraindicated. Patients with prior CD19 targeted therapy other than blinatumomab were excluded. Treatment consisted of lymphodepleting chemotherapy followed by obecabtagene autoleucel as a split dose infusion with a total target dose of 410 × 106 CD19 CAR-positive viable T cells (see section 4.2).
In the pivotal Cohort IIA, 113 patients were leukapheresed (leukapheresed set) and 94 (83.2%) patients were treated with at least one obecabtagene autoleucel infusion (infused set): 19 patients discontinued without receiving infusion for reasons related to death (12 patients), adverse reaction (neutropenic sepsis related to the underlying disease [1 patient]) and physician decision (1 patient). Five out of 113 leukapheresed patients (4.4%) did not receive obecabtagene autoleucel infusion due to manufacturing-related issues.
The median age of the 94 infused patients was 50 years; among them, 83 patients were 26 years of age and above. The sex distribution of male and female patients infused with obecabtagene autoleucel was equal with 47 males and 47 females. Seventy patients were white (74.5%); 29 patients (30.9%) were of Hispanic or Latino ethnicity (Table 5).
Eighty-eight patients (93.6%) received bridging therapy (e.g., chemotherapy, inotuzumab ozogamicin, TKIs) between leukapheresis and lymphodepleting chemotherapy to control tumour burden. All patients received obecabtagene autoleucel infusion on day 1 and were hospitalised until day 10 at minimum.
Table 5. Baseline demographic and disease-related characteristics for the FELIX study (Cohort IIA):
| Infused set (N=94) | Leukapheresed set (N=113) | |
|---|---|---|
| Median age, range (years) | 50 (20 – 81) | 49 (20 – 81) |
| Age category (years), n (%) | ||
| ≥18 years and ≤25 years | 11 (11.7) | 13 (11.5) |
| >25 years | 83 (88.3) | 100 (88.5) |
| Gender, n (M/F) | 47M/47F | 61M/52F |
| Race, n (%) | ||
| Caucasian | 70 (74.5) | 87 (77.0) |
| Philadelphia chromosome positive status (BCR-ABL positive), n (%) | 25 (26.6) | 26 (23.0) |
| Median prior lines of treatment, n (range) | 2 (1 – 6) | 2 (1 – 6) |
| ≥3 prior lines, n (%) | 29 (30.9) | 35 (31.0) |
| Refractory to last prior line of therapy, n (%) | 51 (54.3) | 60 (53.1) |
| Prior HSCT, n (%) | 36 (38.3) | 43 (38.1) |
| Prior blinatumomab, n (%) | 33 (35.1) | 42 (37.2) |
| Prior inotuzumab, n (%) | 30 (31.9) | 37 (32.7) |
| BM blast % at lymphodepletion, median (range) | 43.5 (0 – 100) | 43.5 (0 – 100) |
| BM blast % at lymphodepletion, n (%) | ||
| >75% | 30 (31.9) | 30 (26.5) |
| >20% to 75% | 27 (28.7) | 27 (23.9) |
| 5 to 20% | 14 (14.9) | 14 (12.4) |
| <5% | 23 (24.5) | 23 (20.4) |
| Missing | 0 | 19 (16.8) |
| Extramedullary disease at lymphodepletion, n (%) | 19 (20.2) | 21 (18.6) |
ABL = Abelson murine leukaemia; BCR = breakpoint cluster region; BM = bone marrow; F = female; HSCT = haematopoietic stem cell transplantation; M = male.
The primary efficacy analysis was evaluated in patients who received at least one infusion of obecabtagene autoleucel (infused set) in the pivotal Cohort IIA of the FELIX study (Table 6). Of the 94 patients in the infused set, the median dose received was 410 × 106 CD19 CAR-positive viable T cells (range: 10-480 × 106 CD19 CAR-positive viable T cells). Eighty-five patients (90.4%) received the total target dose of 410 × 106 CD19 CAR-positive viable T cells. Six patients (6.4%) received the first dose only, primarily due to adverse reactions (3.2%), progressive disease (1.1%), manufacturing-related issues (1.1%) and death (1.1%). The median manufacturing time from leukapheresis receipt to product certification was 20 days (range: 17-43 days) and the median time from leukapheresis to obecabtagene autoleucel infusion was 35.5 days (range: 25-92 days). The median follow-up (duration from first infusion to data cut-off date of 07-Feb-2024) was 20.25 months (range: 13-30 months).
The secondary outcome MRD-negative rate among overall remission rate (ORR = CR or CRi) subjects was assessed by next-generation sequencing, polymerase chain reaction and flow cytometry.
Table 6. Efficacy analysis (Cohort IIA):
| Infused set (N=94) | Leukapheresed set (N=113) | |
|---|---|---|
| Overall remission rate (ORR: CR + CRi) | ||
| n (%) | 72 (76.6) | 72 (63.7) |
| 95% CI (%) | (66.7, 84.7) | (54.1, 72.6) |
| Complete remission (CR) at any time | ||
| n (%) | 52 (55.3) | 55 (48.7) |
| 95% CI (%) | (44.7, 65.6) | (39.2, 58.3) |
| MRD-negative rate among CR or CRi (NGS/PCR/flow cytometry)a | ||
| Nb | 72 | 72 |
| n (%) | 64 (88.9) | 64 (88.9) |
| 95% CI (%) | (79.3, 95.1) | (79.3, 95.1) |
| Duration of remission (DOR) | ||
| Nb | 72 | 72 |
| Median in monthsc | 14.06 | 14.06 |
| 95% CI (range in months) | (8.18, NE) | (8.18, NE) |
BM = bone marrow; BOR = best overall response post-Aucatzyl infusion; CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete recovery of counts; DOR = duration of remission; FACS = fluorescence-activated cell sorting; MRD = minimal residual disease; IRRC = Independent Response Review Committee; NE = not estimable; NGS = next-generation sequencing; ORR = overall remission rate; PCR = polymerase chain reaction; SCT = stem cell transplantation.
a Patients in remission by IRRC with MRD-negative BM by central ClonoSEQ NGS/PCR/FACS.
b Patients who achieved BOR of CR or CRi.
c With censoring for SCT and other new anti-cancer therapy.
