The UK has just given regulatory approval to Casgevy (exagamglogene autotemcel) for the treatment of sickle cell disease and transfusion dependent beta-thalassemia (TDT). This is a significant milestone because Casgevy is the first approved CRISPR-based treatment – a gene editing tool that has the potentially to permanently “cure” both diseases. The FDA is currently reviewing the same treatment and may provide approval early next year. The European Medicines Agency has also accepted an application for approval.
I first wrote about CRISPR on SBM in 2017, when I said it was a promising new medical technology that may provide new treatments relatively quickly, but we will have to be patient and wait. Here we are less than a decade later with an approved treatment. That is quicker than I had hoped.
CRISPR stand for Clustered Regularly Interspaced Short Palindromic Repeats. It is a powerful gene-editing tool derived from bacteria. It allows for relatively (compared to older technology) rapid and inexpensive gene editing. The CRISPR molecule is able to target and attach to a specific sequence of DNA. It can also be attached to a payload, commonly CAS-9, which is an enzyme that can sever the DNA strand. Cutting the DNA can inactivate a specific gene. Researchers can also use the precise cut as a location to insert a new gene, using the normal DNA repair mechanism. CRISPR can be used to silence genes, to reversibly turn then off and on, or to insert new genes.
In addition to genetics research and genetically engineering in agriculture, CRISPR hold the promise of treating, and potentially even curing, genetic diseases. When applied to living organisms, however, there is another challenge. While CRISPR itself can target the desired DNA sequence, you also have to get the CRISPR to the target cells. This is the more challenging aspect of gene therapy – which vectors do we use to deliver the CRISPR? But there are some conditions where we can bring the cells to the CRISPR rather than the CRISPR to the cells – diseases of the blood. This is the case for sickle cell and TDT, which is why these are the diseases targeted by the first approved CRISPR therapy.
Sickle Cell and Thalassemia
Sickle cell disease and beta-thalassemia are both genetic disorder of hemoglobin, the molecule in red blood cells that binds to and carries oxygen throughout the body. In sickle cells a mutation causes a conformational change in the hemoglobin when it binds oxygen which causes the red blood cells to form into a crescent or sickle shape. These sickle-shaped red blood cells are also stiff, and they have a hard time passing through the tiny capillaries that are only big enough to allow one flexible red blood cell to pass through at a time. Therefore the sickle-cells clog up the capillaries, interfering with blood and therefore oxygen delivery to the tissues. During a sickle-cell crisis, this blockage is happening all over the body. It is extremely painful and dangerous.
Thalassemia is also a mutation of hemoglobin, but there are literally thousands of possible mutations with different effects. The hemoglobin has four subunits, two alpha and to beta. Each contains an iron molecule that can bind and release oxygen – it binds oxygen when passing through the lungs where the oxygen content is high, and then releases the oxygen when passing through other tissues where the oxygen content is low.
The beta-thalassemias are a host of heterogeneous mutations that in some way reduce or impair the beta-globin subunits of hemoglobin. While some are asymptomatic, the potential result is reduced hemoglobin production and function, and possible anemia (reduction in red blood cells). Clinically an important consideration is whether or not the thalassemia is severe enough that it requires regular red blood cell transfusions – transfusion-dependent thalassemia (TDT). Patients with TDT may require regular blood transfusions every few weeks.
There are about 20 million people with sickle cell disease world wide, 100k in the US and 15k in the UK. TDT affects about 100 thousand people, 1,200 in the US and 1000 in the UK.
How Casgevy Works
It may seem strange that one CRISPR-based drug can treat both sickle cell and TDT, especially since TDT itself comprises so many different specific mutations. This is because both diseases have one thing in common – the mutations affect adult hemoglobin. Fetal hemoglobin dominates in fetuses during gestation and through the first six months of life. Then we transition to adult hemoglobin. Fetal hemoglobin has alpha and gamma subunits (rather than beta). This type of hemoglobin is optimized for the fetus, so that the fetal hemoglobin can get oxygen from the mother’s hemoglobin (because it has an even higher affinity for binding oxygen).
Shortly after birth a specific gene, BCL11A, turns off the production of the gamma globin subunits. What Casgevy does is cut both strands of DNA in the BCL11A gene, silencing it. This unleashes the production of gamma subunits and fetal hemoglobin, which can dominate once again, free of the sickle cell or beta-thalassemia mutations.
In clinical trials, treatment with Casgevy completely relieved 28 of 29 patients with sickle cell disease of painful episodes for at least a year. In TDT, 39 of 42 subjects treated did not need a transfusion for at least a year. These are amazing results, better than any existing treatment for either disease. These benefits may also potentially be permanent.
Treatment involves removing bone marrow stem cells from a patient, then treating those cells with Casgevy in order to silence the BCL11A gene, and finally returning the treated stem cells to the bone marrow of the patient. The bone marrow does have to be treated in order to receive the altered cells, and there is the potential for infection during this procedure. But bone marrow auto-transplants like this are a well-established treatment.
Each treatment is an individualized “one-off” treatment. For this reason, a single treatment for a single patient is expensive. At present it is estimated that in the UK treatment will cost £1 million or more. In the US the estimated cost is $2 million.
That may seem prohibitive, but we need to consider the overall cost-effectiveness of the treatment, which means comparing the cost of treatment to the cost of managing each disease without the treatment. Sickle cell patient require frequent hospitalization, which can be very expensive. One analysis found that Casgevy can be cost effective at £1.5 million or $1.9 million. This is in range of the estimated cost. Also, the longer the treatment benefits last, the more cost effective the treatment becomes. A lifetime of transfusions or hospital admissions adds up.
This, of course, is also just considering monetary cost. There is also extreme benefit to the quality of life of the recipients. Hopefully, with approval in the UK and soon in the US and Europe, Casgevy will prove profitable as well as cost effective, while improving the lives of many people. This will allow further R&D on CRISPR-based treatments. Hopefully it will also allow the cost of treatment to come down, making it available to patients in less wealthy nations.
The approval of Casgevy is a milestone worth noting. It came sooner than I anticipated, meeting all the expectations for the potential of gene-based therapies. Hopefully this is just the beginning.