On December 9, 2024 GSK plc (LSE/NYSE: GSK) reported that the National Medical Products Administration (NMPA) of China has accepted for review a new drug application (NDA) for Blenrep (belantamab mafodotin) in combination with bortezomib plus dexamethasone (BVd) as a treatment for relapsed or refractory multiple myeloma (Press release, GlaxoSmithKline, DEC 9, 2024, View Source [SID1234648901]). Earlier this year, the NMPA granted priority review for this application as well as Breakthrough Therapy Designation1 for the BVd combination, which is intended to expedite development of investigational drugs with potential for substantial improvement over available therapies.

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Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "Today’s regulatory filing acceptance, with a priority review, is a meaningful step forward in our efforts to bring the benefits of Blenrep in combination to patients in China. Multiple myeloma patients need new options that may improve outcomes, particularly at first relapse. The DREAMM-7 trial shows statistically significant efficacy, including overall survival and could redefine treatment in this patient population."

This is the seventh major regulatory filing acceptance this year for belantamab mafodotin in combination for the treatment of relapsed or refractory multiple myeloma based on the results of the DREAMM-7 and DREAMM-8 trials. In 2024, belantamab mafodotin combinations have been accepted for review in the US3, European Union4, Japan5 (with priority review), United Kingdom, Canada and Switzerland (with priority review for DREAMM-8).

The application is based on the interim results of the phase III head-to-head DREAMM-7 trial, which met its primary endpoint, showing statistically significant and clinically meaningful improvement in progression-free survival (PFS) for BVd compared to daratumumab plus bortezomib and dexamethasone (DVd) in relapsed or refractory multiple myeloma. In a subsequent planned interim analysis, the DREAMM-7 trial met the key secondary endpoint of overall survival (OS), showing that BVd significantly reduced the risk of death versus standard of care DVd.

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.6,7 There are approximately more than 180,000 new cases of multiple myeloma diagnosed globally each year.8 In China, multiple myeloma is a growing health concern with approximately 30,000 new cases each year.9 The incidence of multiple myeloma in China has doubled and mortality has increased 1.5-fold in the past three decades.10 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.11

About DREAMM-7
The DREAMM-7 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with bortezomib plus dexamethasone (BVd) compared to a combination of daratumumab and bortezomib plus dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma who previously were treated with at least one prior line of multiple myeloma therapy, with documented disease progression during or after their most recent therapy.

A total of 494 participants were randomised at a 1:1 ratio to receive either BVd or DVd. Belantamab mafodotin was scheduled to be dosed at 2.5mg/kg intravenously every three weeks.

The primary endpoint is PFS as per an independent review committee. The key secondary endpoints include OS, duration of response (DOR), and minimal residual disease (MRD) negativity rate as assessed by next-generation sequencing. Other secondary endpoints include overall response rate (ORR), safety, and patient reported and quality of life outcomes.

Results from DREAMM-7 were first presented12 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series in February 2024, shared in an encore presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, and published in the New England Journal of Medicine.

About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Blenrep is approved as monotherapy in Hong Kong. Refer to the local Summary of Product Characteristics for a full list of adverse events and complete important safety information.

On December 9, 2024 Genmab A/S (Nasdaq: GMAB) reported new long-term results from two ongoing clinical trials evaluating epcoritamab, a T-cell engaging bispecific antibody administered subcutaneously, in adult patients with diffuse large B-cell lymphoma (DLBCL) (Press release, Genmab, DEC 9, 2024, View Source [SID1234648900]). Results from Arm 1 of the Phase 1b/2 EPCORE NHL-2 trial (NCT04663347), evaluating fixed-duration epcoritamab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), demonstrated an overall response rate (ORR) of 100 percent and a complete response (CR) rate of 87 percent in high-risk patients (n=46) with previously untreated DLBCL. Among complete responders, 83 percent remained in remission after two years. Separately, results from the Phase 2 EPCORE NHL-1 trial (NCT03625037), evaluating epcoritamab monotherapy in challenging-to-treat adult patients (n=157) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL; including 148 patients with R/R DLBCL), showed that among the 41 percent of patients who achieved a CR, an estimated 52 percent were still responding at three years (median CR duration: 36.1 months). Both analyses were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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"The unprecedented durability of response seen in these data reinforce the potential of epcoritamab to become a core therapy for the treatment of multiple B-cell malignancies to benefit more patients," said Dr. Judith Klimovsky, Executive Vice President and Chief Development Officer of Genmab. "These results support our ongoing Phase 3 trials for epcoritamab, including as an investigational first-line combination therapy in patients with previously untreated diffuse large B-cell lymphoma."

