Obe-cel, an investigational therapy utilizing CD19 CAR T cells, aims to address the limitations in clinical effectiveness and safety observed with existing CD19 CAR T cell treatments. By incorporating a rapid target binding off-rate, obe-cel is specifically designed to minimize excessive activation of the modified T cells, potentially reducing toxicity and decreasing the likelihood of T cell exhaustion. These features could enhance the longevity of the modified T cells and improve their ability to repeatedly target and eliminate cancer cells.

At ASH 2023, a data update from the pivotal FELIX study demonstrated activity nominally comparable to other CD19-targeted CAR T cell therapies, with a potentially lower incidence of cytokine release syndrome. Since ASH, the major development concerning obe-cel has been the ongoing interaction with the FDA and the EMA. The results from the FELIX trial, a pivotal trial for adult ALL, were submitted and accepted by the FDA, with a PDUFA target action date of November 16, 2024. Additionally, a regulatory submission to the EMA was accepted in April 2024. 

Longer-term follow-up and additional data analysis of the pivotal Phase II FELIX study of obe-cel for adult r/r B-ALL in an oral presentation at ASCO were as follows: 

• The ORR (CR/CRi) in all patients who received obe-cel in the FELIX study was 78% (99/127 patients). 

• At the February 7, 2024, data cut-off date, the majority of ongoing responders showed durable responses. Among the responding patients, at a median follow-up of 21.45 months, 40% were in ongoing remission without subsequent SCT or other therapy, while 18% proceeded to subsequent SCT while in remission, 5% started new anti-cancer therapy while in remission, and 36% relapsed or died. 

• The median event-free survival (EFS) was 11.9 months median overall survival (OS) was 23.8 months and the estimated 12-month EFS and OS rates were 49.5% and 61.1% respectively.

• 18 of 99 responders (18%) had SCT while in MRD-negative remission. 10 of the 18 (56%) had ongoing CAR T persistency before SCT, with eight of these 10 patients (80%) experiencing relapse or death post SCT. 

• Eight out of 18 (44%) patients had lost CAR T persistency before SCT, with five of those eight patients (62%) experiencing relapse before SCT or death post-SCT. Overall, consolidative SCT for patients post-obe-cel did not appear to improve EFS or OS.

• Patients with loss of CAR T persistence had a 2.7-fold increased risk of relapse or death compared to patients with ongoing CAR T persistence. Patients who experienced B-cell recovery had a 1.7-fold increased risk of relapse compared with patients without B-cell recovery. 

• Among patients with CR/CRi beyond 6 months without SCT or new therapies, patients with ongoing CAR T persistence are associated with improved EFS vs. those with a loss of CAR T persistence.

KOL insights

“Obe-cel finally links CART persistence to the durability of response in adults with ALL and shows potential for cure wo allo as well as potential to select those who need allo based on loss of CART persistence” – Expert Opinion.

“[Obe-cel] is another option for patients with relapsed and refractory ALL, and now we’re improving upon [the efficacy of CAR T-cell] products, [which are associated with] less toxicity but equal efficacy [as earlier products”– Expert Opinion.

Conclusion

It is certainly an exciting year for Autolus Therapeutics as they approach the anticipated approval of obe-cel in the US, followed by potential approvals in Europe and the UK. With a PDUFA target action date of November 16, 2024, obe-cel is expected to be approved for ALL this year. However, its use will be significantly limited by a crowded market for salvage therapies and its complicated and costly production. Additionally, the recent FDA mandate for a boxed warning regarding the risk of T-cell malignancies for CAR-T therapies is expected to apply to obe-cel as well. 

In conclusion, the data suggest that obe-cel holds promise for achieving long-term survival outcomes in patients. At a median follow-up of 21.3 months, 40% of responders remained in remission without the need for stem cell transplant (SCT) or other therapy. Additionally, ongoing CAR-T cell persistence and B-cell aplasia were linked to improved event-free survival (EFS), consistent with findings from the Phase 1 ALLCAR19 study. Interestingly, SCT consolidation following remission with obe-cel did not seem to enhance EFS or overall survival (OS).

 

Overall, obe-cel demonstrates strong efficacy, safety, and durability compared to other cell therapies, a combination that is challenging to achieve in cell therapy. This positions obe-cel as a therapy of significant interest, leading to speculation that it could potentially become a new standard of care in this indication.