With the first CRISPR gene-editing drug approved for over ten months now, what exciting developments are there in CRISPR drug development?
According to statistics, there are nearly 20 gene editing clinical trials underway, both in vivo and ex vivo (Table 1). The main areas of research are blood disorders and liver diseases, which include technologies such as ex vivo CAR-T therapies and liver-targeted CRISPR delivery using lipid nanoparticles (LNPs). Additionally, in vivo therapies targeting the retina and muscles using AAV vectors are in progress. CRISPR is also being utilized to design iPSC-derived islet cells for type 1 diabetes treatment.
Table 1. Ongoing Clinical and Preclinical Trials in Gene Editing [1].
Casgevy: “A Multi-Billion Dollar Opportunity”
Casgevy, approved in late 2023 in the UK and the US, is the first CRISPR-based drug on the market. Co-developed by Vertex and CRISPR Therapeutics, Casgevy treats sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).
While Casgevy’s market presence is recent, Vertex revealed in its Q2 2024 financial report that approximately 20 patients have already initiated Casgevy treatment and are in the cell collection process. Vertex describes Casgevy as a “potential multi-billion dollar opportunity” [2].
NTLA-2001: Efficient Enrollment in Phase III Clinical Trials
Among CRISPR therapies, the fastest progressing is NTLA-2001, jointly developed by Intellia and Regeneron, which has entered Phase III trials globally. NTLA-2001 targets ATTR amyloidosis with cardiomyopathy, aiming to evaluate the efficacy and safety of NTLA-2001 in over 35 clinical centers across 12 countries. According to Intellia, the first patient in the Phase III trial received a single dose of NTLA-2001 in March 2024, with patient enrollment proceeding efficiently [4].
NTLA-2001 is an in vivo gene therapy delivered via LNP, carrying CRISPR Cas9 mRNA and sgRNA, designed to knock out the TTR gene in liver cells, thereby preventing transthyretin (TTR) protein production for the treatment of hereditary transthyretin amyloidosis (hATTR) [5].
Figure 2. NTLA-2001 Mechanism Diagram [5].
VERVE-101 and VERVE-102: Pipeline Adjustments Due to LNP Formulation
VERVE-102 is an innovative single-base editing therapy developed by Verve Therapeutics. A single treatment permanently shuts down the PCSK9 gene in the liver, providing long-term reduction of low-density lipoprotein cholesterol (LDL-C) levels. VERVE-102 is in a Phase 1b clinical trial for adult patients with heterozygous familial hypercholesterolemia (HeFH) and premature coronary artery disease (CAD). Verve expects initial data from the Heart-2 trial and an update on the PCSK9 program in early 2025, with plans for a Phase 2 trial later that year [6].
VERVE-101, however, is currently paused. In a Phase 1b trial, one patient of six patients treated with a 0.45 mg/kg dose developed Grade 3 liver enzyme elevation and Grade 3 thrombocytopenia, prompting a trial pause. Verve Therapeutics subsequently launched an investigation, with preliminary data suggesting the clinical issue was related to the LNP formulation used in VERVE-101. As a result, Verve reprioritized its pipeline, asserting that the VERVE-101 pause would not affect cash flow or lead to layoffs.
Figure 3. Both VERVE-102 and VERVE-101 consist of mRNA encoding an adenine base editor (ABE) and sgRNA targeting the PCSK9 gene. However, VERVE-102 uses a different LNP delivery system, including a distinct ionizable lipid and Verve Therapeutics' proprietary GalNAc liver-targeting ligand [7].
Base Therapeutics IND Acceptance and A2 Round Financing Completion
On July 29, 2024, the Center for Drug Evaluation (CDE) of the National Medical Products Administration accepted the IND application for Base Therapeutics’ base-edited universal NK cell product, NK510. This therapy is designed for advanced solid tumor treatment. Notabl, this is world's first clinical trial approval for a base-edited NK cell product. NK510 uses the cytosine base editor AccuBase® for precise NK cell gene modification, achieving over 90% editing efficiency. Recently, Base Therapeutics completed its A2 round of financing, with funds directed toward R&D team expansion, pipeline optimization, and clinical trial acceleration, paving the way for commercialization [8].
