On January 4, 2024 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer and autoimmune disease, reported its 2024 Platform Vision that redefines the future of CAR T by leveraging the unique attributes of allogeneic CAR T products (Press release, Allogene, JAN 4, 2024, View Source [SID1234638961]).

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"Until now, CAR T development has been defined by how autologous CAR Ts are made and used. As a management team with extensive experience in both autologous and allogeneic CAR Ts, and the only Company with the breadth of data to demonstrate comparability between the two, we are uniquely positioned to potentially redefine development and trial design of allogeneic CAR T products that allows us to do what no autologous CAR T has done before," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "We believe this entirely new approach to development creates an advantage for our investigational AlloCAR T products now and in the future while providing a clinical framework to generate far more competitive CAR T products and dramatically expand market opportunity."

The Foundation: Pivotal ALPHA3 1L Consolidation Trial in Large B Cell Lymphoma (LBCL)
In a commanding pivot for the CD19 program, the Company will focus development of its investigational product cemacabtagene ansegedleucel, or cema-cel (previously known as ALLO-501A) as part of the first line (1L) treatment plan for newly diagnosed and treated LBCL patients who are likely to relapse and need further therapy. The groundbreaking design of the ALPHA3 1L consolidation trial builds upon the results demonstrated in the Phase 1 ALPHA2 trial and leverages an investigational cutting-edge diagnostic test developed by Foresight Diagnostics to identify patients who have minimal residual disease (MRD) at the completion of 1L chemoimmunotherapy for treatment with cema-cel.

Although 1L R-CHOP is curative for many with LBCL, approximately 30% of patients who initially respond will relapsei. The standard of care after 1L treatment has been simply to "watch and wait" for the disease to relapse. ALPHA3 takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP, positioning it to become the standard "7th cycle" of frontline treatment available to all eligible patients with MRD. ALPHA3 builds on the growing understanding that administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes. Cema-cel’s Phase 1 safety profile, with low rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), already permits its use in the outpatient setting in relapsed/refractory (r/r) patients and may further improve in patients with no radiological evidence of disease.

Start-up activities for the ALPHA3 trial have been initiated. The study will randomize approximately 230 patients who are MRD positive at the end of 1L therapy to either consolidation with cema-cel or the current standard of care (observation). The design, with a primary endpoint of event free survival (EFS), will initially include two lymphodepletion arms (one with standard fludarabine and cyclophosphamide plus ALLO-647 and one without ALLO-647).

The outcome of this pivotal trial could allow cema-cel to be embedded in the 1L setting to boost cure rates, potentially rendering later-line treatment obsolete, and making cema-cel available in community cancer centers where most earlier line patients seek care. As a result of this differentiated vision for cema-cel which competitively places its use ahead of other CAR T therapies, the Company will focus on quickly advancing this market-defining ALPHA3 trial and deprioritize the currently enrolling third line (3L) ALPHA2 and EXPAND trials.

The Higher Bar: ALPHA2 Cema-Cel Trial in Chronic Lymphocytic Leukemia (CLL)
There is a growing need for effective treatment in CLL post-Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitor (BCL2i) therapies. While recent autologous CD19 CAR T data has been a positive step for patients with r/r CLL, these therapies are still not meeting the efficacy bar or expectations set in r/r LBCL. This is likely due in part to T cell dysfunction and high circulating tumor burden in CLL, making the isolation of functional T cells for autologous CAR T manufacturing difficult.

There is strong scientific rationale to believe that an AlloCAR T product derived from healthy donor cells could raise the bar and potentially create a clinically meaningful advance for these late-stage patients, with a one-time dose and simpler administration and logistics.

The new Phase 1 ALPHA2 cohort of 12 patients treated with the investigational product cema-cel provides the opportunity to set a higher bar where patients with CLL are not reliant on their own T cells’ fitness to benefit from the curative potential of CAR T. This study, driven by investigator enthusiasm, will leverage currently active ALPHA2 trial sites in the U.S. which should allow it to advance quickly. It is expected to begin enrolling in Q1 2024 with initial data projected by YE 2024.

The Disruptor: ALLO-329 CD19 Dagger in Autoimmune Disease (AID)
The Company is applying its deep understanding of CAR Ts to design a next-generation allogeneic CAR T with reduced or chemotherapy-free conditioning that the Company believes can sustain the scale of the AID market while meeting the unique requirements for these patients where they seek care.

