On December 4, 2023 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported an update on its immuno-oncology pipeline of CRISPR/Cas9 gene-edited allogeneic chimeric antigen receptor (CAR) T cell product candidates (Press release, CRISPR Therapeutics, DEC 4, 2023, View Source [SID1234638122]).

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The Company’s first-generation allogeneic CAR T candidates, CTX110 and CTX130, provided important proof of concept that allogeneic CAR T cells can produce durable remissions following a standard lymphodepletion regimen. Preliminary data from ongoing clinical trials of its next-generation candidates, CTX112 targeting CD19 and CTX131 targeting CD70, suggest that these candidates may improve upon that clinical profile. Emerging pharmacology data, including pharmacokinetics, indicate that the novel potency gene edits in CTX112 and CTX131 lead to significantly higher CAR T cell expansion and functional persistence in patients compared to the first-generation candidates. In addition, the next-generation candidates exhibit increased manufacturing robustness, with a higher and more consistent number of CAR T cells produced per batch. Based on these considerations, the Company is focusing on the development of CTX112 and CTX131 and will be transitioning patients treated with CTX110 and CTX130 to long-term follow-up where applicable.

"Our next-generation allogeneic CAR T candidates reflect our mission of innovating continuously to bring potentially transformative medicines to patients as quickly as possible," said Samarth Kulkarni, Ph.D., Chief Executive Officer and Chairman of the Board of CRISPR Therapeutics. "We are excited about our next-generation CAR T platform, and focusing our efforts on these candidates will allow us to advance these potentially best-in-class CAR T therapies more efficiently and rapidly."

"We are very encouraged by the progress and early clinical data from our next-generation candidates. While we saw benefits from consolidation dosing with CTX110, we believe CTX112 could result in even better outcomes for patients," said PK Morrow, M.D., Chief Medical Officer of CRISPR Therapeutics. "We thank the patients, families, and investigators who have participated in our clinical trials of CTX110 and CTX130 and look forward to applying learnings from these programs to expedite the development of CTX112 and CTX131."

In December 2022, the Company presented data from Part A of the Phase 1/2 clinical trial of CTX110 that showed the potential for CTX110 to produce durable complete remissions in heavily pre-treated patients following a standard lymphodepletion regimen. In new data updated today, Part B of the trial demonstrated an increased 6-month complete response (CR) rate following the inclusion of consolidation dosing, as shown in the table below. The safety profile of CTX110 in Part B remained consistent with the positively differentiated safety profile observed in Part A.

Part A
Single dose with optional
re-dosing at ≥DL3 (N=27) Part B
Consolidation dosing at
DL4 (N=31)
ORR 67% 65%
CR rate 41% 39%
6-month CR rate 19% 23%

CTX112 and CTX131 have the potential to improve upon the efficacy observed with CTX110 and CTX130. These next-generation candidates each incorporate two novel gene edits—knock-out of Regnase-1 and transforming growth factor-beta receptor type 2 (TGFBR2)—that have the potential to enhance CAR T potency and reduce CAR T exhaustion. Editing Regnase-1 removes an intrinsic "brake" on T cell function while editing TGFBR2 removes a key extrinsic "brake" on T cell anti-tumor activity. CRISPR Therapeutics identified this combination of edits through systematic screening of dozens of new and previously described genes. In preclinical studies, these edits synergistically improved potency approximately 10-fold compared to the first-generation candidates. Clinical trials are ongoing for CTX112 in B-cell malignancies and for CTX131 in solid tumors. The Company is producing CTX112 and CTX131 for clinical trials at its internal GMP manufacturing facility.

Furthermore, CRISPR Therapeutics announced plans to initiate new clinical trials of CTX112 and CTX131 in additional indications. The Company plans to expand the evaluation of CTX112 beyond oncology into autoimmune diseases. Early clinical studies have shown that CD19-directed autologous CAR T therapy can produce long-lasting remissions in multiple autoimmune indications. CTX112 has the potential to provide similar results with several advantages, including greater scalability, lower cost of goods, and no patient apheresis. The Company plans to initiate a clinical trial in systemic lupus erythematosus (SLE) in the first half of 2024, with the potential to expand into additional autoimmune indications in the future.

About CD19 Candidates
CTX110 is a wholly-owned, healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting cluster of differentiation 19, or CD19, and CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting CD19, which incorporates additional edits designed to 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.

About CD70 Candidates
CTX130 is a wholly-owned, healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting cluster of differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies, and CTX131 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting CD70, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX131 is being investigated in a clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors.