Key questions (and answers) about the historic approval of a CRISPR-based medicine

History just happened.

For the first time, U.S. regulators have cleared a treatment using CRISPR, the gene-editing technology, for patients. The product is Casgevy, a treatment for sickle cell disease and beta thalassemia, two blood disorders. It was developed by CRISPR Therapeutics, the Swiss company co-founded by Nobel laureate Emmanuelle Charpentier, and Vertex Pharmaceuticals, a large Boston-based biotech firm. The treatment was approved by U.K. regulators three weeks ago.

In 2012, when Charpentier and Jennifer Doudna published their landmark paper on editing DNA in a test tube with CRISPR, almost no one believed that a treatment based on the technology would be reaching patients in little more than a decade.

The news is perhaps even bigger because Casgevy is directed at sickle cell disease, a painful and life-shortening disorder that causes red blood cells to become misshapen. It afflicts 100,000 people in the U.S., and is far more common in people of African descent. It was long ignored by researchers and drug companies, although that is changing.

But history is also complicated. This first CRISPR treatment is not an easy treatment to receive, requiring patients to spend weeks, even months, in the hospital before and after the therapy is administered.

Here are some key questions — and answers — about how to think about this milestone moment.

What is CRISPR?

CRISPR is a way to change specific areas of DNA. The system was discovered in bacteria, which use it as an immune system to fend off attacks by viruses. Bacteria store parts of their enemy viruses’ DNA so they can cut the viruses’ genes and defend against them. A CRISPR editing system has two parts: a “guide RNA” sequence and a pair of molecular “scissors.” The guide sequence, like a Dewey decimal number for DNA, leads the scissors to a specific spot on the double helix and the scissors cut the strand of DNA there, inactivating that gene. More recent technologies allow CRISPR systems to insert new DNA into this site, or swap out individual nucleotides — the “letters” in the DNA sequence.

Here is a primer video on CRISPR.

What is sickle cell disease? What is beta thalassemia?

Sickle cell disease is a complex disorder that stems from an inherited mutation. That genetic alteration causes a molecular change in hemoglobin, the protein that carries oxygen through the blood, making it sticky, prone to linking together. That distorts red blood cells from their usual flexible round shape into a stiff crescent, the sickle that gives the disease its name. Those misshapen cells sometimes clog blood vessels, causing excruciating vaso-occlusive pain crises, which patients say make you feel like someone’s stabbing you or taking a hammer and chisel to your bones.

But the damage goes far beyond obstructed blood vessels. The misshapen cells also injure vascular walls, don’t survive as long as healthy red blood cells, and make people more prone to dangerous clots. Tissues often can’t get the oxygen and iron they need. Possible complications are varied, and can appear almost anywhere in the body. They include heart attack, stroke, kidney failure, infection, and bone tissue death requiring a hip replacement, to name just a few. Most patients require frequent blood transfusions and hospital care.

Though the treatments for beta thalassemia are similar to those for sickle cell disease, the condition has a different cause. Hemoglobin has two parts, an alpha chain and a beta chain. In beta thalassemia, genetic mutations prevent the body from producing enough of the beta chain, and thus the person’s red blood cells can’t bind or carry iron. People with beta thalassemia range in how dependent they are upon blood transfusions to compensate for the inadequate blood cells their body makes. Most people with transfusion-dependent thalassemia need blood transfusions every few weeks for their entire lives.

The transfusions create further complications. The body typically takes iron from old red blood cells and recycles them into new red blood cells, but because people with beta thalassemia aren’t making new, working red blood cells and are constantly receiving more iron through their transfusions, they build up a lot of excess iron. This iron accumulates in organs like the heart and liver and impairs organ function and in the past was deadly to people with the disease. But with the advent of medicines that help the body excrete the iron overload, thalassemia has largely turned into a manageable chronic disease in the last few decades.

How does Casgevy work?

Casgevy edits a patient’s own blood stem cells to produce high levels of fetal hemoglobin — the healthy, oxygen-carrying form of hemoglobin that is produced during fetal development but normally shuts down soon after birth. Fortunately, people with mutations in the type of hemoglobin that predominates after birth still have healthy fetal hemoglobin. Researchers had previously identified a certain genetic mutation that causes fetal hemoglobin to persist into adulthood. When this happens to people with sickle cell, their disease is mild and outcomes are greatly improved.