The risk tolerance of these patients is very different than those with cancer, in large part because of patient demographics, wide availability of effective therapies, and rheumatologists’ general lack of experience with chemotherapy, leukapheresis procedures and cell therapies.

Incorporation of the Dagger technology into an off-the-shelf CD19 product for use in AID is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19+ B-cells and CD70+ activated T-cells, both of which play a role in AID. Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025.

The Key: TRAVERSE ALLO-316 in Renal Cell Carcinoma (RCC)
A fundamental discovery in early CAR T trials was the use of tocilizumab and steroids, the "safety key" needed to mitigate treatment-associated CRS without compromising CAR T function or efficacy. The Company believes it may have made the same cornerstone discovery in the TRAVERSE trial in renal cell carcinoma.

During the careful advancement of the TRAVERSE trial with ALLO-316, the Company has observed remarkable allogeneic CAR T cell expansion and persistence driven by its unique CD70 CAR that allows elimination of alloreactive host lymphocytes. This biology has brought the potential for clinical efficacy not often seen in patients with r/r RCC but has also resulted in a hyperinflammatory response in some patients as CD70 CAR T cells expand and persist.

Leveraging recent advances in the management of hyperinflammation following autologous CAR T administration, the Company has developed a diagnostic and treatment algorithm similar to what the management team previously helped develop for CRS and ICANS. Like tocilizumab and steroids, this algorithm may mitigate the treatment-associated hyperinflammatory response without compromising the CAR T function needed to eradicate solid tumors. The Company has recently implemented a protocol amendment to further maximize the benefit-risk of ALLO-316 in patients with CD70+ RCC.

The next update from this trial is planned for a medical forum in Q2 2024 and will discuss the algorithm that is believed to be a critical advance for both the TRAVERSE trial as well as the industry at large. A more robust data update from the ongoing trial with the updated protocol is planned for later in 2024.

The Source: Proprietary Cell Forge 1 Allogeneic CAR T Manufacturing Facility
Cell Forge 1 (CF1), the Company’s wholly owned and fully integrated manufacturing facility, serves as a crucial strategic asset given the potential outlook for allogeneic CAR T product demand. We believe the ability to scale and control manufacturing will allow the Company to deliver a consistently high-quality allogeneic CAR T product.

Financial Runway Extended into 2026
The refined approach of the 2024 Platform Vision results in a streamlined trial footprint as well as a focused pipeline prioritization, allowing the Company to implement a planned restructuring of resources in Q1 2024. The result will reduce cash burn and is expected to extend the Company’s financial runway into 2026. Full 2024 guidance will be provided in the Company’s Q4/YE 2023 quarterly call.

JP Morgan Preview Conference Call
The 2024 Platform Vision Conference Call will be hosted on Thursday, January 4, 2024, at 2:00 p.m. PT/5:00 p.m. ET and include presentations and/or commentary by:

David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder
Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer
Alex Herrera. M.D., Chief, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at The City of Hope
Dr. Chang will also present the 2024 Platform Vision at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 10, 2024, at 8:15 a.m. Pacific Time. This event will be held in San Francisco at the Westin St. Francis.

Conference Call Details
Allogene will host a live conference call today at 2:00 p.m. Pacific Time / 5:00 p.m. Eastern Time to discuss the 2024 Vision for Allogene. If you would like the option to ask a question on the conference call, please use this link to register. Upon registering for the conference call, you will receive a personal PIN to access the call, which will identify you as the participant and allow you the option to ask a question.

JP Morgan Conference
A live audio webcast of the presentation will be made available on the Company’s website at www.allogene.com under the Investors tab in the News and Events section.

Following these live audio webcasts, replays will be available on the Company’s website for approximately 30 days. The materials presented will be available on the Allogene website.

About Cemacabtagene Ansegedleucel (Previously Known as ALLO-501A)
Cemacabtagene ansegedleucel, or cema-cel is a next generation anti-CD19 AlloCAR T investigational product for the treatment of large B cell lymphoma (LBCL). This product candidate is currently being studied in an ongoing potentially pivotal Phase 2 trial in relapsed/refractory (r/r) LBCL. The ALPHA3 pivotal Phase 2 trial in first line (1L) consolidation for the treatment of LBCL is expected to begin mid-2024. In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to cema-cel in third line (3L) r/r LBCL.