Drugmakers have had to confront patient distrust of the medical system and the system’s marginalization of sickle cell patients
Individuals with sickle cell disease compare its painful attacks to a drill going through an arm. Female patients say they prefer childbirth.
The pain can last hours or weeks. Attacks happen several times a year—and there is no treatment.
Pfizer Inc.’s drug, rivipansel, could change that, doing a lot of good for patients and their quality of life in the process.
But the last clinical trial for rivipansel took three years to enroll 75 people, and the phase 3 trial would enroll almost five times as many patients. Though clinical trials can drag on for many years, nine years was too long, as far as Pfizer (PFE) management was concerned.
So the drugmaker did something it had never done before. Pfizer hired an ethnographer.
The goal was to understand both what an attack was like and how to change the company’s approach to enrollment accordingly.
Sickle cell anemia predominantly affects African-American patients and is an inherited condition, in which their red blood cells become shaped like sickles, preventing blood flow and causing painful attacks, fatigue, organ damage, stroke and more.
But after years of neglect, sickle cell disease — now deemed to be an incredibly lucrative market — has become home to a flurry of new development.
In the process, drugmakers have had to confront patient distrust of the medical system and the medical system’s marginalization of sickle cell patients. They’ve also encountered more common issues in clinical trials, like the fact that they’re not all that accessible.
For Pfizer, revelations came quickly. For one, the drugmaker and patients weren’t even speaking the same language. The company called these attacks by their medical name—vaso-occlusive crises—but patients, who called it a “pain crisis,” didn’t know what that was.
The changes Pfizer made as a result paid off. Though the study is still enrolling, it’s on track to finish in about three years, on par with the phase 2 trial, which had far fewer patients.
“This was really one of the first times we went to the patient to ask that question. What do you want to know? What is important to you as a person, as a patient, to want to participate in a clinical trial?” said Brenda Cooperstone, Pfizer’s chief development officer for rare disease. “It was definitely something new for us.”
These new approaches could be game-changing for sickle cell anemia, but also for clinical trial enrollment writ large, where diversity has long been an issue and federal regulators have pushed for change.
“This is probably one of the biggest unmet needs in medicine today,” said Ted Love, chief executive and president of drugmaker Global Blood Therapeutics Inc. (GBT). “There aren’t many diseases where there are 100,000 people in the U.S. dying 20, 30 years earlier than they should where there’s really no good therapies available now.”
A trust issue
At the very moment that sickle cell patients need the medical system most, they are often alienated from it.
Absent a treatment for vaso-occlusive crises, pain medications like opioids and hydration are the only relief available.
But emergency room staff treat sickle cell patients suspiciously, as if they were simply seeking drugs.
Experts believe vaso-occlusive crises lead to the organ failure and poor life expectancy that is common with sickle cell patients.
But opioids don’t stop the underlying bodily process — they just hide the pain.
“It’s the number one issue on the minds of individuals living with sickle cell disease, how they can stop the crises once they start,” said Dr. Biree Andemariam, chief medical officer at the nonprofit Sickle Cell Disease Association of America and a practicing physician who treats sickle cell disease patients. “But we’re not actually treating the root cause” with current options.
Drugs in development aim to cut down on vaso-occlusion in different ways.
Pfizer’s rivipansel is intended to treat the attacks themselves, while Global Blood Therapeutics’ GBT440 and Novartis’ (NVS) SEG101 are more preventative, aiming to reduce the number of such crises.
By contrast, a gene therapy approach from bluebird bio Inc. (BLUE) and a gene editing program from Vertex Pharmaceuticals (VRTX) /CRISPR Therapeutics (CRSP) would, if successful, be one-time treatments that cure the disease or reduce its severity.
But trust issues extend beyond the emergency room.
Two historical atrocities loom particularly large: The Tuskeegee study, in which government researchers declined to diagnose and treat hundreds of African-American men with syphilis over the course of a 40-year clinical trial, and the use of Henrietta Lacks’ cancer cells for decades of medical research without obtaining her consent or paying her for her role.
“Unfortunately, in the United States we have a history of racism and these patients have felt that,” Global Blood Therapeutics’ Love told MarketWatch.
African-American patients may be reluctant to participate in clinical trials because they feel “like they’re going to be a guinea pig. ‘They’re going to try all kinds of things on me,’” said Roslyn Daniels, the president and founder of Black Health Matters, an organization that consults with pharmaceutical companies on patient engagement programs and clinical trial education.
