Editor's note: BioPharma Dive, as part of our gene therapy coverage, is taking a closer look at inherited diseases for which researchers are developing genetic medicines. We aim to give a brief overview of the pipeline and lay out what could come next for such drugs. This, on sickle cell disease, is our latest.

Sickle cell disease is one of the world's most common inherited blood disorders, though that isn't reflected in the number of treatments for it. Three new drugs hit the market between 2017 and 2019. But before those additions, nearly two decades had passed since the Food and Drug Administration last approved a sickle cell medicine.

Now, a handful of companies are looking to not just treat the disease, but potentially cure it. Their goal, broadly, is to fix the mutations that cause sickle cell through the use of cutting-edge gene editing technologies. One of these treatments has already advanced to the final stage of human testing, and is expected to be submitted for approval late next year or early in 2023.

A one-time, possibly curative treatment would be momentous, as the median life expectancy for someone living with sickle cell is estimated to be between 45 to 55 years in the U.S. The disease also causes strokes, organ damage and episodes of severe pain known as vaso-occlusive crises. Genetic medicines developed by Bluebird bio and by CRISPR Therapeutics and Vertex Pharmaceuticals have shown promising signs that they can mostly eliminate vaso-occlusive crises, although further testing is needed to better understand if they have limitations or if their effects might wear off over time.

Such treatments raise tough questions, though. Gene-based treatments are very expensive and fairly difficult to make, which presents a major problem in sickle cell given that many people with the disease live in lower-income countries. Drug developers like Novartis say they're tailoring their work to address some of these issues, but it's unclear how well they'll be able to remedy long-standing problems of access and equity.

How is sickle cell treated?

Sickle cell is caused by mutations in the gene that creates hemoglobin, the protein on red blood cells responsible for carrying oxygen.

Patients therefore experience the disease differently depending on their genetic make-up. Those with two copies of the mutated gene have more serious symptoms, like anemia, which happens because sickled red blood cells die much sooner than their healthy counterparts.

Sickled cells are also hard, sticky and misshapen, so they pose the threat of clumping together and causing a stroke.

In more severe cases, the symptoms require patients to get blood transfusions. There are also a few medications available specifically for complications of the disease, in particular the painful episodes that happen when sickled cells clog a blood vessel. The FDA approved a drug called hydroxyurea in the late 1990s for adults experiencing these vaso-occlusive crises. Then it approved another, an oral powder, in 2017.

In 2019, the FDA cleared two more medicines for market: Novartis' Adakveo, which helps reduce the frequency of vaso-occlusive crises, and Global Blood Therapeutics' Oxbryta, which is meant to inhibit red blood cells from sickling and breaking down. Novartis and Global Blood set the monthly list prices for their drugs between $7,000 and $10,400.

Additionally, a cure for sickle cell exists in the form of bone marrow transplants, though the treatments can cause life-threatening side effects and even death.

How could gene therapy be used?

As with other diseases, genetic medicines for sickle cell are being positioned as long-lasting and, potentially, curative treatments. 

If the therapies now showing promise continue to prove effective over time, they could eliminate the long-term symptoms of sickle cell, allowing patients to go without blood transfusions. Lessening or removing the need for blood transfusions would both lower the cost of care as well as avoid the related buildup of iron in the blood, which can require separate treatment.

Gene-based treatments could also prevent vaso-occlusive crises — a main reason for hospitalization among sickle cell patients, who sometimes need strong painkillers like opioids.

Some clinical studies of sickle cell gene therapies are enrolling children. However, should any therapy come to market, older children or adults would likely be the first recipients, given the risks and uncertainties. 

Which companies are working on gene therapies?

A handful of companies have ushered genetic medicines for sickle cell into clinical trials, with the majority still in earlier stages. The farthest along is Bluebird's LentiGlobin, which is designed to deliver an engineered version of the gene that codes for hemoglobin.

Select gene therapies for sickle cell
Company Gene therapy Development Phase Trial Number Status
Bluebird bio LentiGlobin Phase 3 NCT04293185 Ongoing, not recruiting
CRISPR/Vertex CTX001 Phase 1/2 NCT03745287 Recruiting up to 45 participants
Sanofi/Sangamo SAR445136 Phase 1/2 NCT03653247 Recruiting up to 30 participants
Aruvant Sciences ARU-1801 Phase 1/2 NCT02186418 Ongoing, not recruiting
Novartis/Intellia OTQ923/HIX763 Phase 1/2 NCT04443907 Recruiting up to 30 participants
Editas EDIT-301 Phase 1/2 NCT04853576 Recruiting up to 40 participants
Graphite Bio GPH101 Phase 1/2 NCT04819841 Not yet recruiting

SOURCE: Companies, clinicaltrials.gov

To make LentiGlobin, Bluebird takes a patient's stem cells, uses special viruses to outfit them with the corrected gene and then reinfuses them.

This is different from the gene-editing approach favored by several other main developers. At least two sets of partners — CRISPR and Vertex, and Novartis and Intellia Therapeutics — are using the Nobel Prize-winning CRISPR-cas9 technology to get stem cells to produce high levels of what's known as fetal hemoglobin. Fetal hemoglobin is a form of the vital protein, but it stops being produced roughly six months after a person is born. Gene editing, in theory, keeps the switch for this protein on, helping remedy the main problems associated with sickle cell.

Genetic medicines have already shown promise treating sickle cell. A small study of Bluebird's found that, after treatment, hemoglobin levels were close to what's considered normal, and almost no patients experienced vaso-occlusive crises or acute chest syndrome, another symptom of the disease.

CRISPR and Vertex gave a similarly positive update on their program last month. The companies' said that the small group of sickle cell patients given their therapy, named CTX001, had yet to experience vaso-occlusive crises following treatment. Data also suggest their therapy can have a long-lasting effect.

The breakthroughs didn't come without setbacks, however. Bluebird's LentiGlobin program has faced multiple delays tied to manufacturing and safety concerns. In February, the company halted two of its sickle cell studies after one participant developed leukemia and another appeared to have a disease of the bone marrow. Bluebird has since conducted an investigation and determined its therapy was "very unlikely" to be related to the cancer case.

In April, Bluebird said the bone marrow diagnosis had been revised to a condition known as transfusion-dependent anemia.

What's next?

Bluebird was allowed to resume its sickle cell studies in June. Prior to the study halt, the company had said it planned to ask for approval in late 2022, although that may now be delayed.

Sticking to that timeline would put Bluebird well ahead of rival therapies, according to an analysis by the investment bank Raymond James. The next closest is CRISPR and Vertex's treatment, which Raymond James analysts think could be submitted for approval in two to three years. Testing, after a slower start, is now moving quickly, however. 

Behind that, genetic medicines from Aruvant Sciences and partners Sanofi and Sangamo Therapeutics are on track to be filed in three to five years, according to Raymond James.

In the meantime, there are many uncertainties to contend with. Researchers are still trying to understand whether genetic medicine will work for all sickle cell patients, or whether it'll live up to its potential as a lifelong fix for the disease.



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