New sickle cell therapies will be out of reach where they are needed most

Friday’s Food and Drug Administration approval of two groundbreaking gene therapy treatments for sickle cell disease has brought a rare moment of hope and joy for people with the painful blood disease.

But there is no clear path to the new therapies – one-time treatments that are so effective in clinical trials that they are being hailed as a cure – to reach the countries where the vast majority of people with sickle cell disease live. Shortly after approval, their manufacturers announced sticker prices in the millions of dollars: $3.1 million for Lyfgenia, made by Bluebird Bio, and $2.2 million for Casgevy, made by Vertex Pharmaceuticals.

Lyfgenia launches in the United States. The pinnacle has been prioritizing winning approval in six rich countries – the United States, Italy, Britain, France, Germany and Saudi Arabia – that according to one estimateharbor 2 percent of the global sickle cell population.

Three quarters of the world’s sickle cell patients are in sub-Saharan Africa. Several million of them are believed to be sick enough to qualify for the new therapies, compared with about 20,000 in the United States.

Many African patients have been closely following online news about the success of treatments in clinical trials. In Tanzania, information about Casgevy spread a few months ago through a WhatsApp group that Shani Mgaraganza set up for mothers of children with sickle cell disease. Her son, Ramadhani, 12, and daughter Nasra, 10, have the hereditary condition, which causes bouts of searing pain and damages their organs. She said the therapy sounded like a miracle.

“Everyone said, ‘Thank God, our kids are doing well,’” she said.

Then the mothers heard what it would probably cost. “It would amount to billions of Tanzanian shillings,” Ms Mgaraganza said. “No one can afford this. It was demoralizing.”

The access question is at the heart of Jennifer Doudna, of the University of California, Berkeley, scientist who shared the Nobel Prize in Chemistry for her pioneering work on the gene-editing method, CRISPR, that Casgevy supports. “Today it won’t 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: the treatments are far too expensive for governments struggling to pay for basic healthcare. In some cases there may be significant additional costs, for example if a patient has to stay in hospital longer to receive gene therapy.

The second barrier is the medical infrastructure: administering the treatment is a months-long process in medical centers that can perform stem cell transplants. Patients’ cells must be harvested and flown to a laboratory for editing, put through grueling chemotherapy and remain in the hospital while the edited cells do their work.

“A drug as resource-intensive as this may not be appropriate in many places where healthcare resources are more limited,” said Vertex’s Chief Scientific Officer, Dr. David Altshuler.

He said the company is working to develop cheaper and easier approaches to treating sickle cell patients around the world, including a simple pill, which has not yet been tested in humans. “This has been a long time coming and I feel like we are at the beginning of the next phase,” he said.

A spokeswoman for Bluebird Bio, Jess Rowlands, said it was “the unfortunate 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 debut in rich countries years before arriving in poorer parts of the world. The disparities have widened in recent years as a wave of advanced therapies with breathtaking price tags has transformed the lives of patients in wealthy countries. Vertex in particular has been criticized for keeping its groundbreaking cystic fibrosis drugs out of reach of thousands of patients in low-income countries.

Manufacturers charge high prices even when it is clear that lower income countries cannot afford these costs to protect their ability to demand higher prices in countries such as the United States and Europe.

Dr. Obiageli Nnodu, director of a sickle cell program at the University of Abuja in Nigeria, discussed the new gene therapy with some of her patients. It’s a source of joy, she said, “but it’s just a moonshot away.”

The mutation that causes sickle cell disease is believed to have originated in West Africa 7,000 years ago. (Worldwide, most people with the disease are of African descent.) The disease was most common in places where malaria was endemic, because a single copy of the gene protects against infection with malaria. But two copies of the gene cause red blood cells to deform into a sickle shape that can block blood vessels, causing excruciating pain, strokes and other problems that shorten lives.

Casgevy alters patients’ DNA to correct the underlying cause of their disease. In a clinical trial, it eliminated pain crises for 29 out of 31 patients with sickle cell disease.

Questions about access extend 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 get Casgevy in the United States and other high-income countries will go to medical centers accredited to perform stem cell transplants. Almost 200 clinical programs in eight countries — the vast majority in the United States and none in Africa — have received that stamp of approval from the Foundation for the Accreditation of Cellular Therapy, a U.S.-based group that monitors hospitals.

Patient cells collected at those hospitals will be flown to a production facility in the United States or Europe. There, scientists will use the gene editing system CRISPR-Cas9 to switch off a key gene. This is the first approved therapy using CRISPR.

That complex and expensive process is a far cry from the level of care available to most African sickle cell patients today.

Few African countries routinely screen newborns for sickle cell disease, which is standard in wealthy countries. If left undiagnosed, these children miss out on crucial penicillin treatment that can prevent the pneumonia that often kills sickle cell patients as infants. In Nigeria, there are estimates that up to half of children with sickle cell disease die before their fifth birthday.

In addition, many do not have access to a drug called hydroxyurea, which keeps red blood cells around and reduces episodes of severe pain. That drug costs about $7 per patient per month in Nigeria, still putting it out of reach for many families, said Dr. Nnodu. 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 are wiped out and replaced with healthy cells from a donor who does not have sickle cell. The procedure is reserved only for the most serious cases because it does not always work and is risky; it kills 5 to 20 percent of those who undergo it, depending on age.

Several medical centers in sub-Saharan Africa have recently started 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 picking up the tab of about $50,000 per patient. Dr. Stella Malangahe, a hematologist there, said her patients often ask her when the hospital will offer 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 with 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, said Dr Vikas Dua, chief of pediatric hematology.

Ms Mgaraganza, the Tanzanian mother who works at a bank in Dar es Salaam, temporarily moved her family to India in September so her two children could receive transplants there. She donated her healthy stem cells and the children underwent chemotherapy and received an infusion of the new cells. The final bill for two transplants could be $80,000 — and she’s still figuring out how to get that money.

The children suffer from side effects of the transplant medications. Ms Mgaraganza would have preferred they receive gene therapy, which she learned about by watching YouTube videos. But her children couldn’t wait for someone to find a way to bring it to Africa, she said.

Nkem Azinge, a government project manager in Abuja, Nigeria, has saved money to pay for a bone marrow transplant in India. At 34, she knows she is within a decade of the average life expectancy of a Nigerian sickle cell patient, and that every pain crisis she experiences causes further damage to her organs. Now she is considering whether to shelve her plan for India and instead try to find a way to get gene therapy abroad.

“If I had the opportunity to do this, I would do it because I live in unimaginable pain,” she said.

In addition to industry, other research groups, including the National Institutes of Health and Dr. Doudna in Berkeley, techniques that would make gene therapy for sickle cell disease cheaper and easier to administer. But experts warn that these approaches have not yet been shown to work and will take many years.

The population of sickle cell disease patients in Africa will continue to grow as screening and access to basic interventions expand and fewer children die in infancy. This increases the chance that two people with the genetic trait of sickle cell disease will have a child who could have the hereditary disease.

Dr. Léon Tshilolo treats patients with sickle cell disease in a hospital in Kinshasa, the capital of the Democratic Republic of Congo. Some struggle to raise even $7 a month for basic medicines; two have traveled abroad for bone marrow transplants. They are increasingly wondering what gene therapies are.

“My young patients, adolescents, have the Internet,” he said, “and they say, ‘Doctor, I saw some people who have this getting completely healed – when will this come to Kinshasa?’”