Initial CRISPR Gene Editing Therapy has been Approved. What is the Domestic Progress?

On November 16th, local time in the United States, Vertex Pharmaceuticals and CRISPR Therapeutics announced that their jointly developed CRISPR gene editing therapy CASGEVY (exagaglogene autotemcel, exa-cel) has been conditionally approved for marketing by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). Exa-cel is the world's first CRISPR gene editing drug to be approved for marketing.

SCD is a genetic blood disease caused by abnormal hemoglobin. Abnormal hemoglobin causes blood cells to deform and clump together, sometimes blocking blood vessels, leading to tissue hypoxia, resulting in long-term damage and pain, known as vaso-occlusive crisis (VOC). SCD can cause severe pain, organ damage, and may even shorten lifespan.

TDT is also a genetic blood disease characterized by a lack of red blood cells (anemia), causing many patients to require regular blood transfusions to meet their body's needs, but transfusions can lead to toxicity and cannot fundamentally treat the disease.

The only curative method for SCD and TDT patients is hematopoietic stem cell transplantation, however, there are fewer matched donors, and there are risks of rejection and complications after transplantation. The approval of exa-cel is a milestone, providing a new treatment option for SCD and TDT patients.

Exa-cel uses CRISPR to edit the enhancer region of the BCL11A gene, which typically inhibits the production of a specific type of hemoglobin (HbF) that is only produced with fetuses. HbF is a form of hemoglobin that can carry oxygen and naturally exists at birth. Exa-cel helps release HbF by disrupting the BCL11A gene. This HbF does not carry the abnormal adult hemoglobin associated with SCD or TDT patients. Treatment with exa-cel could potentially reduce or eliminate VOC symptoms in SCD patients and reduce or alleviate the need for blood transfusions in TDT patients.

What are the efficacy of exa-cel?

CLIMB-111 and CLIMB-121 studies announced in June this year, both met the main and secondary endpoints. These two studies evaluated the safety and efficacy of a single dose of exa-cel in 12-35 year old TDT or SCD patients characterized by VOC recurrence. Among the 83 patients (48 TDT patients + 35 SCD patients) treated with exa-cel and followed for up to 43.7 months, all patients treated with exa-cel showed clinical benefit.

In the clinical trial for TDT, there were 27 patients available to evaluate the primary and key secondary endpoints. Of these, 88.9% of patients (24 out of 27) met the primary endpoint of no transfusions for at least 12 months (TI12) and the secondary endpoint of no transfusions for at least 6 months (TI6). The average time free from transfusion was 20.5 months, with the longest being 40.7 months.

In the clinical trial for SCD, there were 17 patients available to evaluate the primary and key secondary endpoints. Of these, 94.1% of patients (16 out of 17) reached the primary endpoint of being VOC-free for at least 12 months (VF12). All patients (17 out of 17) reached the key secondary endpoint of not being hospitalized due to VOCs for at least 12 months (HF12).

As of now, there have been no significant safety issues in these ongoing clinical trials, and the safety of SCD and TDT patients treated with exa-cel is generally consistent with myeloablation treatment using busulfan and hematopoietic stem cell transplantation.

In addition, exa-cel is being evaluated in long-term open-label trials such as CLIMB-131, CLIMB-141, and CLIMB-151, which aim to assess the efficacy and safety of exa-cel treatment in 2-11 year old TDT or SCD patients.

There is still a long way to go on the road to safety and commercialization

The CRISPR/Cas system is currently the most widely used genome editing technology. It consists of the Cas protein with endonuclease function and a single guide RNA (sgRNA) designed from a target gene, which guides the Cas protein to knock out, insert, and modify target genes.

Since the birth of CRISPR gene editing technology in 2012, off-target effects have been one of the main factors constraining its development. Off-target effects refer to CRISPR gene editing technology inadvertently cutting DNA fragments other than the intended target, potentially disrupting the function of non-targeted genes, leading to serious consequences.

What is the safety of exa-cel? At the FDA external expert meeting held on October 31 this year, experts stated that there is currently no evidence of off-target editing risk with exa-cel. Therefore, experts recommended long-term monitoring of patients undergoing treatment after approval, and follow-up studies to assess off-target effects and their risks. The approval of exa-cel and the optimistic assessment of its safety by experts have boosted confidence in the industry.

Commercialization will be the huge challenge facing exa-cel going forward. Although the price of exa-cel has not been disclosed, considering that the prices of several marketed gene therapies are priced at over $2 million, the road to commercialization for exa-cel will be a challenging journey.

Research progress of gene editing in China

In China, the enterprises with faster progress in gene editing technology include BRL Medicine, Reforgene, EdiGene Inc., and Vitalgen.

BRL Medicine's BRL-101 is a gene therapy product self-developed by the company based on its independently developed hematopoietic stem cell platform (ModiHSC), indicated for transfusion-dependent β-thalassemia, and is about to enter the Phase II clinical stage.

Reforgene's RM-001 is its independently developed autologous hematopoietic stem cell gene editing product for the treatment of TDT. RM-001 uses CRISPR/Cas gene editing technology to permanently modify the γ-globin promoter, activate natural fetal hemoglobin synthesis in the body, restore the normal physiological function of red blood cells and get rid of transfusion, achieving the goal of curing β-thalassemia with a single dose. Currently, RM-001 is under Phase I clinical study.

EdiGene Inc.'s ET-01, a CRISPR/Cas9 gene-modified autologous CD34+ hematopoietic stem cell injection targeting the BCL11A erythroid enhancer, is an autologous, ex vivo gene editing cell therapy used for the treatment of TDT, and is currently in Phase I clinical research.

The CRISPR technology has broad prospects in disease treatment, gene function regulation, drug development, and many other areas. The approval of exa-cel has a milestone significance, marking the first step towards the marketization of gene editing therapy. In the future, relevant pharmaceutical companies should consider how to improve safety and accessibility, among other aspects.

Reference:

1. https://news.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene.

2. https://www.nature.com/articles/d41586-023-03317-7.

3.https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023#event-materials.