100 Years But Only One Drug: Sickle Cell Patients Wait For Help

Xconomy National — 

Last week, 100,000 Americans with sickle cell disease and millions more around the world got encouraging news. Investors gave a vote of confidence, in the form of a $120 million IPO, to Global Blood Therapeutics (NASDAQ: GBT), a four-year-old biotech working on a pill that could become the biggest medical advance ever for the disease.

That pill, which just began its first human trial in January, is a once-a-day medicine that a patient would have to take for life. If approved, the drug would be only the sickle cell treatment to potentially halt the effects of the disease. The lone drug currently on the market for the disease only addresses some of its symptoms.

Patients with sickle cell disease carry a mutated form of hemoglobin that causes normally disk-like red blood cells to change into rigid crescent-shaped cells. Those misshapen cells get hung up in the blood vessels, wreaking all sorts of havoc. In the face of the disease’s worst complications—strokes, deadly lung complications, bouts of excruciating pain, anemia, and more—one pill a day doesn’t seem like much burden. (Global Blood CEO Ted Love declined to answer questions, citing quiet period regulations.)

But even more tantalizing hope lies on the horizon. Gene therapy, ideally a one-shot cure, could arrive in the next decade.

“The first documented sickle cell patient was in 1910, and we only have one medication,” says Sonja Banks, president of the Sickle Cell Disease Association of America in Baltimore, MD. “Anything cutting edge is great; we’re so far behind in the game.”

Banks is fully aware that, as with any new area of medicine, there are still hurdles to overcome in the field of gene therapy, which has seen a renaissance in the past few years. Just recently two gene therapy companies, Celladon (NASDAQ: CLDN) and Avalanche Biotechnologies (NASDAQ: AAVL), cratered after terrible late clinical results, while others, namely Spark Therapeutics (NASDAQ: ONCE) and Bluebird Bio (NASDAQ: BLUE), have watched investors flee the stock despite no public setbacks.

And gene therapies for sickle cell, specifically, have a long, long way to go. Bluebird has one in development, called LentiGlobin, and it’s the most advanced. Positive data from a single patient was enough to cause a stir earlier this year, as my colleague Ben Fidler reported.

The therapy requires extracting a sample of the patient’s hematopoietic, or blood-producing, stem cells from the bone marrow, modifying them outside the body, and giving them back to the patient. The technique uses a virus to deliver a healthy copy of the hemoglobin-beta gene into the stem cells. It’s supposed to be a gentler version of bone marrow transplant, which is the only cure so far for the disease.

A bit farther behind Bluebird is a different form of gene therapy, called gene editing, and it should soon provide early milestones in two very different programs. One is based on CRISPR/Cas9, the gene editing system that has spread around the world’s research labs because it’s so easy to use. Three startups—Crispr Therapeutics, Editas Medicine, and Intellia Therapeutics—have raised hundreds of millions of dollars, collectively, to move the system forward into human therapeutics. They have in recent months revealed plans to work on cancer immunotherapy, blood diseases known as hemoglobinopathies (sickle cell is a hemoglobinopathy), and, most recently with Editas, a genetic form of blindness.

But the first data on a CRISPR/Cas9 therapy for sickle cell disease—or any disease, for that matter—to be unveiled could come from a nonprofit effort.

At the Innovative Genomics Initiative, a University of California-funded group on the Berkeley campus, researchers collaborating with Children’s Hospital in nearby Oakland, CA, have been trying to cure sickle cell disease in mice. (IGI was cofounded by Jennifer Doudna, the Berkeley professor who helped turn CRISPR/Cas9, a bacterial defense system, into a gene editing tool. How much she invented is in dispute, as I detailed most recently here.)

IGI scientific director Jacob Corn and colleagues should know in less than two months if their experiments have worked. They’ve removed the hematopoietic stem cells from mice with an approximate version of sickle cell disease, replaced the mutated gene with the healthy version using CRISPR/Cas9, and put the cells back into the mice. Will their blood contain sickled red blood cells? Will the stem cells that repopulate their bone marrow have the sickle mutation? If so, in what numbers?