They also fear receiving the placebo, rather than the actual medication, and worry that participation could cause their health to worsen, Daniels said.
Because of these misconceptions, companies must work to get involved in the community and educate patients about what it means to participate in a clinical trial, she said.
Global Blood Therapeutics’ Love said that is exactly what his company has done, including speaking to patients about barriers to trial participation and working to address them, which he described as “common sense things.”
Love, an African-American doctor who has long worked in the pharmaceutical industry and led clinical trials, also said that he has worked to be out there personally interacting with patients.
“I’m kind of a natural fit to solve some of these issues,” he said. “I think if I hired an ethnographer, they’d tell us to do what we’re doing.”
Global Blood Therapeutics recently presented research showing that opioid use has remained stable among sickle cell disease patients in recent years, combating the perception of patients as opioid-seekers.
The company also brought advocates into its offices and got involved with walks and runs that raise funds for sickle cell disease research, bringing blankets to such events because patients are often cold.
It heard from patients that communication was an issue. For example, when they previously participated in clinical trials, patients never found out what the outcome was.
Global Blood Therapeutics told them, “that is not going to happen here,” Love said.
In Pfizer’s case, the company worked to educate emergency room staff about sickle cell disease, in the hopes of increasing empathy for patients.
The drugmaker also realized it shouldn’t be approaching patients about the trial during crises, when they were in terrible pain, but rather when they were stable and through a trusted doctor.
Companies also went outside the U.S. to enroll patients. Sickle cell disease is rare inside the U.S., but much more common in other countries. Being a carrier for sickle cell disease helps protect against malaria, so the disease is seen more where malaria is common.
Global Blood Therapeutics is enrolling patients in Kenya, Lebanon, Egypt, Turkey, Oman and other countries within Europe in addition to the U.S. for an about 400-patient phase 3 clinical trial.
About 30% of patients in the trial should be from the U.S., according to Love. The company began clinical trials in humans in Feb. 2015 and expects topline results from the pivotal study in the first half of 2019.
The privately held Swedish biotech Modus Therapeutics is running clinical trials for its sickle cell drug, sevuparin, in the Middle East, where sickle cell disease is prevalent and there’s less competition with big U.S. pharmaceutical companies.
“When only five patients are seen at each center, it’s much more difficult than my center in Bahrain with 80 beds that are constantly occupied with sickle cell patients,” Modus Therapeutics Chief Executive Ellen Donnelly told MarketWatch.
Enrollment in the Middle East also shouldn’t be a risk, since it’s believed that sickle cell disease manifests similarly in all patients, she said.
When it was approved last summer, Emmaus Medical Inc.’s Endari became the first new sickle cell disease product in 20 years and just the second Food and Drug Administration-approved drug for the condition.
Endari is a powder that gets mixed with cold fluid or food, and was approved to reduce sickle cell disease’s severe complications.
But when Yutaka Niihara was first developing the therapy, “established pharma companies weren’t interested,” Niihara, now chairman of the privately held Emmaus, told MarketWatch. “Now they’re interested, 15 years later.”
He attributes the change to sickle cell’s “orphan disease” status in the U.S., which gives drugmakers various financial incentives and typically translates to staggeringly high drug prices.
The status has been around for many years, but the drug category has largely been immune to more recent restrictions on other expensive drugs by health insurers and pharmaceutical middlemen.
“Pharma companies are jumping now at any orphan drug potential,” he said. “$150,000 to $200,000 a year sounds ridiculous, but it’s what people are willing to do.”
Other explanations for the explosion in sickle cell disease development include companies wising up to the disease’s unmet need, along with major advances in gene editing and gene therapy.
Most of the science in sickle cell disease is “pretty old,” Love said, but sometimes drug development in a certain area just gets very hot. Sickle cell patient advocacy groups have also become stronger, experts said.
But stigma, and marginalization of African-American patients, may also explain why sickle cell disease development took so long to take off. And pharmaceutical companies still have a long way to go in this area, Daniels said.
“Here we are in 2018, why are we just now seeing therapies being developed for African Americans? This is something you would think would have been worked on many, many years ago,” she said.
Emma Court covers healthcare for MarketWatch from New York. You can follow her on Twitter @EmmaRCourt.
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