EPCORE NHL-2 Results in First-Line DLBCL (Abstract #581)
The EPCORE NHL-2 trial enrolled 46 patients considered to have high-risk DLBCL, identified by International Prognostic Index (IPI) scores of 3 to 5, a range associated with poor long-term outcomes. The IPI is a key tool used by oncologists to predict the prognosis of aggressive B-cell lymphomas.i At screening, 35 percent of patients (n=16) had bulky disease (>10 cm) and 21 percent (n=6) of evaluable patients (n=28) had double-hit/triple-hit LBCL based on gene rearrangements identified by central analysis.

With a median follow-up of 27.4 months (range, 0.8-33.9), 87 percent of patients remained alive at two years and 74 percent were progression free.
At two years, a minimal residual disease (MRD) analysis showed MRD negativity was achieved in 91 percent of evaluable patients (30/33), indicating no detectable disease.
Epcoritamab in combination with R-CHOP is being studied further in the ongoing, randomized, Phase 3 EPCORE DLBCL-2 trial (NCT05578976).

"More first-line treatment options for diffuse large B-cell lymphoma are needed, especially for patients with aggressive disease prognostic markers that may impact the efficacy of current standard first-line therapies," said Lorenzo Falchi, MD, Lymphoma Specialist, Department of Medicine, Memorial Sloan Kettering Cancer Center.ii "Relapse rates with the R-CHOP treatment regimen can reach 50 percent, so the durable responses observed in the study suggest significant potential for this first-line epcoritamab-based combination."

The most common treatment-emergent adverse events (TEAEs) were neutropenia (70 percent), anemia (69 percent), cytokine release syndrome (CRS; 60 percent), fatigue (49 percent), nausea (47 percent), pyrexia (42 percent), and injection-site reaction (40 percent). Four patients (9 percent) discontinued epcoritamab due to TEAEs; fatal TEAEs occurred in two patients (COVID-19 and septic shock). CRS events were mostly low grade (45 percent Grade 1, 11 percent Grade 2, 4 percent Grade 3) and mainly occurred after the first full dose. All CRS cases resolved, and none led to discontinuation. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two patients (one Grade 1; one Grade 2) and resolved in a median of 2.5 days without leading to discontinuation.

Use of epcoritamab + R-CHOP in first-line DLBCL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use as a combination therapy in DLBCL have not been established.

EPCORE NHL-1 Results in Third-Line LBCL (Abstract #4480)
Three-year follow-up results from the Phase 2 EPCORE NHL-1 trial evaluated epcoritamab monotherapy in 157 patients with R/R LBCL and demonstrated that epcoritamab continues to deliver durable responses in challenging-to-treat patients.

The ORR was 59 percent, and the CR rate was 41 percent. Median duration of response was 20.8 months (95 percent CI, 13.0-32.0) and median duration of CR was 36.1 months (95 percent CI, 20.2 to not reached [NR]).
52 percent of patients who experienced a CR were still responding at three years (median CR duration: 36.1 months).
Of the 119 patients who were MRD-evaluable, 54 (45 percent) achieved MRD-negativity. In a cycle 3-day 1 landmark analysis, 3-year PFS rates were 52 percent among MRD-negative patients and 18 percent among MRD-positive patients.

The most common TEAEs were CRS (51 percent; 32 percent Grade 1, 16 percent Grade 2, 3 percent Grade 3), fatigue (25 percent), and pyrexia (25 percent); CRS rates remained unchanged since prior reports. Fatal TEAEs were reported in 20 patients; 10 patients had Grade 5 COVID-19 (including COVID-19 pneumonia). Seventy-three percent of patients treated with epcoritamab for two or more years did not experience a Grade 3 or higher infection after two years (median follow-up after 2 years, 12.3 months). Incidence of Grade 3 or higher cytopenias was highest (27 percent) during the first eight weeks of treatment and rates were within 0-13 percent in subsequent 12-week time periods up to week 144. Immunoglobulin G levels decreased by a median of approximately 20 percent after the start of epcoritamab treatment (baseline median, 540.0 mg/dL) and remained stable over time.

About Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is the most common type of non-Hodgkin’s lymphoma (NHL) worldwide, accounting for approximately 25-30 percent of all NHL cases.iii,iv In the U.S., there are approximately 25,000 new cases of DLBCL diagnosed each year.v DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men.vi,vii DLBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge. viii,ix

About the EPCORE NHL-2 Trial
EPCORE NHL-2 is a Phase 1b/2 open-label interventional trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab as a monotherapy and in combination with other standard of care agents in patients with B-cell non-Hodgkin’s lymphoma (B-NHL). The trial consists of two parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The primary objective of Part 1 is safety, and the primary goal of Part 2 is preliminary efficacy. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint.

Arm 1 of the trial is epcoritamab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL). More information on this trial can be found at View Source (NCT: 04663347).

About the EPCORE NHL-1 Trial
EPCORE NHL-1 is an open-label, multicohort, single-arm, Phase 1/2 trial of epcoritamab in participants with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL). The trial was conducted at 88 sites across 15 countries and consisted of three parts: a Phase 1 first-in-human, dose escalation part; a Phase 2a expansion part; and a Phase 2a dose optimization part. More information on this trial can be found at View Source (NCT: 03625037).

About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.x

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication.

Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigator’s choice chemotherapy (NCT04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT05409066), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL (NCT06508658). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information.

On December 9, 2024 EnnoDC, a clinical-stage biotech company pioneering the design and development of first-in-class Dendritic Cell-targeting immunotherapies, reported that new preliminary data of a Phase I/IIa clinical study evaluating its immunotherapy candidate CD40 (Press release, EnnoDC, DEC 9, 2024, View Source [SID1234648898]). HVac in patients with human papillomavirus (HPV16)-associated oropharyngeal carcinoma (OPC), will be presented at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2024, 11-13 December 2024 in Geneva, Switzerland.

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The poster titled, "Preliminary results of a multicentric randomized Phase I/IIa trial of an immunotherapy targeting dendritic cells (DC), CD40.HVac, in patients with HPV16-positive oropharyngeal carcinoma (OPC)", will be presented byDr Caroline Even, Department Head of the Head and Neck Medical Oncology Unit at Gustave Roussy, on Thursday, 12 December during the poster display session in the foyer mezzanine from 12:30 – 13:30 CET (see the abstract online).

EnnoDC’s first-in-class approach combines the power of vaccines and immunotherapy antibodies to provide targeted immune responses for both cancer and infectious diseases. CD40.HVac is an immunotherapy candidate targeting the E6/E7 antigens of the virus in patients with HPV16+ OPC, the most common form of this disease which accounts for more than 60% of Head & Neck cancers. It is currently evaluated in a Phase I/II multicentric double-blind placebo-controlled dose escalation trial (NCT06007092). The study is being conducted by Gustave Roussy Cancer Campus, European first cancer center.

Christophe Hubert, Chief Executive Officer of EnnoDC, commented:

"These preliminary data provide the first clinical results of our technology inducing HPV-specific CD4+ and CD8+ T cells and showcase for the first time our new immunotherapies which are under development for the treatment of HPV-induced cancers and prostate cancer. We look forward to reporting upcoming results from this trial in the coming months and taking the next steps to develop a new class of treatments for patients that fail to respond to available immunotherapies."

Details of the poster presentation are:

Abstract title: Preliminary results of a multicentric randomized Phase I/IIa trial of an immunotherapy targeting dendritic cells (DC), CD40HVac, in patients with HPV16-positive oropharyngeal carcinoma (OPC)
Presenter: Dr Caroline Even, Department Head of the Head and Neck Medical Oncology Unit at Gustave Roussy

Date/Time: 12 December 2024, 12:30 -13:30 pm CET

Location: Palexpo exhibition centre, Foyer Mezzanine

The ESMO (Free ESMO Whitepaper) IO poster will be available on ENNODC’s corporate website after the poster sessions have been opened.

On December 9, 2024 Electra Therapeutics, Inc., a clinical stage biotechnology company developing antibody therapies against novel targets for immunological diseases and cancer, reported the presentation of positive results from the completed Phase 1b study of ELA026 for the treatment of secondary hemophagocytic lymphohistiocytosis (sHLH) (Press release, Electra Therapeutics, DEC 9, 2024, View Source [SID1234648897]). ELA026 is a first-in-class monoclonal antibody that targets SIRP-α/β1/γ on the cell surface of myeloid cells and T lymphocytes, the principal pathological immune cells that induce the cytokine storm and hyperinflammation in sHLH. Targeting SIRP to selectively deplete pathogenic immune cells has potential for broad therapeutic applications in immunology, inflammation and cancer. The results of the ELA026 study in sHLH are being presented today at 2:45 PM PST in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