Corn declines to project what kind of data would move the program closer to a human trial, or to speculate on the timing of a trial , which would take place at Children’s Hospital. But he feels the urgency, not just from doctors and patients but from other academics who are “hot on this trail,” he says.

Taking hematopoietic stem cells out of the body, editing them, and putting them back into the bone marrow to spawn healthy versions of red blood cells is an obvious use of gene editing. “People have wanted to cure sickle cell disease for a long time this way,” says Corn. “It’s a very worthwhile problem, and it’ll be huge when someone cracks the nut. We hope to be the first.” (IGI researchers have used a technical advance that they hope will persuade the edited cells to function properly when reintroduced; Corn declined to reveal the technique until the data are published.)

Gene editing might be a quantum technological leap, but, like Bluebird’s LentiGlobin gene therapy, it would still require a form of bone marrow transplant. When the cells are taken out for editing, the patient’s remaining bone marrow cells would be killed, a precarious procedure that leaves the patient with a compromised immune system for a period of time.

The hope, however, is that both the gene therapy and gene editing approach will lessen the severity and danger of the procedure for several reasons—in part because the patient’s own cells, not a donor’s, are being transferred back, which theoretically could make for better immune compatibility and less need for harsh drugs.

Another advantage to gene editing or therapy is availability: a patient is his or her own bone marrow donor. In the U.S., sickle cell disproportionately affects African Americans—one in 500 children are born with the disease. The next highest prevalence is in Hispanic Americans, with 1 in 36,000 children born with the disease.

One in 12 black Americans has sickle cell trait, which is an inherited gene from one parent but not the other. Having the ‘trait’ instead of disease doesn’t entirely preclude someone from developing symptoms, however.

For traditional transplants, though, African Americans have a much harder time finding matched donors than any other group.

All in all, it’s estimated that only a few hundred sickle cell patients have had a transplant, and it’s not clear how many of them have succeeded. (A U.S.-funded database shows 353 transplants from 2008 to 2012; survival data is incomplete but shows that patients receiving marrow from unrelated donors have a lower rate of survival.)

Meanwhile, the only approved pharmaceutical for sickle cell is hydroxyurea, a repurposed chemotherapy. It’s useful for relieving the pain episodes, known as crises, and acute chest syndrome, a lung-related complication that can turn deadly.

There are maintenance therapies and ever more sophisticated plans for giving sickle cell patients better lives. For example, one doctor who runs a sickle cell center at a big-city U.S. hospital told me that kids born with either of two genetic variants of the disease get an ultrasound at the age of two. There are four main variants of sickle cell; the two in question are correlated with more strokes. The ultrasound helps predict near-term stroke risk—within the next year—and if the results come back in the danger zone, the child is put on blood transfusions every three to five weeks. (The conversation was on background because the doctor was not cleared by the center to speak to the press.)

Another gene editing program for sickle cell is in the works from Sangamo Biosciences (NASDAQ: SGMO) of Richmond, CA. Sometime in the second half of 2016, Sangamo and its development partner Biogen (NASDAQ: BIIB) will ask FDA permission to start human trials with its program.

To do its gene editing, Sangamo uses a system called zinc finger proteins, which it owns. No one else can use zinc fingers without a license, and Sangamo, with 20 years of development under its belt, is the only company to advance a gene-editing product into human trials, for HIV.

CRISPR/Cas9 hasn’t been around as long as zinc finger proteins, and the technology has a major hurdle to overcome: making sure the molecular “scissors” it uses are making DNA cuts in the right places. Right now, the methods used to detect off-target cuts simply aren’t sophisticated enough. And all it takes is one cut in the wrong place to trigger a tragic unintended consequence. The fear dates back to gene therapy experiments fifteen years ago, in which genes meant to heal kids with severe combined immunodeficiency—the so-called “bubble boy disease”—inserted themselves in the wrong place and triggered cancer. Being more precise with gene editing tools, like CRISPR/Cas9, is still a goal, not a reality.

