The Latest Updates From the Gene-Editing Clinical Trials (October 2024)

Intellia Therapeutics initiates pivotal Phase 3 trial of NTLA-2002 in hereditary angioedema

Intellia Therapeutics announced yesterday that it has initiated a global, pivotal Phase 3 trial of NTLA-2002 for the treatment of hereditary angioedema (HAE). The trial, called HAELO, will enrol 60 adults with Type I or Type II HAE, where patients will be randomised 2:1 to receive a single intravenous infusion of NTLA-2002 or a placebo.

HAE is a rare genetic disease characterised by severe inflammatory attacks with swelling in various organs and tissues. Plasma kallikrein is a protein known to drive multiple inflammatory pathways, including the production of the inflammatory mediator bradykinin, which is overproduced in HAE.

NTLA-2002 is designed to knock out the target gene kallikrein B1 (KLKB1) in hepatocytes. This gene encodes prekallikrein, a precursor of plasma kallikrein, thus its knockout permanently reduces plasma kallikrein activity and halts the production of bradykinin to prevent HAE attacks. NTLA-2002 is administered intravenously as a single dose of Cas9 mRNA and gRNA via lipid nanoparticles.

Long-term Phase 1 data showed dramatic reductions in HAE attack rate, as well as consistent and durable reductions in plasma kallikrein levels. Intellia also previously announced positive topline data from the Phase 2 portion of that study. Patients randomised to receive placebo in the HAELO trial will be eligible for optional crossover to NTLA-2002 at Week 28. Patient screening for the HAELO trial is already ongoing following a succesful end-of-Phase 2 meeting with the FDA. The primary endpoint will be the change in number of HAE attacks from Week 5 through Week 28.

According to the official press release published yesterday, Intellia plans to present detailed results from the Phase 2 portion of the NTLA-2002 trial later this month at the 2024 American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

NTLA-2002 has received five special designations, including Orphan Drug and RMAT (both from the FDA), Innovation Passport (UK Medicines and Healthcare Products Regulatory Agency), Orphan Drug Designation by the European Commission and PRIME designation (EMA).

Poseida Therapeutics announces positive interim Phase 1 data for P-BCMA-ALLO1 in heavily pre-treated multiple myeloma patients

Poseida Therapeutics recently reported new interim clinical data from its ongoing Phase 1/1b trial of P-BCMA-ALLO1 in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received three of more prior lines of therapy.

The data revealed a 91% overall response rate (ORR) and compelling safety results in the 23 heavily pre-treated patients in an optimised lymphodepletion arm. This includes a 100% ORR in BCMA-naïve patients, and an 86% ORR in those who had received at least one prior BCMA- and/or GPRC5D-targeting treatment modality. G protein–coupled receptor class C group 5 member D (GPRC5D) is another important therapeutic target in MM.

The data was presented at the 21st International Myeloma Society Annual Meeting in Rio de Janeiro, P-BCMA-ALLO1 led to high overall response rates in heavily pre-treated MM patients. A comprehensive summary of the data can be found in the official press release.

P-BCMA-ALLO1 is being developed by Poseida as a fully allogeneic, T stem cell memory (T_SCM)-rich CAR-T therapeutic candidate. It is engineered to target the B cell maturation antigen (BCMA), which is primarily expressed by malignant and healthy plasma cells and by some mature B cells, and is the best-studied target in CAR-T-based approaches to MM. The candidate is developed using Poseida’s proprietary piggyBac® DNA Modification System and the hybrid Cas-CLOVER™ Site-Specific Gene Editing System.

The ongoing trial is investigating the safety and efficacy of P-BCMA-ALLO1 in adults with relapsed or refractory MM, in partnership with Roche. The two-part study, which is ongoing at multiple clinical sites in the US, includes a dose-escalation portion followed by administration at fixed doses. Previous clinical data revealed at the American Society of Hematology Annual Meeting in December 2023 showed early positive signs of safety and efficacy in heavily pre-treated MM patients, following suitable lympodepletion therapy. This data also showed that allogeneic T_SCM-rich CAR-T cells trafficked to bone marrow and differentiated to cell-killing effector T cells that persisted for at least 6 weeks. Poseida also presented encouraging clinical data on a subset of recently enrolled patients that did not respond to prior BCMA-targeting therapy at the American Association for Cancer Research Annual Meeting held in April 2024.