Among the patients aged 26 years and above in the infused set (N=83), the ORR was 78.3% (95% CI [confidence interval]: 67.9, 86.6) with a CR rate of 57.8% (95% CI: 46.5, 68.6). The median DOR was 14.1 months (95% CI: 8.1, NE [not estimable]) in responding patients.
Among the patients who received the total recommended dose of 410 × 106 CAR-positive viable T cells, the ORR rate was 81.2% with a CR rate of 61.2%. The median DOR was 14.1 months (95% CI: 8.2, NE) in responding patients. For 9 patients (9.6%) who did not receive the target dose, including 6 patients who only received the first dose, the ORR rate was 33.3% with a CR rate of 0%. The median DOR was 5.2 months (95% CI: NE, NE) in responding patients (CRi).
For patients who received both doses (N=88; 93.6%), patients receiving a lower first dose of 10 × 106 cells (>20% blasts in BM, high disease burden, N=56) had a numerically lower ORR (75.0%; 95% CI: 61.6, 85.6) than patients receiving a higher first dose of 100 × 106 cells (≤20% blasts in BM, low disease burden, N=32) (87.5%; 95% CI: 71.0, 96.5). The median DOR was 12.5 months (95% CI: 7.1, NE) in responding patients receiving a lower first dose of 10 × 106 cells and 14.2 months (95% CI: 10.7, NE) in responding patients receiving a higher first dose of 100 × 106 cells.
Among patients who experienced relapse prior to start of new anti-cancer therapies, 46.4% had CD19-negative relapse, 10.7% had CD19-mixed relapse, 42.9% had CD19-positive relapse.
The European Medicines Agency has deferred the obligation to submit the results of studies with Aucatzyl in one or more subsets of the B ALL paediatric population. See section 4.2 for information on paediatric use.
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetics (PK) of obecabtagene autoleucel were assessed in 94 patients with r/r CD19+ B ALL receiving a median dose of 410 × 106 CD19 CAR-positive viable T cells (range: 10-480 × 106 CD19 CAR-positive viable T cells).
A rapid expansion occurred after infusion of the first dose in the majority of the patients and continued after the second dose up to the median time of maximal expansion to peak (Tmax) at day 14 (range: 2-55 days).
Decline of CAR T concentrations started shortly after day 28 and reached a stabilised concentration from month 6; with a maximum persistency observed at 27.7 months.
A high level of expansion was generally observed regardless of response status (CR/CRi vs. non-CR/non-CRi). A total of 84.6% (22/26) of patients who had ongoing remission had ongoing CAR T persistency at the last laboratory assessment.
Table 7. Summary of PK parameters in peripheral blood by BOR (Cohort IIA, infused set:
| Parameter metric | Best overall response | Overall (N=94) | |
|---|---|---|---|
| CR/CRi (N=72) | Not CR/CRi (N=22) | ||
| Cmax (copies/μg DNA) | |||
| N | 72 | 22 | 94 |
| Geometric mean (Geo-CV%) | 117 381 (206.0) | 107 465 (832.7) | 114 982 (287.6) |
| Range (min - max) | 2 120-478 000 | 129-600 000 | 129-600 000 |
| Tmax (days) | |||
| N | 72 | 22 | 94 |
| Median | 14 | 17 | 14 |
| Range (min - max) | 2-55 | 6-28 | 2-55 |
| AUC(0-28d) (copies/μg DNA*days) | |||
| N | 68 | 14 | 82 |
| Geometric mean (Geo-CV%) | 1 089 908 (236.0) | 1 404 899 (186.4) | 1 138 188 (225.6) |
| Range (min - max) | 17 900-6 730 000 | 176 000-7 230 000 | 17 900-7 230 000 |
AUC(0-28d) = area under the concentration-time curve from day 0 to day 28; BOR = best overall response; Cmax = maximum concentration; CR = complete remission; CRi = complete remission with incomplete recovery of counts; DNA = deoxyribonucleic acid; Geo-CV% = geometric coefficient of variation; PK = pharmacokinetic; Tmax = time to maximum concentration.
Patients who received a first split dose of 10 × 106 cells (>20% blast) demonstrated a higher expansion of CAR T cells (Cmax and AUC0-28d) compared with patients who received a first split dose of 100 × 106 cells (≤20% blast). In turn, patients with high expansion tended to have higher rates of CRS and ICANS. Therefore, high tumour burden is the main risk factor for onset of CRS and ICANS.
In the FELIX study, the median body weight was 75.75 kg (range: 42.6-230.6 kg). The PK profile was comparable between patients with lower (<75.75 kg) and higher (≥75.75 kg) body weight.
Gender or age (below 65 years, between 65 and 74 years, and between 75 and 84 years) did not have a significant impact on the PK of Aucatzyl (Cmax, AUC0-28d or persistency).
The data in the non-white population (Table 5) are too limited to draw any conclusions on the impact of race on PK parameters.
Hepatic and renal impairment studies of Aucatzyl were not conducted.
Aucatzyl comprises engineered human T cells; therefore, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for medicinal product development were not performed.
No carcinogenicity or genotoxicity studies have been conducted with Aucatzyl. No studies have been conducted to evaluate the effects of Aucatzyl on fertility, reproduction and development.
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