The Food and Drug Administration’s approval Friday of two breakthrough gene therapy treatments for sickle cell disease brought a rare moment of hope and celebration to people with the distressing blood disease.
But there’s no clear path for the new therapies – one-off treatments so effective in clinical trials that they have been hailed as cures – to reach countries where the vast majority of people with diseased cells live. Shortly after approval, their manufacturers announced multimillion-dollar prices: $3.1 million for Lyfgenia, manufactured by Bluebird Bio, and $2.2 million for Casgevy, manufactured by Vertex Pharmaceuticals.
Lyfgenia will launch in the United States. The summit was prioritize winning approval in six rich countries – the United States, Italy, Great Britain, France, Germany and Saudi Arabia – which, by an estimateare home to 2 percent of the world’s sickle cell population.
Three quarters of diseased cell patients in the world are found in sub-Saharan Africa. It is estimated that several million of them are sick enough to benefit from the new therapies, compared to about 20,000 in the United States.
Many African patients closely follow online information about the success of treatments in clinical trials. In Tanzania, information about Casgevy spread a few months ago thanks to a WhatsApp group created by Shani Mgaraganza for mothers of children with sickle cell disease. Her son, Ramadhani, 12, and daughter Nasra, 10, suffer from a hereditary disease, which causes episodes of burning pain and damages their organs. She said the therapy felt like a miracle.
“Everyone was like, ‘Thank God our kids are going to be OK,’” she said.
The mothers then learned what it was likely to cost. “This would amount to billions of Tanzanian shillings,” Ms Mgaraganza said. “No one can afford it. It was demoralizing.
The issue of access is a major concern for Jennifer Doudna of the University of California, Berkeley, a scientist who shared the Nobel Prize in chemistry for pioneering the gene-editing method, CRISPR, which under -tends Casgevy. “Today it’s not going to be widely available,” she said. “Now that we have this approval, we really need to figure out how we’re going to open it up to more people.”
Two key factors put it out of reach for patients in Africa.
First, the price: treatments are far too expensive for governments which struggle to finance basic health services. In some cases, significant additional costs may be necessary, for example for an extended hospital stay to receive gene therapy.
The second obstacle is medical infrastructure: administering the treatment takes months in medical centers capable of performing stem cell transplants. Patients must have their cells harvested and flown to a lab for editing, undergo grueling chemotherapy and endure a lengthy hospitalization.
“Such a resource-intensive drug may not be appropriate in many places where the amount of resources devoted to health care is more limited,” said Vertex Chief Scientific Officer Dr. David Altshuler.
He said the company was working to develop cheaper and easier approaches to treating patients with diseased cells around the world, including a simple pill, which has not yet been tested in humans. “It’s taking a long time and I feel like we’re at the start of the next phase,” he said.
A spokeswoman for Bluebird Bio, Jess Rowlands, said it was “the sad reality” that the infrastructure needed for such gene therapies “does not exist in much of the world”. Bluebird “will continue to invest in approaches that can support global access in the future,” she said.
New drugs often appear in rich countries years before arriving in poorer parts of the world. Disparities have been exacerbated in recent years, as a wave of cutting-edge therapies at eye-popping prices have transformed the lives of patients in wealthy countries. Vertex, in particular, has been criticized for keeping its pioneering cystic fibrosis drugs out of reach of thousands of patients in low-income countries.
Manufacturers charge high prices even though it is clear that low-income countries cannot afford to pay these costs to protect their ability to charge higher prices in countries like the United States and Europe.
Dr. Obiageli Nnodu, director of a sickle cell disease program at the University of Abuja in Nigeria, discussed the new gene therapy with some of his patients. It’s a source of joy, she says, “but it’s within reach.”
The mutation that causes sickle cell disease is thought to have emerged 7,000 years ago in West Africa. (Worldwide, most people with the disease are of African descent.) It became more common in areas where malaria was endemic, because only one copy of the gene protects against malaria infection. But two copies of the gene cause red blood cells to distort into a sickle shape that can block blood vessels, causing excruciating pain, strokes and other life-shortening problems.
Casgevy modifies patients’ DNA to correct the underlying cause of their disease. In a clinical trial, it eliminated pain attacks during 29 out of 31 patients with a diseased cell.
