Understanding CRISPR Clinical Trials: Your Questions Answered

CRISPR clinical trials themselves take many years to complete, but the process of developing a cell and gene therapy product actually starts years beforehand. Proof-of-concept studies, known as discovery research, are the first major milestone in the journey. In this stage of drug discovery, researchers must pinpoint a potential treatment for a disease (target identification) and then prove that the treatment is feasible (target validation). This can take several years, especially if little is known about the disease or the genes and molecular mechanisms that cause it.

For a CRISPR gene therapy that aims to treat a genetic disorder, proof-of-concept research is typically performed in cells. The cells can either be immortalized cell lines or, better yet, primary cells taken from human patients that suffer from the disease in question. Primary cells are preferred because they more accurately reflect the biological reality of the disease compared to immortalized cells and therefore respond to potential treatments similarly.

After identifying a target, such as a genetic mutation, that causes the disease phenotype in the cells, researchers must prove not only that CRISPR gene therapy can edit the mutation at the genetic level in patient cells, but also that the editing improves the phenotype of the cells. They must also demonstrate minimal to no off-target editing or other adverse effects on the cells. If this is successful, the researchers can move on to pre-clinical research.

For CRISPR gene therapy and gene-edited cell therapy drugs, one of the key starting materials is the sgRNA. In discovery and proof-of-concept research, drug developers (known as ‘sponsors’) can use unregulated reagents to generate the therapy because it is only tested in cells; research use only (RUO) sgRNAs are usually sufficient for this stage of development.

Before it’s possible to start CRISPR clinical trials, the next major stage of development for a CRISPR cell or gene therapy is to conduct rigorous pre-clinical research, typically in an animal model/s of the disease. This type of research aims to assess if the treatment works, how much is needed for a therapeutic dose, and if it is safe. This stage of development is a major challenge because cells grown in the lab respond to a potential CRISPR therapy treatment very differently compared to whole animals. As such, many potential therapies fail in this early stage.

Mammals such as mice are often the first model in which a drug will be tested, typically followed by larger animals. Some drugs also require testing in non-human primates, particularly if they affect physiological systems that are unique to primates. To ensure the treatment is effective and safe, it is essential that any animal model used in pre-clinical research accurately recapitulates the genotype, phenotype, and progression of the disease in question.

Throughout this stage of development, researchers have the opportunity to converse with the FDA about the therapy via different types of non-compulsory meetings. CRISPR cell and gene therapy drugs have complex manufacturing requirements that differ from traditional biologics, making these meetings particularly pertinent.

The first is an Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) meeting, an informal meeting in which sponsors of CRISPR clinical trials can be advised on the chemistry, manufacturing, and controls (CMC), pharmacology and toxicology, and clinical aspects of their potential therapy by the FDA.

The second is a pre-IND meeting, the first formal meeting between the sponsor of the CRISPR clinical trial and the FDA. Pre-IND meetings are used to discuss whether the data gathered in pre-clinical development are sufficient for the FDA to approve the CRISPR gene therapy to progress to human trials when the full IND submission is made. The FDA will also advise the sponsor about current Good Manufacturing Practice (cGMP) requirements that researchers must adhere to during the development of the drug.

The data gathered during pre-clinical research is used by CRISPR therapy sponsors in their application to the FDA to begin clinical trials of the product, otherwise known as an Investigational New Drug (IND) filing. If the CRISPR-based therapy appears safe and effective in animal models, it will be given the green light to begin clinical trials in human subjects.

During pre-clinical research, the FDA often recommends that CRISPR therapy sponsors use high-quality gRNAs with some level of documentation to support their purity. To address this need, Synthego provides INDe gRNAs, which comply with the equipment, facility, and material controls in the relevant sections of 21 CFR part 58 on guidelines for Good Laboratory Practice (GLP) for nonclinical laboratory studies to be used for IND-enabling studies. When providing gRNAs for CRISPR gene therapy products, Synthego’s regulatory specialists also offer full support with the preparation of IND applications for CRISPR clinical trials.

During phase I trials, the drug is usually administered to healthy subjects as well as patients with the disease in question. For more common diseases, the number of subjects can be between 20 to 80. However, for a rare genetic disease, there may be even fewer.

Clinical trials for a CRISPR therapy work much the same as any other type of drug product, progressing through phase I, II, and III trials. These different phases of CRISPR clinical trials assess key aspects of the therapy or drug - including safety, tolerability, and efficacy - in increasingly large patient populations. Each phase of a CRISPR clinical trial must be successfully completed before proceeding to the next, optimizing and refining the treatment with each step. CRISPR gene therapy and cell therapy drugs in clinical trials are required to use GMP gRNAs with extensive documentation.

The success of CRISPR clinical trials is measured according to clinical endpoints, which are pre-defined, measurable outcomes agreed upon by the sponsor and the FDA before the trials begin. Clinical endpoints vary considerably based on the disease and treatments in question. However, they can include things like increased life expectancy, increased or decreased levels of a disease-specific biomarker, or a reduction in disease symptoms.

The FDA typically has stringent criteria for allowing a new drug to proceed through the phases; 90% of drugs fail at some stage of the process. If the FDA does not receive sufficient evidence for the CRISPR therapy to progress into the next phase or there are problems with the manufacturing of the therapy, the FDA may place a clinical hold that prevents the CRISPR clinical trials from continuing until their conditions are met. If there are severe adverse events or the death of trial patients, the trial will usually be terminated unless the sponsor provides evidence that the drug was not the cause of death.

In cases where the CRISPR therapy offers a considerable benefit over what is currently available, there are limited or no available treatments, or it fulfills an urgent or unmet medical need, the FDA may agree to give the therapy a different IND designation (see glossary of terms below). These designations, such as fast track (FT) or breakthrough therapy (BT) typically help speed up the clinical trial process, sometimes by allowing two or more trial phases to run in parallel. Let’s explore the different phases of CRISPR clinical trials, what is involved, and how they are assessed.

In December 2023, we saw the first US approval of a CRISPR therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals, also approved in Europe. The CRISPR gene therapy drug called Casgevy (exa-cel) is an ex vivo cell therapy for the treatment of sickle cell disease and beta-thalassemia. Many more CRISPR gene therapy and cell therapy drugs are currently in clinical trials, making the next few years a particularly exciting time for CRISPR clinical trials as we see more results trickle in. If you’ve been keeping up with the broader CRISPR field, you may have also noticed an increase in discovery and pre-clinical research using CRISPR derivative technologies, such as base editing, prime editing, and PASTE. These spin-offs of CRISPR still use gRNAs to direct editing, but do not induce DSBs. We’ll likely see more of these alternatives enter the clinic in the coming years.