-58% overall response rate (ORR) and 38% complete response (CR) rate in large B-cell lymphoma (LBCL) with a single dose of CTX110 at Dose Level 2 (DL2) and above on an intent-to-treat (ITT) basis-
-Durable responses in LBCL achieved with six-month CR rate of 21% and longest response on-going at over 18 months after initial infusion-
-Response rates and durability are similar to approved autologous CD19 CAR-T therapies on an ITT basis-
-Positively differentiated safety profile; no Grade 3 or higher cytokine release syndrome (CRS) and low rates of infection and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)-
-Expanding CARBON into a potentially registrational trial in 1Q 2022-
ZUG, Switzerland and CAMBRIDGE, MA, USA I October 12, 2021 I CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced updated results from the Company’s ongoing Phase 1 CARBON trial evaluating the safety and efficacy of CTX110™, its wholly-owned allogeneic CAR-T cell therapy targeting CD19+ B-cell malignancies.
“We are excited to share positive data from our CARBON trial, which show that CTX110 could offer patients with large B-cell lymphomas an immediately available ‘off-the-shelf’ therapy with efficacy similar to autologous CAR-T and a differentiated safety profile,” said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. “Furthermore, we have the potential to improve upon already observed efficacy with a consolidation dosing strategy. Based on these encouraging results, we are planning to expand CARBON into a potentially registrational trial in the first quarter of 2022.”
CARBON Trial Overview
The Phase 1 CARBON trial is an open-label, multicenter clinical trial evaluating the safety and efficacy of CTX110 in adult patients with relapsed or refractory B-cell CD19+ malignancies who have received at least two prior lines of therapy. To date, enrollment has been focused on patients with the most aggressive disease presentations, including diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), high-grade double- or triple-hit lymphomas, and transformed follicular lymphoma. The majority of patients had Stage IV lymphoma and were refractory to their last line of therapy before entering the trial. Nine patients received prior autologous stem cell transplant. Patients who received prior autologous CAR-T therapy were not eligible.
As of the August 26, 2021 data cutoff, 30 patients with large B-cell lymphoma (LBCL) had been enrolled, of which 26 patients had received CTX110 with at least 28 days of follow-up and are included in the analysis. Only one enrolled patient did not receive CTX110. Three patients at the time of the data cut had less than 28 days of follow-up and were not evaluable for this analysis.
Patients were infused with a single CTX110 infusion following three days of a standard lymphodepletion regimen consisting of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day). Patients could be re-dosed with CTX110 following disease progression. The primary endpoints include safety as measured by the incidence of dose limiting toxicities (DLTs) and overall response rate (ORR). Key secondary endpoints include complete response (CR) rate, duration of response and overall survival.
Additional details may be found at clinicaltrials.gov, using identifier: NCT04035434.
Safety
CTX110 was well tolerated across all dose levels. The adverse events of interest for all evaluable patients are shown in the table below.
- There were no cases of Graft versus Host Disease (GvHD) and no infusion reactions to either lymphodepleting chemotherapy or CTX110.
- All cases of cytokine release syndrome (CRS) were Grade 1 or 2 per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria and either required no specific intervention or resolved following standard CRS management. Neither the frequency nor severity of CRS has increased in patients who were re-dosed with CTX110.
- The only case of Grade 3 or higher immune effector cell-associated neurotoxicity syndrome (ICANS) was in the patient with concurrent HHV-6 encephalitis who was previously disclosed. There have been no cases of ICANS in any other patients treated at Dose Level (DL3) through Dose Level (DL4).
- Only two patients experienced Grade 3 or higher infections: the previously discussed patient with HHV-6 encephalitis, and one patient who developed pseudomonal sepsis that resolved in four days.
