The company that just got approval to sell the first gene-editing treatment in history, for sickle-cell disease, is already looking for an ordinary drug that could take its place.

Vertex Pharmaceuticals has a 50-person team working “to make a pill that doesn’t do gene editing at all,” says David Altshuler, head of research at the Boston drug company.

“We’re trying to out-innovate ourselves,” he says. 

Vertex won approval in the US to sell the world’s first treatment using CRISPR, the gene-editing technique, on December 8. It took eight years to develop, and at huge expense. Regulatory documents filed with the government during the approval process exceeded a million pages.

Yet now that medicine’s CRISPR era has begun, some of the technique’s limitations are already visible.

The treatment, called Casgevy, is both tough on patients and hugely expensive. Patients must spend several weeks in a hospital as doctors remove, genetically edit, and then reintroduce their bone-marrow stem cells, which make blood. The treatment will cost $2.2 million, not including hospital costs, according to Vertex.

The company proved the gene fix can be a permanent remedy for people who have the most severe sickle-cell symptoms. These individuals, numbering around 16,000 in the U.S., suffer recurring pain crises when misshapen red blood cells block blood vessels in their bodies.

But it’s unclear how many Americans will opt for gene editing. In an opinion column for MIT Technology Review, one patient who got the treatment, Jimi Olaghere, said the bone-marrow replacement an “intense months-long journey” that will create barriers to access.

Previously, several gene therapies have floundered in the marketplace because of a combination of high prices and too few patients.

“It’s simultaneously a miracle and has a drawback that prevents wide use,” says Geoffrey von Maltzahn, a partner at Flagship Pioneering, who leads biotech ventures but was not involved in the sickle-cell treatment. “That is a common duality.”

Such drawbacks are why a pill to alleviate sickle-cell, if developed, could sweep CRISPR from the playing field. A pill version could also resolve a brewing moral dilemma: Vertex so far has no plans to offer its gene-editing treatment in those countries where sickle-cell is most common.

A wide ribbon of lower-income nations across the middle of Africa, including Nigeria and Ghana, account for 80% of sickle-cell cases but, according to US researchers, lack the hospitals, medical expertise, and money to implement this complex intervention.

“One question I get a lot is: How are we going to get to the rest of the world?” says Altshuler. “And I think the answer is not by trying to do bone-marrow transplants in the rest of the world. It’s just too resource intensive, and the infrastructure is not there. I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively.”

Three strategies

In an interview with MIT Technology Review, Altshuler outlined three ideas Vertex is exploring to improve on its breakthrough CRISPR treatment.

One is to come up with a substitute for the intense chemotherapy that’s used to kill a person’s bone marrow and make space for the edited cells to take over. Vertex and other gene-editing companies, like Beam Therapeutics, say they are looking into gentler methods that could make the procedure easier for patients.

A second strategy Vertex and other companies are exploring is called “in vivo” editing. That’s when gene-editing molecules are dripped directly into a person’s veins, or even injected like a vaccine, no transplant needed.

To achieve in vivo editing for blood diseases, research groups are trying to develop homing systems—viruses or special nanoparticles—that would convey CRISPR directly to a person’s blood-making stem cells. Such “single shot” editing concepts have won substantial support from the Bill & Melinda Gates Foundation, which thinks it could help solve sickle-cell and HIV in Africa. But it remains at an experimental stage, and some question if it will ever be possible.

The final idea is a conventional drug, the kind you swallow. That would be the easiest to distribute where it’s needed. Angela Koehler, a biochemist at MIT, says “broadly accessible” drugs with a “low barrier to access” would have the greatest impact on sickle-cell disease globally.

“This does not diminish my excitement about the CRISPR-based approaches, but it partially explains the motivations of folks trying to develop ‘traditional’ drugs,” says Koehler.

Keep innovating

Sickle-cell is caused by defects in hemoglobin, the oxygen-carrying molecule in red blood cells. The CRISPR treatment stops the worst disease symptoms by making a targeted DNA edit that turns on “fetal hemoglobin,” a second version that we all have but is largely inactive after we’re born.

By early 2019, Altshuler says, he had seen results from the first gene-edited patients who volunteered for the company’s trial. It was clear then that the theory was true: turning up fetal hemoglobin was a cure.

Within weeks of seeing those results, Altshuler says he’d launched a hunt for a conventional drug that could do the same thing, even as the CRISPR program steamed ahead. “The goal is to achieve a similar profile with a pill instead of a gene editing,” he says.

Reaching the whole world with a treatment was part of the motivation, but it wasn’t the only one. Part of what is driving Vertex is a painful lesson it learned following the 2011 launch of its breakthrough drug for hepatitis C, called Incivek. The drug had the fastest increase in sales for any product in history at the time, reaching $1.5 billion in a year.

Yet within three years, Vertex had to stop selling Incivek after a competitor, Gilead Sciences, came up with a more effective alternative with fewer side effects. 

The brutal lesson: keep innovating.

“Something I have never understood about biopharma: they discover the first medicine in a disease, and let other people eat their lunch,” Altshuler says. “They stop doing research and wait.” 

Pill hunt

The pill hunt remains shrouded in secrecy—Altshuler won’t reveal any of the details, saying the lack of information in the public domain is part of what makes it an attractive project. 

But it’s likely that Vertex’s search centers on the same biological “target” that CRISPR changes. That is a gene called BCL11A, which acts like a switch controlling fetal hemoglobin. Gene editing turns that gene down, allowing fetal hemoglobin to rise.

It’s not easy to get an ordinary drug to copy that effect. The tricky part is that the BCL11A gene manufactures a transcription factor, a type of protein that’s floppy and formless and lacks the precise kinks and corners that chemists can aim drugs at. Indeed, such molecules have the reputation of being “undruggable.”

According to Altshuler, no marketed drug currently works by binding to a transcription factor.

Although the hunt for a drug has so far been low key and out of sight, clues have started to spill out, including some from other companies pursuing similar goals. This week, at a major blood-disorders meeting, the pharmaceutical company Novartis said it had screened several thousand molecules and found some that were able to raise fetal hemoglobin.

Separately, a team at Children’s Hospital in Boston said at the same meeting it had made discoveries about how the BCL11A protein folds, highlighting potential ways drugs could act on it.

That lab is led by Stuart Orkin, a scientist whose discoveries about the fetal-hemoglobin switch we recently profiled in MIT Technology Review. “Some people are trying to find new targets, but I don’t think there is anything else worth studying,” says Orkin. “I think it’s the only one that will get us to the other side of the problem.”

Orkin says he’s been looking for a drug, too, but those attempts, some in collaboration with Koehler, have not yet paid off. “I can say we’ve tried a lot of things that don’t work,” he says.

Orkin also still believes gene editing will be a better treatment, if you can get it. “If I had a child and the choice was a cure versus taking pills for life, I would go for the editing. If you can fix it, I would,” he says. “But many patients are not ready for the rigors of transplant, and many are not in a setting where it can be done. There aren’t enough hospitals or physicians.”

And that is the irony of CRISPR’s first treatment. It can cure individuals but can’t yet conquer a disease. In fact, the problem of sickle-cell is only expanding. That is because countries with high rates of this inherited condition also have booming populations. Every year, more people, not fewer, suffer with the disease. CRISPR can’t yet reverse the trend, but a pill might.

“It’s solved from a disease standpoint, but not a burden-of-disease standpoint,” says Orkin. “That is the next chapter. Sickle-cell is a big problem. And it’s growing, not shrinking.”