Casgevy uses the CRISPR/Cas9 enzyme to mimic this protective genetic mutation. It makes a cut at a specific spot in a gene called BCL11A. The edit, in turn, disables a DNA brake on the production of fetal hemoglobin.

While Casgevy is infused into patients just once, it is not an easy or fast treatment for patients to receive. The entire process can take months, even up to a year.

First, hematopoietic, or blood-producing, stem cells are collected from patients and sent to a lab, where the actual CRISPR editing is done. After quality testing, the Casgevy-treated stem cells are shipped for use. Before the edited cells can be administered, patients must undergo a preparatory treatment with busulfan, a chemotherapy drug, to obliterate any native stem cells that might remain in their bone marrow. This “conditioning” step is crucial because it provides space in the bone marrow for the functional, CRISPR-edited cells to engraft and grow.

But busulfan, like most chemotherapies, can cause severe side effects, including low levels of infection-fighting white blood cells. For this reason, patients must be hospitalized in sterile conditions. The actual injection of Casgevy-treated cells is quick, but patients must remain in the hospital until their immune system recovers and the risk of serious infection abates.

How is this different from existing bone marrow transplants?

For the last 30 years or so, there’s already been a so-called “one-time” therapy available to some sickle cell disease patients: bone marrow transplant. This bears some similarity to the new therapy. As with CRISPR-based treatment, patients getting a bone marrow transplant need to have their own bone marrow obliterated with chemotherapy. That does away with the stem cells that’ve been producing unhealthy red blood cells, making room for something else.

The difference lies in the source of the replacement: In the new therapy, you become your own bone marrow donor, with the help of gene editing in the lab. In a bone marrow transplant, the replacement comes from someone else. That’s part of the advantage of the CRISPR-based treatment: With bone marrow transplants, it can be very hard to find a donor who’s properly matched, and even when that’s possible, there may still be concerns about the host’s body reacting to another person’s cells.

Who will get this treatment?

Vertex estimates that there are approximately 32,000 people with sickle cell disease or beta thalassemia in the U.S. and European Union who might be good candidates for Casgevy. Of those, 25,000 have sickle cell disease.

Given the complexity involved with treatment and the associated risks, experts believe people with more severe disease are likely to be more suitable candidates. In their clinical trial, Vertex and CRISPR Therapeutics enrolled participants experiencing an average of four pain crises and two hospitalizations per year.

Sickle cell is a progressive disease, meaning the damage done to organs and tissue that results from obstructed blood vessels cannot be reversed, even by a CRISPR-based treatment. U.S. and U.K. regulators approved Casgevy for patients 12 years or older, which means it could be offered to adolescents and younger adults before significant damage to their bodies takes hold.

Vertex said Casgevy’s price will be set at $2.2 million, in line with prices set for other cell and gene therapies. An independent drug-pricing watchdog group has said Casgevy is likely to be cost-effective at its expected price, given the existing high cost of care for people living with sickle cell disease over their lifetime.

But high prices can still be a barrier that prevent a large number of patients from accessing new medicines like Casgevy. In the U.S., many people with sickle cell disease are covered by Medicaid, which may have limited financial resources to pay for treatment.

What concerns does the sickle cell community have?

“Approval does not mean access,” said Teonna Woolford, CEO of the Sickle Cell Reproductive Health Education Directive, a patient advocacy group — and the extent to which the patients who want this therapy will be able to get it is a huge question.

Another has to do with the extent to which this therapy is “curative” and what long-term effects it might have. While some hopefully refer to the CRISPR-based treatment as a potential cure, others, like Woolford, point out that they want to see far-reaching data about that before using such a charged word — ideally not just 10 or 15 years out, but following patients through the rest of their lives.