| Adverse events of interest N (%) | ||||||||||||
| DL1 (N=3) | DL2 (N=3) | DL3 (N=6) | DL3.5 (N=6) | DL4 (N=8) | DL2+ (N=23) | |||||||
| Gr 1-2 | Gr 3+ | Gr 1-2 | Gr 3+ | Gr 1-2 | Gr 3+ | Gr 1-2 | Gr 3+ | Gr 1-2 | Gr 3+ | Gr 1-2 | Gr 3+ | |
| CRS | 1 | – | 2 | – | 2 | – | 3 | – | 6 | – | 13 | – |
| (33) | (67) | (33) | (50) | (75) | (57) | |||||||
| ICANS | – | – | 1 | – | – | – | – | – | – | 1 | 1 | 1 |
| (33) | (13) | (4) | (4) | |||||||||
| GvHD | – | – | – | – | – | – | – | – | – | – | – | – |
| Infusion reactions | – | – | – | – | – | – | – | – | – | – | – | – |
| Infections1 | – | 1 | – | – | 1 | 1 | 1 | – | 1 | 1 | 3 | 2 |
| (33) | (17) | (17) | (17) | (13) | (13) | (13) | (9) | |||||
| CRS and ICANS graded per ASTCT criteria; other adverse events graded per CTCAE; (1) All infections (bacterial, fungal, and viral) included | ||||||||||||
The emerging safety profile of CTX110 is positively differentiated from autologous CAR-T therapies that show high frequencies of severe CRS and ICANS, and from other allogeneic CAR-T therapies that require more toxic lymphodepletion regimens and can result in prolonged immunosuppression and increased risk of serious infections.
Clinical Activity
Data are shown below for the 26 patients that received CTX110 and had at least 28 days of follow-up. The ORR and CR rates for patients treated at DL2 and above are shown both on an intent-to-treat (ITT) and modified ITT (mITT) basis. ITT includes all enrolled patients (n=24 at DL2 and above) whereas mITT includes only those patients who received an infusion of CTX110 (n=23 at DL2 and above). Dose-dependent responses and durable complete responses were seen with CTX110. Disease assessment was performed by investigator review according to the 2014 Lugano response criteria.
| Cell dose | DL1 | DL2 | DL3 | DL3.5 | DL4 | DL2+ mITT | DL2+ | |
| (CAR+ T cells) | 30×106 | 100×106 | 300×106 | 450×106 | 600×106 | N=23 | ITT | |
| N=3 | N=3 | N=6 | N=6 | N=8 | N=24 | |||
| Overall response rate (ORR), N (%) | 0 (0%) | 1 (33%) | 3 (50%) | 4 (67%) | 6 (75%) | 14 (61%) | 14 (58%) | |
| Complete response (CR) rate, N (%) | 0 (0%) | 1 (33%) | 2 (33%) | 3 (50%) | 3 (38%) | 9 (39%) | 9 (38%) |
- A single dose of CTX110 at DL2 and above resulted in a 58% ORR and 38% CR rate on an ITT basis.
- Responses were seen in a variety of patients, including patients who had refractory disease, bulky disease, or who had progressed after prior autologous stem cell transplant.
- The data demonstrate the potential for CTX110 to produce durable remissions, as evidenced by a 21% six-month CR rate (4 of the 9 patients who achieved CR at Day 28, remained in CR at 6 months; 5 patients had not reached their 6-month evaluation point), which is in the range of durable remissions observed with approved autologous CAR-T therapies on an ITT basis.
- The data provide a strong rationale that consolidation dosing can improve on an already competitive profile for CTX110.
Based on this safety and efficacy profile, the Company plans to expand into a potential registrational trial that incorporates consolidation dosing in Q1 2022. In parallel, the Company continues to advance the rest of its immuno-oncology portfolio and scale its manufacturing capabilities in its new state-of-the-art manufacturing facility in Framingham, Massachusetts.
Conference Call and Webcast
To access the conference call, please dial +1 (866) 952-8559 (domestic) or +1 (785) 424-1743 (international) and reference the conference ID “CRISPR.”
A live webcast of the event will be available on the “Events & Presentations” page in the Investors section of the Company’s website at https://crisprtx.gcs-web.com/events. A webcast replay will be available on the CRISPR Therapeutics website after the event and will be archived for 14 days.
About CTX110
CTX110, a wholly owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting Cluster of Differentiation 19, or CD19. CTX110 is being investigated in the ongoing CARBON trial.
About CARBON
The ongoing Phase 1 single-arm, multi-center, open label clinical trial, CARBON, is designed to assess the safety and efficacy of several dose levels of CTX110 for the treatment of relapsed or refractory B-cell malignancies.
About CRISPR Therapeutics
CRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit www.crisprtx.com.
SOURCE: CRISPR Therapeutics