Figure 4. Overview of BASE-NK Cell Therapy: showcasing high transduction efficiency, industry-leading expansion capability, advanced NK cell expansion system, and precise gene editing with zero off-target effects [8].
Prime Editing: A New Gene Editing Technique Rapidly Advancing to Clinical Stages
On April 29, Prime Medicine announced FDA IND approval for a global Phase I/II clinical trial of PM359, its ex vivo gene editing drug aimed at chronic granulomatous disease (CGD) with a p47 phox mutation [9]. PM359 is the first prime editing-based autologous hematopoietic stem cell drug. Currently, PM359 has received both Rare Pediatric Disease and Orphan Drug designations from the U.S. Food and Drug Administration. Prime Medicine anticipates initial clinical data by 2025.
Figure 5. How prime editing can correct different types of mutations [10].
KACTUS Off-the-Shelf Gene Editing Enzyme Portfolio
To support cell and gene therapy development, KACTUS has established a GMP production facility and certified quality management system to produce GMP-Grade gene editing enzymes. This includes our off-the-shelf GMP Cas9 protein and GMP-Grade Cytosine Base Editor, AccuBase®.
GMP Cas9 Protein
KACTUS’ GMP-grade Cas9 protein is manufactured in a GMP-compliant facility to meet the highest quality standards required for clinical and therapeutic applications. Our Cas9 protein ensures consistent purity, high editing activity, and reliability for precision gene editing. Effective in multiple cell types with 80-95% editing efficiency, this product is available in long-term, bulk supply to support your gene editing applications from preclinical through commercial manufacturing. Our GMP-grade Cas9 has been filed with the FDA Drug Master Files (DMF #039509) and is supporting multiple IND applications. Learn more about our Cas9 here.
GMP AccuBase® Cytosine Base Editor
AccuBase® is an engineered cytosine base editor designed by Base Therapeutics and manufactured and sold exclusively by KACTUS. AccuBase® offers high base editing activity with near-zero off-target effects. The deaminase is encapsulated inside the Cas9n protein, and is exposed upon target DNA binding, thereby offering near-zero off-target editing. AccuBase® is manufactured in a cGMP facility with regulatory documentation support and rigorous quality control. Learn more about AccuBase® here.
References
- Ma, Y., & Qi, L. S. (2024). The realization of CRISPR gene therapy. Nature chemical biology, 20(7), 791–795. https://doi.org/10.1038/s41589-024-01645-x
- Vertex Second Quarter 2024 Financial Results. https://investors.vrtx.com/static-files/ad6251e9-8f7e-481b-bcf3-4f2417b7d63b
- Lonza and Vertex Sign a Long-Term Commercial Supply Agreement for CASGEVY® (exagamglogene autotemcel). https://www.lonza.com/news/2024-09-24-14-00
- Intellia Therapeutics Announces Second Quarter 2024 Financial Results and Highlights Recent Company Progress. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-second-quarter-2024-financial
- Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., Seitzer, J., O'Connell, D., Walsh, K. R., Wood, K., Phillips, J., Xu, Y., Amaral, A., Boyd, A. P., Cehelsky, J. E., McKee, M. D., Schiermeier, A., Harari, O., Murphy, A., Kyratsous, C. A., … Lebwohl, D. (2021). CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. The New England journal of medicine, 385(6), 493–502. https://doi.org/10.1056/NEJMoa2107454
- Verve Therapeutics Announces Pipeline Progress and Reports Second Quarter 2024 Financial Results. https://ir.vervetx.com/news-releases/news-release-details/verve-therapeutics-announces-pipeline-progress-and-reports-1#:~:text=Verve%20continues%20to%20expect%20its,the%20second%20quarter%20of%202023.
- Potent, Specific, and Durable Liver Editing of PCSK9 in Preclinical Studies of the CRISPR Base Editing Medicine VERVE-101. https://www.vervetx.com/sites/default/files/2024-07/Japan%20Atherosclerosis%20Conference_FINAL.pdf
- https://www.basetherapeutics.com/
- Prime Medicine Unveils Strategically Focused Pipeline. https://investors.primemedicine.com/news-releases/news-release-details/prime-medicine-unveils-strategically-focused-pipeline
- https://primemedicine.com/science/
