Cassandra Trimnell has sickle cell disease. She also loves to travel. For her 30th birthday last year, she and her husband planned a trip to Indonesia, and she figured she would be fine. Growing up in Iowa, she was sick all the time, in and out of hospitals with severe pain episodes, or “crises,” and other complications caused by the genetic blood disorder. But when she moved to California her disease changed, and she has rarely been ill. “It probably has to do with the weather,” says Trimnell, who lives in the Bay Area town of Fremont.
Indonesia was calling. Soon after landing, however, her health went south. On her second day there, she woke up with extreme pain in her arm. She went to the hospital. Pain medicine didn’t help, not even morphine. When she told the doctors how much to give her, they balked, afraid it would kill her. “I’m of small stature,” says Trimnell (pictured).
She needed a blood transfusion. She developed acute chest syndrome, a bloodstream infection, and a blood clot in her heart. She needed to be airlifted right away to Singapore. Her husband called the insurance company, and she says the agent on the line had a father who died of sickle cell disease. Without that empathy, Trimnell wonders if the flight would not have been expedited. It was; she flew to Singapore and recovered in a few weeks. Now a patient advocate who focuses on social media outreach, Trimnell says more treatments can’t come fast enough.
Sickle cell disease, which stems from a mutation on the HBB gene, was first documented a century ago. Its hallmark is abnormal crescent-shaped red blood cells that clog blood vessels, block the flow of oxygen, and cause a host of debilitating symptoms, including anemia, bouts of excruciating pain, strokes, and organ damage. Only two drugs have been approved to treat the symptoms. One is a repurposed chemotherapy, the other is a version of a dietary supplement. Beyond medicines, there are blood transfusions and ever more sophisticated plans to improve lives. In Wisconsin, for example, a program has started to reduce emergency room visits for kids and young adults.
But even with the best care possible, symptoms can shorten a person’s life by decades. Sixty is an old age in the sickle cell world. There is a cure—bone marrow transplant—but for several reasons it is rarely an option. Even when it is, there is risk of lethal complications.
The next decade could bring relief, with dozens of experimental therapies and bone marrow transplant improvements under development. “A lot of eyes are on sickle cell right now,” says Lakiea Bailey, executive director of the Sickle Cell Community Consortium in Atlanta. “If only five percent of those become drugs on the market, it will double what we have right now.”
Some, but not all, of those experimental therapies aim to modify the disease’s underlying genetic mutation with tools like gene therapy and the gene editing system CRISPR-Cas9. “There’s been an explosion of biological understanding,” says Elliott Vichinsky, founder and director of the treatment center for sickle cell and other blood disorders at UCSF Benioff Children’s Hospital Oakland (California). “We know not just what the mutation is, but we also better understand how that mutation gets translated into proteins” that drive the disease.
World Sickle Cell Day is June 19. In the next two weeks, drug developers will provide updates on some of those therapies.
First up is Bluebird Bio (NASDAQ: BLUE) of Cambridge, MA, which today at a hematology meeting in Stockholm, Sweden, is updating a Phase 1 study of its gene therapy that replaces the faulty HBB gene with a healthy one in patients with severe forms of sickle cell disease. Bluebird is developing a treatment based on a patient’s own blood stem cells, which are genetically modified outside the body then reintroduced to produce healthy red blood cells. The latest: Four patients treated with Bluebird’s updated technology are producing healthy, non-sickling red blood cells at levels that the company believes could greatly reduce symptoms. (Click here for Xconomy’s deeper dive into the details.)
Phase 1 is typically a very early, cautious test of the safety of a new therapy. But the FDA has been willing to move cutting-edge medicines quickly if the medical need is great. Commissioner Scott Gottlieb said recently that a media prediction of 40 gene therapies approved by 2022 was “directionally correct.” He said the agency is open to approving treatments quickly then monitoring long-term safety and efficacy post-approval, as it is doing more often with cancer products. With cell and gene therapy, “the initial clinical efficacy is often established early, and sometimes in small series of patients,” Gottlieb said.
Gene-editing medicines are also in development. Sangamo Therapeutics (NASDAQ: SGMO) and partner Bioverativ (NASDAQ: BIVV) have one that employs Sangamo’s zinc-finger editing technology, and last month was cleared to enroll patients in an early human study. Partners Vertex Pharmaceuticals (NASDAQ: VRTX) and CRISPR Therapeutics (NASDAQ: CRSP) are on the cusp of clinical studies with a treatment using CRISPR-Cas9. In the U.S., the FDA recently held up the program for an undisclosed amount of time. In Europe, studies should start by the end of this year. (It could be the first CRISPR-based therapy to be tested in humans in the West.)
