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Novartis When Zolgensma, a gene therapy for the treatment of spinal muscular atrophy (SMA), was first launched, it not only caused heated discussions because of its most expensive price in history, but also "One-time" treatment methods have also attracted industry attention. Now, another company claims that one injection can permanently prevent cardiovascular diseases.
Recently, Verve Therapeutics announced that the gene editing therapy VERVE-101 it developed has been administered to the first patient with heterozygous familial hypercholesterolemia (HeFH) in New Zealand . In this clinical trial, Verve will The safety and efficacy of VERVE-101 are tested in 40 HeFH patients. Preliminary clinical data from the trial are expected to be obtained next year. The article in "MIT Technology Review" pointed out that this important progress heralds the use of gene editing technology to prevent heart disease. The future of vascular disease, the world’s “number one killer”.
According to Verve Therapeutics, VERVE-101 is a new type of investigational gene editing drug and a single-course, one-time treatment designed to deliver base editing technology through lipid nanoparticles (LNP) ( Base Editing) permanently shuts down the expression of the PCSK9 gene in the liver, thereby reducing low-density lipoprotein cholesterol (LDL-C) and achieving the prevention and treatment of cardiovascular diseases, including HeFH. It should be noted that unlike the viral vector commonly used in gene therapy, the single base editing therapy delivered by LNP only exists briefly in the human body, further reducing the off-target risk of single base editing.
The clinical research progress of VERVE-101 (Picture source: Verve Therapeutics official website)
Verve Therapeutics founder and CEO and famous cardiologist Sekar Kathiresan said: "VERVE-101 is a first-class gene editing drug that targets liver cells DNA once. Modify, thereby permanently shutting down the disease-causing gene. The first human clinical trial using this drug is a major achievement for Verve Therapeutics and the field of gene editing , and preclinical data for VERVE-101 shows that it is possible. Providing game-changing treatment options for patients with conditions including HeFH, transforming the traditional chronic care model into a single-session, lifelong treatment solution.
LDL-C Also known as “bad” cholesterol, these bad cholesterol The continuous accumulation in blood vessels eventually makes it difficult for blood to flow into the heart. The consequences are high blood pressure and difficulty in oxygen supply to the heart. It is an important culprit in causing arteriosclerosis, cardiovascular disease, stroke and other diseases. Although diet control and exercise can It is effective in lowering LDL-C levels, but most people cannot strictly follow this lifestyle for a long time. Although there are already oral statins , as well as innovative therapies that are injected once a week, every month, or even every six months, they are not yet popular. Medication compliance is another major challenge in the prevention and treatment of cardiovascular disease.
In addition, other studies have shown that the PCSK9 protein expressed by the PCSK9 gene can bind to the LDL receptor (LDL-R) on the surface of liver cells, causing the degradation of LDL-R, thereby increasing the levels of low-density lipoprotein cholesterol in the plasma. Reducing the expression of PCSK9 gene or inhibiting the binding of PCSK9 protein to LDL-R can reduce the level of low-density lipoprotein cholesterol in plasma, thus preventing the occurrence of cardiovascular diseases.
At the International Society for Stem Cell Research held previously, Verve Therapeutics announced that two weeks after intravenous injection of gene editing tools into 14 monkeys, PCSK9 gene expression in the monkeys’ liver cells decreased by 67%, and blood PCSK9 protein dropped by 89%, while "bad cholesterol" levels dropped by 61%. More than 6 months after the experiment ended, the treatment level remains very good, and the most worrying off-target effects and toxic effects of gene editing therapy have not appeared. This is the first time that a gene-editing therapy to prevent and treat cardiovascular disease has been successfully tested on primates. To some extent, this research means that the dream of lowering LDL cholesterol and preventing cardiovascular disease will be achieved once and for all. accomplish.
But Verve Therapeutics' VERVE-101 faces stiff competition if it wants to replace existing treatments.
For example, the pharmaceutical giant Amgen has spent more than 10 years launching the targeted drug evolocumab, which inhibits PCSK9 expression. The results of a cardiovascular outcomes study (FOURIER) that included 27,564 patients showed that evolocumab On the basis of statins, the level of low-density lipoprotein LDL-C is further reduced by an average of 59%, the risk of cardiovascular events is reduced by 15%, the risk of myocardial infarction is reduced by 27%, the risk of stroke is reduced by 21%, and coronary revascularization is The risk is reduced by 22%. Overall, as a groundbreaking cholesterol-lowering drug, evolocumab can significantly reduce LDL-C levels in patients with cardiovascular disease, thereby reducing the risk of myocardial infarction and stroke.
Another example is Medicines' (acquired by Novartis in 2019) inclisiran (a siRNA drug targeting PCSK9 mRNA). Its previously announced first pivotal phase III study data showed that 300mg can be administered by subcutaneous injection twice a year. All met primary and secondary endpoints, and were well tolerated and safe.
In addition, many experts are not optimistic about VERVE-101. They believe that both statins and PCSK9 inhibitor have been proven to be safe and effective. It is difficult to imagine that in some poor countries and regions, people will choose to use gene editing. medicine, rather than other cheaper medicines. Therefore, outsiders believe that even if Verve's gene therapy is effective, it will be difficult to find a market and be widely used in the future, and patients and doctors should also remain vigilant about gene therapy.
However, this has not affected Verve Therapeutics’ optimism about VERVE-101. It believes that currently existing drugs all work after gene transcription (such as siRNA drugs) or after expression (such as PCSK9 monoclonal antibodies). It treats the symptoms rather than the root cause and requires long-term medication or injections. Through gene editing and treatment at the DNA level, it is possible to achieve a one-time injection and permanently prevent cardiovascular disease, which not only relieves the burden of long-term medication, but also saves treatment costs. . Article by
| Biological World Medical Valley
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