Poseida reported in March 2024 FDA had granted Orphan Drug Designation to P-BCMA-ALLO1 for the treatment of MM. P-BCMA-ALLO1 was also recently granted RMAT designation from the FDA.

YolTech Therapeutics receives Orphan Drug Desigation for YOLT-203 to treat primary hyperoxaluria type 1

Shanghai-headquartered YolTech Therapeutics announced late last month that the FDA had granted orphan drug designation to YOLT-203, an in vivo gene-editing therapeutic candidate developed to target the root cause of primary hyperoxaluria type 1 (PH1). YOLT-203 was previously awarded Rare Pediatric Disease Designation from the FDA.

PH1 belongs to a family of inherited metabolic disorders and arises through mutations in the AGXT gene, which results in deficiency or dysfunction of the enzyme alanine-glyoxylate aminotransferase. This leads to a harmful accumulation of oxalate in the kidney and other organs. PH1 typically debuts in childhood, and most patients experience kidney failure and require intensive haemodialysis while waiting for dual liver/kidney transplantation.

YOLT-203, which is the first in vivo gene-editing therapy for PH1 to reach the clinic, is designed to permanently reduce the harmful oxalate levels in the blood by correcting mutations in AGXT, thereby offering a potential one-time, curative treatment for PH1. The early Phase 1 trial, which is sponsored by RenJi Hospital (Shanghai), aims to evaluate the safety and tolerability of YOLT-203 in Chinese individuals with PH1, and to preliminarily assess the impact of a single dose of YOLT-203 on plasma oxalate levels. A total of seven participants are estimated to be enroled in the trial, of which the first adult was dosed on 5^th Aug 2024 and the first child was dosed on 20^th Aug 2024.

In pre-clinical studies, YOLT-203 demonstrated significantly high gene-editing activity in prokaryotic and eukaryotic cells, as well as high-efficiency in vivo editing via LNP-mRNA delivery in mice and non-human primates.

For further details, see the official press release by YolTech Therapeutics here. Read more about YOLT-203 and PH1 in a previously clinical trial update here.

KSQ Therapeutics gets FDA nod to start clinical trial of CRISPR-edited TIL therapy KSQ-004EX

KSQ Therapeutics (US) announced late last month that the FDA had cleared its IND application for KSQ-004EX, a CRISPR-Cas9 engineered tumour-infiltrating lymphocyte (TIL) therapeutic candidate. This means that KSQ can now initiate a Phase 1/2 clinical trial of KSQ-004EX, which is sponsored by The University of Texas MD Anderson Cancer Center.

The candidate will be evaluated for efficacy and safety in patients with advanced solid tumours, including those with melanoma, head and neck squamous cell carcinoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer and cervical cancer.

KSQ-004EX consists of TIL in which Suppressor of cytokine signaling 1 (SOCS1) and Regnase-1 are inactivated using CRISPR-Cas9 gene editing. KSQ previously identified SOCS1 and Regnase-1 as key regulators of anti-tumour potency and persistence of TIL in pre-clinical models, including anti-tumour function in solid tumour models refractory to PD-1 inhibition. Based on those data, KSQ-004EX is being advanced as a potential best-in-class treatment for advanced solid tumour indications.

KSQ-004EX is KSQ's second gene-edited TIL candidate to reach the clinic; the company is also advancing KSQ-001EX (TIL with SOCS1 knockout) for the treatment of several advanced solid tumours, including melanoma, head and neck squamous cell carcinoma and non-small-cell lung cancer. KSQ-001EX is being evaluated for efficacy and safety in a Phase 1/2 trial.

For more information, see the official press release by KSQ Therapeutics here.

We will continue to update you on the gene-editing clinical trials as new details emerge. In the meantime, can find all of our coverage on clinical-stage gene editing programmes here.

For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.