On December 9, 2024 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported data from the Company’s ongoing Phase 1/2 dose escalation clinical trial evaluating the safety and efficacy of CTX112, a next-generation CD19 allogeneic CAR T cell therapy, in relapsed or refractory (R/R) CD19-positive B-cell malignancies at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, CRISPR Therapeutics, DEC 9, 2024, View Source [SID1234648896]). Additionally, the Company announced that the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation to CTX112 for the treatment of R/R follicular lymphoma and marginal zone lymphoma.

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"We are excited by these encouraging results on safety and efficacy for CTX112, which demonstrate the potential of an allogeneic CAR T treatment to produce complete remissions in heavily pre-treated patients," said Naimish Patel, M.D., Chief Medical Officer of CRISPR Therapeutics. "The data support a well-tolerated safety profile and the possibility to address the unmet need in this patient population with an off-the-shelf CAR T therapy. These results also support the potential treatment of certain autoimmune diseases by CTX112, and we are continuing to advance our SLE trial. We would like to extend our deepest gratitude to the patients, their families, and the investigators who have participated in our clinical trials. Their dedication and contributions are invaluable to advancing our programs and bringing us closer to potentially innovative treatments."

"We are very encouraged by the progress and early clinical data from CTX112, which could result in better outcomes for patients," said Armin Ghobadi, M.D., Professor of Medicine and Clinical Director, Center for Gene and Cellular Immunotherapy (CGCI), at Washington University School of Medicine. "CTX112 has shown dose-dependent efficacy and response rates that are comparable to the early autologous CAR T trials. These early results highlight the potential for CTX112 to emerge as an effective, off-the-shelf CAR T therapy for patients with relapsed or refractory CD19-positive B-cell malignancies."

CTX112 Trial Overview
The Phase 1/2 clinical trial is an open-label, multicenter study evaluating the safety and efficacy of CTX112 in relapsed or refractory (R/R) B-cell malignancies. Eligible disease subtypes include large B-cell lymphoma (LBCL), follicular lymphoma (FL) grade 1-3a, marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL). CTX112 was infused after a standard course of lymphodepleting chemotherapy (3 days of 30 mg/m2 fludarabine and 500 mg/m2 cyclophosphamide).

Data were presented from 12 subjects treated during the dose escalation with CTX112 doses ranging from 30 x 106 (Dose Level [DL] 1) to 600 x 106 (DL4) CAR+ T cells. The study population was enriched for patients with high-risk characteristics, including: 1) primary refractory disease or early relapse to first-line therapy (75%); 2) high tumor burden (SPD > 4000 mm2, 50%); and 3) high disease prognostic index score (IPI, FLIPI, MZL-IPI ≥3) or elevated lactate dehydrogenase (75%).

Safety
CTX112 was well tolerated across all dose levels. The adverse events of interest are shown in the table below.

There were no reported dose limiting toxicities (DLTs) and no reported Grade ≥3 infections. All grade 3 or 4 cytopenias (i.e., neutropenia, thrombocytopenia, anemia) following lymphodepleting chemotherapy resolved to Grade 2 or better within 1 month of CTX112 infusion. There were no reported cases of Graft versus Host Disease (GvHD),
All cases of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were Grade 1 or 2 per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. These low-grade CRS and ICANS events followed standard toxicity management protocols.
Table 1. Summary of Adverse Events of Interest

Cell dose
(CAR+ T cells) DL1
30×106
N=3 DL2
100×106
N=3 DL3
300×106
N=3 DL4
600×106
N=3 Total
N=12
Gr1-2 Gr ≥3 Gr1-2 Gr ≥3 Gr1-2 Gr ≥3 Gr1-2 Gr ≥3 Gr1-2 Gr ≥3
CRS, n (%) 1 (33) 0 2 (67) 0 1 (33) 0 3 (100) 0 7 (58) 0
ICANS, n (%) 0 0 1 (33) 0 1 (33) 0 2 (67) 0 4 (33) 0
Infections, n (%) 1 (33) 0 0 0 2 (67) 0 2 (67) 0 5 (42) 0

Clinical Efficacy
CTX112 produced responses at all dose levels. Disease assessment was performed by investigator review according to the Lugano criteria.

Table 2. Summary of Clinical Efficacy

Cell dose
(CAR+ T cells) DL1
30×106
N=3 DL2
100×106
N=3 DL3
300×106
N=3 DL4
600×106
N=3 Total
N=12
Objective Response Rate (ORR), n (%) 2 (67) 2 (67) 2 (67) 2 (67) 8 (67)
Complete Response Rate (CRR), n (%) 1 (33) 2 (67) 1 (33) 2 (67) 6 (50)
Partial Response Rate, n (%) 1 (33) 0 1 (33) 0 2 (17)

Objective and complete responses were seen at all dose levels and in all treated NHL subtypes (i.e., FL, MZL, MCL and LBCL).
Responses were also seen in patients with poor prognostic factors including primary refractory disease, early relapse, and high baseline tumor burden (e.g., SPD > 4000 mm2).
Five patients (of the 12 treated) have achieved responses lasting for more than 6 months, including one patient whose 6-month response was confirmed after the data cut-off date. One patient treated at DL1 remains in complete remission over a year after initial CTX112 infusion. The clinical efficacy of CTX112 is supported by a clearly differentiated pharmacokinetic profile for an allogeneic CAR T cell therapy.
The mean peak concentration and total exposure were significantly higher at DL3 and DL4 vs. DL1 and DL2. This dose dependence suggests the possibility of deeper and more durable responses as the trial moves from dose escalation to dose optimization.
Comparing DL3, the addition of Regnase-1 and TGFβR2 edits results in 7-fold higher peak concentration (Cmax) and 9.7-fold higher mean area under the curve (AUC) for CTX112 relative to CTX110. Furthermore, at DL4, both Cmax and AUC are showing significantly more consistent and predictable increases. This suggests that the novel CRISPR/Cas9 potency edits are leading to higher CAR T cell expansion and functional persistence without enhanced or increased lymphodepleting chemotherapy doses.
These preliminary data demonstrate that CTX112 has the potential to provide meaningful clinical benefit with a well-tolerated safety profile. Given the inherent difficulties of manufacturing a CAR T therapy from a patient’s own diseased cells, allogeneic cellular therapy approaches have greater potential to address the unmet need in this patient population. These promising findings underscore the potential of allogeneic cell therapies to offer a transformative option for patients, and we remain committed to advancing this innovative approach to address the significant unmet medical need in this area.

Regenerative Medicine Advanced Therapy (RMAT) Designation
Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising regenerative medicine pipeline products. A regenerative medicine therapy is eligible for RMAT designation if it is a cell therapy, therapeutic tissue engineering product, human cell and tissue product or any combination product of such therapies that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such disease or condition. Similar to Breakthrough Therapy designation, RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the biologics license application (BLA) and other opportunities to expedite development and review.

About CTX112
CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 19, or CD19, which incorporates edits designed to evade the immune system, enhance CAR T potency and reduce CAR T exhaustion. CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. In addition, CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with system lupus erythematosus.