Patients also wonder to what extent fertility preservation — and assisted reproductive technology — will be accessible to patients who get this therapy. As with bone marrow transplants, the chemotherapy involved in the CRISPR-based treatment can impair fertility. Will egg-freezing and sperm-freezing be available to patients? Even if it is, that doesn’t necessarily mean they’ll be able to use those banked reproductive samples to try to have kids, given that in vitro fertilization is expensive, and often not covered by insurance. “What good does it do to have a bunch of eggs that you can’t actually turn into a birth because you can’t afford the IVF when you’re ready to have a baby?” said Woolford.

How do we know this treatment edits only the genes it’s supposed to and not anything else?

This is one of the biggest questions that arises in gene-editing discussions, as so-called “off-target” effects could theoretically result in leukemia, for instance. There are now tools that can help scientists search in edited cells for the location of every double-stranded break in the genome. Combined with advances in sequencing technology, these methods have become pretty good at detecting off-target changes. What’s more difficult is knowing what biological consequences those changes might have, given how much of our DNA remains a mystery.

While regulators have decided that the benefits of this treatment outweigh the risks given the current ability to monitor for off-target effects, there is still much to learn.

What do investors expect regarding sales for this treatment?

Until shown otherwise, investors and analysts are relatively skeptical about the business prospects for Casgevy. Even Vertex, which is running point on the commercial launch, has been cautioning investors to expect uptake to be slow, given the complexity of treatment and the need to sort out reimbursement and access.

According to Bloomberg consensus estimates, Casgevy sales aren’t expected to reach $1 billion until 2027, or more than three years after approval. Peak sales in 2030 and beyond could rise to more than $2.2 billion, according to Bloomberg.

To put that in perspective, Vertex is expected to report nearly $10 billion in sales of its drugs for cystic fibrosis this year.

Under the collaboration agreement between Vertex and CRISPR Therapeutics, Vertex will record and report all sales of Casgevy worldwide. Profits made from the drug will be split 60%-40% in Vertex’s favor.

For CRISPR Therapeutics, Casgevy is its first approved product, and will deliver meaningful revenue to help offset substantial spending on research and development.

What other CRISPR-related treatments are being developed?

The arrival of a CRISPR-based therapy is one of the biggest leaps in biomedical innovation since the invention of drugs based on recombinant proteins in the 1980s that helped launch the biotech sector, CRISPR Therapeutics CEO Samarth Kulkarni told STAT. “Genome editing is something special and it may redefine the paradigm of medicine over the next 30-40 years. Exa-cel’s [Casgevy’s] approval represents the start of it.”

Intellia Therapeutics is developing treatments for inherited diseases that perform the CRISPR gene editing inside the body.

New variations of CRISPR are also being developed, such as base editing, which allows changes to be made to individual letters inside DNA. Recently, an experimental treatment based on base editing from Verve Therapeutics lowered levels of bad cholesterol in patients with a type of inherited cardiovascular disease.

While so-called CRISPR 1.0 is primarily used to cut genes like a molecular scissor, a newer technology called prime editing incorporates additional enzymes and genetic instructions to insert, delete or rewrite short segments of DNA.

Why are these treatments so expensive?

Part of the answer is that these drugs are difficult to develop and manufacture. But the biggest factor is simply this: Medicines for rare diseases are expensive. They commonly cost hundreds of thousands of dollars per patient per year. And because gene therapies are meant to be given once in a lifetime, companies have argued that they should be as expensive as multiple years of treatment. The high prices do mean the products are lucrative, and have led investors to pour hundreds of millions of dollars into CRISPR Therapeutics and competitors such as Intellia Therapeutics and Editas Medicine.

This is, however, a big concern for many of the researchers working on the technology, including Jennifer Doudna of the University of California, Berkeley, who shared the 2020 Nobel Prize in Chemistry with Charpentier for development of CRISPR-Cas9, the gene editing enzyme used in Casgevy.

“I don’t think we want to live, or I don’t want to live, in a world where only a few wealthy or connected people can get access to something like this,” Doudna told STAT. She said that researchers at the Innovative Genomics Institute, which she runs, are focused “on this question of how you make sure that CRISPR is going to ultimately be available to people worldwide who can benefit from it.”

“It’s a big challenge,” Doudna said.

This story has been updated with news of the FDA’s approval of Casgevy.