The FDA asked Verve to provide evidence of whether its base-editing treatment would be passed on to offspring

Base editing therapy company Verve Therapeutics issued a statement that the FDA has suspended clinical trial research new drug applications
for its primary drug candidate, Verve-101.

Verve-101 is the first in vivo base editing therapy to enter the clinic, VERVE-101 therapy aims to permanently turn off the expression of the PCSK9 gene in the liver through a base editor delivered by lipid nanoparticles (LNP), thereby reducing low-density lipoprotein cholesterol (LDL-C) to enable the prevention and treatment
of cardiovascular diseases including heterozygous familial hypercholesterolemia (HeFH).

On December 5, 2022, the FDA sent an official letter to VerveTherapeutics setting out the reasons for suspending its base-editing therapy, and the FDA wanted more data from Verve to allay concerns, including whether patients' edited genes would be passed on to their children
.

The FDA requested Verve to provide more preclinical data on efficacy differences between human and non-human cells, germline editing risks and off-target analysis of non-hepatocyte types, as well as preliminary data
from human clinical trials conducted in New Zealand.
In addition, the FDA required Verve to add additional contraception to clinical trial participants and increase the interval between
doses.

In fact, these questions raised by the FDA have always been of concern to Verve, and on October 31, 2022, Verve published a paper in the journal Circulation, and experimental data in non-human primates confirmed the safety, efficacy, durability, and tolerability of Verve-101 therapy editing the PCSK9 gene, and further confirmed that the therapy does not affect germ cells
.

The results showed that monkeys receiving a dose of 0.
75mg/kg had an average reduction of 67% in blood PCSK9 protein and an average reduction in LDL-C by 49%
after one year of treatment.
In an assessment 476 days after treatment, monkeys receiving a dose of 1.
5 mg/kg had an average reduction of 83% in blood PCSK9 protein and an average reduction in LDL-C of 69%
after 476 days of treatment.

In addition, the study also showed that no editing of PCSK9 was found in the sperm of 6 male monkeys after base editing treatment, and no editing of PCSK9 was found in the offspring of female mice after base editing
treatment.

On July 12, 2022, Verve announced that its base-editing therapy, VERVE-101, completed the first patient dosing in New Zealand for the treatment of heterozygous familial hypercholesterolemia (HeFH), the world's first clinical trial
of base editing in vivo.
This marks the beginning of clinical trials of the next generation of gene-editing technology, base editing, and the beginning of gene editing technology into the treatment
of common diseases.

Currently, Verve has completed dosing to 3 patients who were well tolerated and had no treatment-related adverse events
.
Verve is required to submit specific data
on the treatment of these patients to the FDA.

Principles of Verve-101 therapy

Low-density lipoprotein (LDL) is a cholesterol-rich lipoprotein, and when it is excessive, the cholesterol it carries accumulates on the artery wall, which is easy to cause cardiovascular diseases
such as arteriosclerosis.
Therefore, low-density lipoprotein (LDL) is also known as "bad cholesterol"
.

Sekar Kathiresan, while studying genes associated with coronary artery disease, found more than 60 genes that reduce blood levels of "bad cholesterol," which can be used to prevent cardiovascular disease
.

Among these genes that can reduce the level of "bad cholesterol", the most deeply studied is the PCSK9 gene, which expresses the PCSK9 protein that binds to the LDL receptor (LDL-R) on the surface of liver cells, degrading LDL-R, thereby increasing plasma LDL-protein cholesterol levels
.
Reducing the expression of the PCSK9 gene or inhibiting the binding of the PCSK9 protein to LDL-R can reduce plasma LDL cholesterol levels, thereby preventing cardiovascular disease
.

Existing drugs all work after gene transcription (such as siRNA drugs) or after expression (such as PCSK9's monoclonal antibody), but Sekar Kathiresan believes that these therapies or drugs are palliative, requiring long-term use of drugs or injections, and through base editing, treatment at the DNA level, can achieve one-time injection, permanently prevent cardiovascular disease, not only relieve the burden of long-term medication, but also save treatment costs
.