“Our ability to find off targets isn’t great right now,” says Corn. “No matter how bullish you are, the field [of gene therapy] has been bitten by kids getting leukemia. That should keep everyone in the hematopoietic field up at night.”

(For more on the rollercoaster history of gene therapy, read Ben Fidler’s feature on hemophilia published in March.)

The rapid spread of CRISPR/Cas9—it might not be long before high school students are doing experiments with it—is also keeping people worried for another reason: the potential engineering of human eggs, sperm, and embryos to modify people for aesthetic or social reasons, not medical reasons, and allow those traits to passed on to future generations. There’s also concern that traits engineered into plants and animals meant to spread to entire populations—to create less harmful mosquitoes, for example—could spread out of control.

(My colleagues and I have written about these developments here and here, and Antonio Regalado at Technology Review has done important reporting on the topic. Spurred by papers penned by Doudna, Sangamo CEO Edward Lanphier, and several others, the U.S. National Academy of Sciences and National Academy of Medicine will hold a summit this fall to discuss guidelines on germline editing.)

Curing sickle cell disease should hold no such controversy, of course.

But it holds other cautions. Patient advocate Banks worries that the eventual cost of a product will be out of reach for many U.S. sickle cell patients, 70 percent of whom are low income, she says. If and when that time comes, insurers like the state Medicaid programs will no doubt weigh the savings of a cure against what the drug companies decide to charge.

What will those savings be? It’s not entirely clear. But a 2009 study tabbed the costs sickle cell treatments–culled from 2001-2005 Florida Medicaid data—at $892 a month for young children up to $2,562 per month for people from 50 to 64 years old. The average was $1,389 per month. Three years earlier, this study estimated that in 2004, 113,000 hospitalizations for sickle cell disease in the U.S. cost nearly half a billion dollars.

The health economics disparities within the U.S. pale next to those between the U.S. and regions like Africa and India, where sickle cell disease takes a huge toll.

For example, there are roughly 100,000 people with the disease in the U.S.; more than 100,000 babies are born with the disease every year in Nigeria alone, the highest burden in the world, according to the U.S. Centers for Disease Control.  (Having sickle cell trait helps protect against malaria, which explains why so many people in areas with endemic malaria survive to pass on the gene.)

A biopharma veteran says another hurdle could be difficulty getting people to join trials. For good reason, African Americans have historically been suspicious of the medical community. Checkmate Pharmaceuticals CEO Art Krieg, who has had tours of duty with several companies, remembers looking at sickle cell while at Rana Therapeutics and at Pfizer (NASDAQ: PFE). “From a scientific point of view we liked it,” he says, but clinical and commercial questions blunted the companies’ enthusiasm. “We didn’t get too far.”

(Krieg has worked for years on the problem of delivering RNA-based drugs into cells, which CRISPR/Cas9 companies will need to solve. He is a scientific advisor to CRISPR/Cas9 developer Intellia.)

Krieg also notes that hydroxyurea, while it doesn’t work for everyone, has gone generic. Insurers will have to be convinced that new, pricey therapies will not just be marginally better than existing treatments, including bone marrow transplant.

Banks stresses that sickle cell disease (sometimes still called “sickle cell anemia”) is complicated. A patient’s genetic variant doesn’t always line up with the severity of his or her disease. There’s no easy way to say, in advance, who might be eligible for a future gene therapy. Jacob Corn says if the IGI program, using CRISPR/Cas9 to edit blood stem cells, gets to humans, the plan is to start with those who’ve already had a stroke or who’ve had a lot of pain crises or acute chest syndrome. “We’d like to start with people who are already ill and reverse their disease,” he says.

If he’s still saying that in two months, it’ll be a good step forward.