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The Phase 1b study was an open-label, single-arm, multicenter study designed to evaluate the safety and efficacy of ELA026, assess the pharmacodynamic (PD) and pharmacokinetic (PK) profile, and identify a dose regimen for further evaluation in a Phase 2/3 study (NCT05416307). The Phase 1b study demonstrated that for sHLH patients with the poorest prognosis, those with malignancy-associated HLH (mHLH), treatment with ELA026 in frontline settings achieved 100% overall response rate by week 4 and 100% hospital discharge, as well as 92% survival at two months. Various PD and HLH-related biomarkers showed that ELA026 rapidly attenuated inflammation, which correlated with clinical responses.

"ELA026 has shown potential to be a transformative treatment for sHLH, a life-threatening disease with no approved therapies. Compared with available treatment, which may include chemotherapy and single cytokine-directed therapies, ELA026 may offer a safer, more effective approach to address the overwhelming immune reaction in sHLH. The Phase 1b study results showing rapid PD and biomarker effects and improved survival at two months are particularly promising," said Swaminathan P. Iyer, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "There is a growing appreciation that controlling the cytokine storm early in the sHLH disease course is necessary to prevent multiorgan failure and allow for proper treatment of the underlying cancer. It is clear that overcoming this critical early period of hyperinflammation in sHLH provide significant clinical benefits for patients."

"We are highly encouraged by these compelling results for sHLH patients, and Electra is working to advance ELA026 into a pivotal study as rapidly as possible. Through rigor and resolve, our team has pioneered a drug development program targeting SIRP, going from a novel idea to pivotal study readiness in five years," said Kathy Dong, PharmD, MBA, President and CEO of Electra Therapeutics. "We have demonstrated the therapeutic value of selectively depleting pathological immune cells to modulate inflammation and look forward to applying this novel approach with ELA026 and our pipeline to expand to other diseases with high unmet need."

Phase 1b Study Results Presented in Oral Session at ASH (Free ASH Whitepaper)
The oral presentation at the ASH (Free ASH Whitepaper) Annual Meeting, entitled "ELA026, a monoclonal antibody targeting signal regulatory protein-α/β1/γ, rapidly controls inflammation and improves 2-month survival in treatment-naïve malignancy-associated hemophagocytic lymphohistiocytosis," is being presented by the lead author, Abhishek Maiti, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. This presentation was featured in the section "Granulocytes, Monocytes, and Macrophages: From Inflammation to Hemophagocytic Lymphohistiocytosis." The clinical results presented for ELA026 described the analysis of 12 mHLH patients treated in frontline settings in the completed Phase 1b clinical study. Highlights of the Phase 1b results are as follows:

ELA026 was well tolerated with manageable adverse events.
ELA026 demonstrated rapid PD effects on monocytes and lymphocytes, followed by reduction of markers of inflammation, including ferritin, sCD25, and C‑reactive protein (CRP).
mHLH patients receiving ELA026 in frontline settings achieved treatment outcomes that surpass those observed with available therapies (existing treatments used in the absence of an approved therapy for sHLH):
– 100% overall response rate (12 of 12) ~40% with available therapies.1

– 100% hospital discharge alive (11 of 11, 1 patient withdrew from study before evaluation of this endpoint) inpatient mortality of 20-30% with available therapies.2

– 92% survival at Day 60 (11 of 12) ~50% with available therapies.3

"Because sHLH is a complex, rapidly progressing disease with limited development precedents, advancing ELA026 required a focused approach that our Electra team boldly took on, in collaboration with leading researchers and clinicians. It is gratifying to see the positive Phase 1b results for ELA026 and the potential to improve outcomes for sHLH patients who face this life-threatening condition," said Kim‑Hien Dao, DO, PhD, Chief Medical Officer at Electra. "We have a clear path forward based on recent alignment with the US FDA on the pivotal study design and are moving towards initiating a global Phase 2/3 study in 2025 to address the significant disease burden in sHLH."

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, life-threatening hyperinflammatory disease for which there is no approved treatment. It can be triggered by cancer, infection, autoimmune disease, or immunotherapy. sHLH is associated with a severe inflammatory response for which patients require immediate intervention. Without treatment, patients may experience multiorgan failure and death. sHLH is associated with high mortality early in the disease course, with malignancy-associated HLH (mHLH) patients having a mortality rate of approximately 50% at two months with available therapies.

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.