HARD TO FIND A MATCH
Gene modification still requires transplant-related procedures and chemotherapy-like blasts of drugs. But treatments like Bluebird’s LentiGlobin use the patient as his or her own donor. That’s a big deal. In the U.S., the roughly 100,000 sickle cell patients are disproportionately African-American. One in 500 African-American children are born with the disease, and one in 12 has sickle cell trait, which is an inherited gene from one parent but not the other. (The disease’s origins, and greater prevalence today, is in areas where malaria is endemic.) Having the trait instead of disease doesn’t preclude someone from developing symptoms, however.
African-Americans have an uphill climb finding a transplant donor.
There have been advances, such as techniques that allow for a “half-match” instead of a full match, and ongoing efforts to improve various components of the complicated transplant procedure.
Advocates like Trimnell are recruiting donors to join a nationwide registry called Be the Match. Trimnell’s Sickle Cell 101 organization, which has funding from drug companies and Be the Match, is producing social media content to show the faces of both donors and patients who were cured through transplant. “A lot of people don’t know what it takes to go through a transplant,” says Trimnell. “We want to tell stories of how people made their decisions.”
Much farther along in development, with no transplant-like procedures required, is a once-a-day pill from Global Blood Therapeutics (NASDAQ: GBT) of South San Francisco, CA, which will discuss results from Part A of its pivotal Phase 3 HOPE study by the end of June. The pill, called voxelotor, prevents red blood cells from sickling. The main goal with voxelotor is to boost patients’ levels of hemoglobin, the protein inside red blood cells that carries oxygen, by more than one gram per deciliter of blood after 24 weeks of treatment. Higher hemoglobin levels should provide better outcomes, much like the volume of virus in HIV patients (viral load) is a stand-in for how well they are responding to treatment.
But historically the FDA has wanted to see a decrease in pain crises. Global Blood wants to show those improvements, too, but through a new lens. Part A of the HOPE study is meant not just to find the right dose of voxelotor but to nail down how to measure those improvements in the upcoming Part B, with a five-minute, nine-question survey that participants take daily to record their pain and fatigue levels. Global Blood CEO Ted Love says asking patients directly instead of the standard measure of counting hospital visits could also change medical practice around sickle cell, which is clouded by the tense relationship between African-Americans and the healthcare system.
“Care isn’t very good, and patients feel discriminated against,” says Love, a cardiologist and veteran biotech executive. “They often go to emergency rooms and are treated in a way that makes them not want to go back.” Love and others in the field suspect pain crises are underreported; people tough them out at home.
If it hits its marks and gets the FDA’s nod, voxelotor could be on the market in 2020, by the company’s estimate. It’s not a cure; sickle cell patients would have to take voxelotor in perpetuity. (Global Blood is also reporting this weekend mid-stage data for voxelotor in pediatric patients aged 6 to 17.)
Access to new medicines is a major concern, says patient advocate Bailey, who has been a paid consultant to drug developers, including Bluebird. She sees too many people turning to crowdfunding to cover medical bills. “GoFundMe shouldn’t be the option for getting life-saving medicines,” Bailey says. “As long as our health system is designed as it is, about profit and not human lives, I don’t know how we’ll change it.”
A Global Blood spokeswoman says it will announce the cost of voxelotor when it launches, which is standard industry practice. The company is committed to a “value based approach” based in part on the drug’s clinical results, she says, but offers no more specifics. Some drug makers have translated that vague phrase into rebates for their patients who suffer setbacks: cancer that doesn’t respond to treatment, say, or a stroke or heart attack that occurs despite a cholesterol-lowering therapy.
The outlook for genetic fixes or cures for sickle cell is complicated, too. The FDA is bullish, but it remains to be seen if companies set prices at hundreds of thousands of dollars, perhaps even $1 million for a treatment, with government insurers as the main payers in the U.S. Companies will say prices reflect the elimination of years of chronic treatment, hospital costs, and emergency room visits. (California alone reported that in-patient and emergency room visits by sickle cell patients in 2014 totaled at least $738 million, not including those covered by HMOs.)
But there are no long-term data; no one knows if effects will wear off, or when. And even though it stems from a known mutation, sickle cell is a multifaceted disease with diverse environmental factors seemingly at play. The “value” for one patient might be different than for another. Some people want their pain crises to go away; others can deal with the pain but can’t take the staggering exhaustion. “It’s the fatigue that knocks me on my behind,” says Bailey, a former researcher who advocates for more patient input into drug development and policy.
“The biology is complicated,” says Vichinsky of Children’s Hospital Oakland, “so what kind of clinical impact do you need for a drug to be used by everybody? If you can decrease the pain events and other complications by 50 percent, the drug will be used.”
Photo courtesy of Cassandra Trimnell.