Special Update: News From the Gene-Editing Clinical Trials

Positive initial data on first CRISPR-based therapy for HIV

In September 2022, U.S.-based CRISPR company Excision BioTherapeutics announced in a press release that the first participant had been dosed in the Phase 1/2 clinical trial of EBT-101 for human immunodeficiency virus type 1 (HIV-1). According to that press release, the individual was dosed in July 2022, and initial safety findings indicate that EBT-101 has been well tolerated so far. The company also revealed that the participant continues to be monitored for safety and is anticipated to qualify for analytical treatment interruption of their background anti-retroviral therapy in an evaluation of a potential cure.

EBT-101 is the first CRISPR-based therapy to enter a clinical trial for HIV. HIV is an RNA virus, and when it first infects an individual, its RNA is reverse-transcribed into DNA by virally-encoded reverse transcriptase and RNase H enzymes that convert the viral RNA to double-stranded DNA (dsDNA) and degrade any remaining viral RNA, respectively. The resulting dsDNA is integrated into the host genome and this is referred to as proviral RNA.

EBT-101 is designed to excise HIV proviral DNA using CRISPR-Cas9 and two guide RNAs (gRNAs). The CRISPR cargo is delivered to cells as a one-time treatment via an adeno-associated virus (AAV). The two gRNAs target three sites within the HIV genome (Figure 1), thereby cutting out large portions of the HIV genome and minimising potential viral escape.

On November 2nd 2022, Excision BioTherapeutics will host a key opinion leader webinar about HIV and the ongoing EBT-101 as a potential cure for HIV. Read more about EBT-101 in our previous clinical update.

First patient dosed in TALEN-edited PD-1 knockout for solid cancer

Iovance Biotherapeutics announced earlier this month that the first patient had been dosed and completed the safety observation period in the Phase 1/2 IOV-GM1-201 trial for IOV-4001.

IOV-4001 is Iovance’s TALEN-modified, PD-1-inactivated tumour-infiltrating lymphocyte (TIL) therapeutic candidate for several solid cancers. IOV-GM1-201 is a first-in-human study investigating the safety and efficacy of IOV-4001 in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or advanced melanoma.

IOV-4001 is developed using Cellectis' TALEN® gene-editing technology under licence. Specifically, it is generated from TILs that are isolated from patient tumours. TILs encompass a population of lymphocytes (including B cells, T cells, and other immune cell types) that naturally invade tumour tissue and are implicated in killing tumour cells. Following isolation, the TILs are subjected to TALEN gene editing to inactivate the PD-1 protein. IOV-4001 is designed as an adoptive cell therapy that combines the natural anti-tumour activity of TILs with PD-1 knockout to prevent immune escape by cancer cells.

Initial cardiomyopathy data released for NTLA-2001 in transthyretin amyloidosis

Intellia Therapeutics and Regeneron shared a press release last month announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTR gene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

Other updates

RMAT designation for T-cell cancer candidate CTX130

CRISPR Therapeutics reported in September 2022 that the FDA had granted a regenerative medicine advanced therapy (RMAT) designation to CTX130, for the treatment of cutaneous T-cell lymphomas. CTX130 is a donor-derived CRISPR-Cas9-edited CAR-T investigational therapy targeting CD70, an antigen expressed on various solid tumours and hematologic malignancies. The candidate is currently being assessed in two Phase 1 clinical trials: the COBALT-LYM trial for T or B cell cancers and a trial for safety and efficacy of several dose levels in renal cell carcinoma.

At the European Hematology Association Hybrid Congress in June this year, the company presented positive clinical results from the ongoing COBALT-LYM trial. CTX130 has previously received Orphan Drug Designation from the FDA for the treatment of T-cell lymphoma. You can read about the clinical data for CTX130 and its mechanism of action here.

First patient dosed in Chinese CRISPR trial for B-cell acute lymphoblastic leukaemia

Clinical-stage CAR-T company Gracell Biotechnologies (China) announced last week in a press release that it has dosed the first patient in its Phase 2 portion of a registrational Phase 1/2 clinical trial to evaluate GC007g for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL). The trial is currently ongoing in China. GC007g is Gracell's allogeneic, human leukocyte antigen (HLA)-matched, donor-derived, CD19-directed CAR-T cell therapy candidate under development for the treatment of a subset of B-ALL patients who relapsed after allogeneic human stem cell transplant.

According to the same press release, data from the Phase 1 trial of GC007g showed encouraging efficacy and a favorable safety profile. The ongoing registrational Phase 2 trial will further assess the safety and efficacy of GC007g in r/r B-ALL patients at the recommended Phase 2 dose.

FDA grants a rolling review for sickle cell disease and beta thalassemia candidate exa-cel

CRISPR Therapeutics and Vertex Pharmaceuticals recently announced that the FDA has granted exa-cel a rolling review. Exa-cel (formerly known as CTX001) is an ex vivo CRISPR-Cas9-based candidate therapy that edits a patient's haematopoietic stem cells to reactivate the production of foetal haemoglobin (HbF). HbF is highly expressed and critical during foetal development, and is then rapidly suppressed early in life. HbF reactivation has emerged as an attractive strategy to treat sickle cell disease and beta thalassemia by compensating for the lack of functional adult haemoglobin seen in these blood disorders.

According to the FDA, a rolling review means that a drug developmemt company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. Exa-cel is the most advanced clinical-stage gene-editing candidate for SCD and beta thalassemia to date. You can read more about the therapeutic strategy behind exa-cel and previous clinical data here.

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