Questions about access have spread to the United States, where many people with the disease are poor and live in states that have not expanded their Medicaid programs.
Those who can obtain Casgevy in the United States and other high-income countries will go to accredited medical centers to perform stem cell transplants. Nearly 200 clinical programs in eight countries — the vast majority in the United States and none in Africa — have received this seal of approval from the Foundation for Cellular Therapy Accreditation, a U.S.-based group that monitors hospitals.
Patient cells collected at these hospitals will be flown to a manufacturing facility in the United States or Europe. There, scientists will use the CRISPR-Cas9 gene-editing system to turn off a key gene. This is the first approved therapy to use CRISPR.
This complex and costly process is a far cry from the level of care most African sickle cell patients receive today.
Few African countries even have routine screening of newborns for sickle cell disease, which is the norm in rich countries. Undiagnosed, these children miss out on crucial penicillin treatment that can prevent the pneumonia that often kills sickle cell patients as babies. In Nigeria, it is estimated that up to half of children with diseased cells die before their fifth birthday.
Beyond that, many don’t have access to a drug called hydroxyurea that keeps red blood cells round and reduces episodes of severe pain. The drug costs about $7 per patient per month in Nigeria, which still keeps it out of reach of many families, Dr. Nnodu said. Many of her patients struggle to afford even basic painkillers such as folic acid and painkillers, she said.
Until new gene therapies, the only cure for sickle cell disease was a bone marrow transplant, in which patients’ stem cells were removed and replaced with healthy cells from a donor who did not have sickle cell disease. The procedure is reserved for the most serious cases because it does not always work and is risky; it kills 5 to 20 percent of those who experience it, according to age.
Several medical centers in sub-Saharan Africa have recently begun performing bone marrow transplants for sickle cell patients, but only a handful of wealthy African patients can afford them.
In Dodoma, Tanzania’s capital, Benjamin Mkapa Hospital has carried out five transplants so far, with the government footing the bill of about $50,000 per patient. Dr. Stella Malangahe, a hematologist there, said her patients often ask her when the hospital will start offering gene therapy. She has no answer.
A small but growing number of African patients are traveling to India for bone marrow transplants, where they are cheaper and hospitals have more experience performing them. The Fortis Memorial Research Institute in Gurugram, on the outskirts of New Delhi, has performed such transplants on nearly 100 African sickle cell patients, according to Dr. Vikas Dua, head of the pediatric hematology department.
Ms Mgaraganza, the Tanzanian mother who works in a bank in Dar es Salaam, temporarily moved her family to India in September so that her two children could undergo transplants there. She donated her healthy stem cells, and the children underwent chemotherapy and received the new cells. The final bill for two transplants could be $80,000 – and she’s still figuring out how to find the money.
Children struggle with side effects of transplant drugs. Ms Mgaraganza would have preferred them to undergo gene therapy, which she learned about while watching YouTube videos. But her children couldn’t wait for someone to find a way to bring her to Africa, she said.
Nkem Azinge, a government project manager in Abuja, Nigeria, saved money to pay for a bone marrow transplant in India. At 34, she knows she is one step removed from the average life expectancy of a Nigerian sickle cell patient and that each attack of pain she causes further damages her organs. Now she is wondering if she should put her project in India on hold and try to find a way to benefit from gene therapy abroad.
“If I had the chance, I would because I live with unimaginable pain,” she said.
Beyond industry, other research groups, including the National Institutes of Health and Dr. Doudna’s team at Berkeley, are developing techniques that would make gene therapy for sickle cell disease less expensive and easier to administer. But experts warn that these approaches have not yet proven their effectiveness and that we will have to wait many years.
The sickle cell patient population in Africa will continue to grow as screening and access to basic interventions expand and fewer children die in infancy. This will increase the chances that two people with the genetic trait of diseased cells will have a child who could have inherited the disease.
Dr. Léon Tshilolo treats patients with diseased cells at a hospital in Kinshasa, the capital of the Democratic Republic of Congo. Some struggle to raise even $7 a month to buy basic medicines; two traveled abroad for bone marrow transplants. More and more, they are wondering about gene therapies.
“My young patients, teenagers, they have the Internet,” he said, “and they say: ‘Doctor, I saw that some people who have it are completely cured, when will this happen in Kinshasa ?'”
