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In December 2023, US Food and Drug Administration approved two gene therapy-based drugs for sickle cell disease treatment.
CASGEVY (exagamglogene autotemcel) is the first approved CRISPR/Cas9 genome-edited cell therapy for the treatment of Sickle Cell Disease – SCD, in patients 12 years or older with frequent vaso-occlusive crises (VOCs). CASGEVY has been developed by Vertex Pharmaceuticals and CRISPR Therapeutics and has been shown to reduce or eliminate vaso-occlusive crises for SCD patients.
The FDA also approved Bluebird Bio’s LYFGENIA (lovotibeglogene autotemcel), an autologous hematopoietic stem cell-based gene therapy for the treatment of patients 12 years of age or older with sickle cell disease (SCD) and a history of vaso-occlusive crises (VOCs). LYFGENIA is produced individually for each patient using their own blood stem cells. It’s infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT) after myeloablative busulfan conditioning.
Despite the approval, though, Bluebird finds itself in a tough position compared to its competitor. For one, it released pricing for LYFGENIA at $3.1 million, compared to the $2.2 million price tag that Vertex placed on CASGEVY. Second, the FDA approval for Lyfgenia includes a safety warning that requires patients to be monitored for a potential cancer risk, something that Casgevy’s approval does not.
The most common side effects of CASGEVY include low levels of platelets, low white blood cells, febrile neutropenia (fever and low white blood cells), headache, itching, mouth sores, nausea / vomiting, muscle pain, stomach-area pain. Symptoms may include fever, chills, infections, headache, bruising, and bleeding.
LYFGENIA carries a Boxed Warning for development of certain blood cancers. Other warnings and precautions include delayed platelet engraftment, neutrophil engraftment failure, insertional oncogenesis, and hypersensitivity (allergic) reactions. Common side effects (≥ 20%) include stomatitis (mouth, lips, throat sores), thrombocytopenia (low platelet counts), low red or white blood cells counts, and febrile neutropenia.
Several points in the above news need elaboration for better understanding. Here we go.
Sickle Cell Disease – SCD
Sickle cell disease (SCD) is a debilitating, progressive, and life-shortening disease. SCD is an inherited blood disorder that affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or “sickled” red blood cells. The clinical hallmark of SCD is VOCs, which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires a lifetime of treatment and results in a reduced life expectancy. In the U.S., the median age of death for patients living with SCD is approximately 45 years. A cure for SCD today is a stem cell transplant from a matched donor, but this option is only available to a small fraction of patients living with SCD because of the lack of available donors. SCD patients report health-related quality of life scores well below the general population, and the lifetime health care costs in the U.S. of managing SCD for patients with recurrent VOCs is estimated between $4 and $6 million. This approval means that for the first time, approximately 16,000 patients with SCD in the USA may be eligible for a durable one-time therapy that offers the potential of a functional cure for their disease by eliminating severe VOCs and hospitalizations caused by severe VOCs.
Globally, each year, approximately 515,000 babies are born with SCD and the majority of these births, over 75%, occur in Africa. Without appropriate treatment, about 30% of children with untreated SCD in Africa will not survive beyond the age of five. The new approvals shall not benefit children in Africa due to the astronomical cost.
Gene Therapy
Gene therapy is a technique that uses a gene(s) to treat, prevent, or cure a disease or medical disorder. Often, gene therapy works by adding new copies of a gene that is broken, or by replacing a defective or missing gene in a patient’s cells with a healthy version of the gene. Both inherited genetic disease, such as hemophilia, sickle cell disease, and acquired disorder such as leukemia have been treated with gene therapy.
The potential risks associated with gene therapy depend upon the type of therapy, type of delivery mechanism (vector) and the way in which it is delivered to the cells. They may include:
- a negative immune system reaction
- complications from inadvertently targeting the wrong cells
- adverse effects associated with inserted genetic material
- unexpected gene expression
The Food and Drug Administration and the National Institutes of Health closely monitor gene therapy trials, and techniques are continually researched and refined. Patients are closely monitored by their treatment team for years after gene therapy
The goal of gene therapy is to change the course of disease by targeting its genetic cause.
CRISPR-Cas9 Technology
Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 is a gene-editing technology causing a major upheaval in biomedical research. It makes it possible to correct errors in the genome and turn on or off genes in cells and organisms quickly, cheaply and with relative ease. It has a number of laboratory applications including rapid generation of cellular and animal models, functional genomic screens and live imaging of the cellular genome. It has already been demonstrated that it can be used to repair defective DNA in mice curing them of genetic disorders, and it has been reported that human embryos can be similarly modified. Other potential clinical applications include gene therapy, treating infectious diseases such as HIV and engineering autologous patient material to treat cancer and other diseases.
The Nobel Prize in Chemistry 2020 was jointly awarded to Emmanuelle Charpentier and UC Berkeley professor Jennifer A. Doudna for their work on Crispr-Cas9, a method to edit DNA. It was the first time the award has gone to two women.
Cas9 enzymes together with CRISPR sequences form the basis of a technology known as CRISPR-Cas9 that can be used to edit genes within the organisms. This editing process has a wide variety of applications including basic biological research, development of biotechnological products, and treatment of diseases.
While CRISPR-Cas9 system is highly intended to be used on humans, it does raise ethical and logistical questions. One reason, for ethical dilemma is the concern on “designer babies” and hence exploitation of this technique to alter genomic profile of embryos. Normally, the process of approval of a therapeutic technique is done using validations in vitro, in vivo (in pre-clinical trials) and then in human subjects (in clinical trials). However, very recently, a highly controversial step was taken by a doctor, Dr. He Jiankui, who applied CRISPR-Cas9 therapeutic strategy against gene CCR5 (plays a role in HIV) based on preliminary data based on pre-clinical data in human embryos. The uproar this caused, led to imprisonment of the doctor on ethical grounds, however it was noted that the gene-edited baby girls born were healthy and have been under observation. Individuals with CCR5 gene mutation are more resistant to HIV infection, so the doctor included this sequence as a donor template to allow HDR. The two children who received these constructs do have off-target integration of the CRISPR sequence; however, they are born healthy. So far, it appears to be a success. While the data is very preliminary and strategy of use very controversial, it does favor the use of CRISPR-Cas9 technology in humans.
SUM UP
Despite all the hype, the process of commercially producing and transporting to individual patients poses several challenges. It will take several months to sort out these issues.
Advancements in treatment modalities are extremely welcome. However, it also widens the inequality between rich and poor nations because the vast majority of poor patients in low- and middle-income countries shall never be able to afford such treatments in the foreseeable future. Novartis was the first company to receive approval for their gene therapy drug ZOLGENSMA, for a rare genetic disorder SMA – Spinal Muscular Atrophy. They priced it at US$2.12 million, with the option to pay in five years. Novartis also announced a draw every year for awarding free treatment to five patients worldwide. It is a good step, though it cannot be said how much benefit it will accrue compared to incidence. SCD has a much higher incidence anyway and needs more generous support.
Concluded.
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