Two possibly curative gene therapies for the disease, which disproportionately affects Black people, are under consideration by the FDA.
Biologics license applications were filed recently for 2 potentially curative gene therapies in sickle cell disease (SCD), representing an astonishing advance for a condition characterized by crippling pain and a shortened life span even with current treatments.
“I couldn’t be more excited for the SCD community, because it’s long overdue,” said Terri Newman, PharmD, MS, an assistant professor of pharmacy and therapeutics at University of Pittsburgh School of Pharmacy, where she researches outcomes in SCD and barriers to treatment.
“This is a neglected disease, and we are years behind where we should be in terms of having treatment options for this population. But it’s a long road ahead to establish these gene therapy treatments as viable treatment options. We have to look at access (to current therapies) now,” she said.
Discovered in 1910, sickle cell disease is an inherited hemoglobin disorder that is characterized by red blood cells that take on a C-shape similar to a sickle instead of being round. The misshapen red blood cells stick together and clog blood vessels and starve the body of oxygen, which can lead to stroke, pain and organ damage, among other conditions.
Hydroxyurea, first used in SCD off-label in the 1980s and approved by the FDA for SCD in 1998, reduces sickling and raises the amount of fetal hemoglobin, increasing oxygenation. This versatile drug was a major breakthrough in SCD, which affects an estimated 100,000 individuals in the US, 90% of whom are Black. One percent of children with SCD die before the age of 3, according to the CDC.
Hydroxyurea was followed by other disease-modifying treatments (DMTs), including Endari (L-glutamine) in 2017, Oxbryta (voxelotor) in 2019 and Adakveo (crizanlizumab) in 2019. In August 2023, the European Commission followed the advice of an advisory committee and withdrew a conditional marketing approval for Adakveo in Europe, although it remains approved by the FDA.
Hydroxyurea is far and away the most frequently prescribed of the DMTs. Yet just 31% of patients with severe SCD are treated with DMTs, according to a recent study led by Newman, who says patients with SCD are chronically underserved by a medical community that is not adequately trained or focused on treating patients with this condition.
Resources for elucidating the nature of SCD and developing new treatments have tended to be less available than for other diseases, she says, a conclusion supported by other medical authorities.
“There’s disparate research funding. Cystic fibrosis has received much more funding than sickle cell disease, and providers have reported in surveys that they do not feel comfortable with managing care for this disease. Some of them rely on information they learned in residency. Some just don’t have the competency,” Newman said.
Severe SCD shortens the life of a patient by 30 years on average. It can involve frequent hospital stays, quick returns to hospital after treatment and regular blood transfusions. Disease outbreaks can be triggered by physical stress or oxygen-reduced environments, such as high altitudes or airplanes. Cases of post-traumatic stress disorder have been documented following the agony that sickling brings on.
Although currently policies lean toward limiting opioid prescriptions, the CDC has recommended an exception for individuals with SCD, “acknowledging the important role of opioids in pain management and the dangers of inadequate pain management,” according to the Institute for Clinical and Economic Review (ICER), which published in July 2023 a cost-effectiveness analysis of the SCD gene therapies.
Patients with SCD often find it challenging to obtain opioid prescriptions when needed because they may be stereotyped as addicts by inexperienced hospital staff.
For all these reasons, it is important to better align medical resources with the unmet need in SCD, Newman says. This should involve the development of comprehensive care centers that treat the whole disease with a multipronged approach involving diverse drug agents and specialists who know the full psychosocial-physical spectrum of SCD.
“Before, people didn’t make it into adulthood. There was more care and attention paid to the younger community. There was a lot of evidence-based medicine going toward improving outcomes in young people with sickle cell disease. But now we see that after the transition to adulthood, there are many gaps in care because there are not that many comprehensive care centers for adults. There’s fragmentation of care, not continuity of care.”
Although DMTs can meaningfully improve the quality of life for those with SCD, the 2 gene therapies under FDA review offer the potential of freeing patients from a lifetime of disease and its treatment.
Lovo-cel (lovotibeglogene autotemcel), from Bluebird Bio, works by inserting a correctly functioning hemoglobin gene into a patient’s stem cells, and exa-cel (exagamglogene autotemcel) developed by Vertex Pharmaceuticals and CRISPR Therapeutics, involves gene editing to increase fetal hemoglobin. The FDA has set decision dates in December 2023 for both treatments. In addition, exa-cell has a decision date in March 2024, as treatment for transfusion-dependent beta-thalassemia, a blood disorder that reduces production of red blood cells
One notable drawback of both treatments is that they require myeloablative conditioning (use of the chemotherapy busulfan) to create space for the reengineered cells to take root. This adds time to the treatment process and involves risks of infection. In clinical trials for both products, serious adverse events attributed to the chemotherapy “were not infrequent,” according to ICER.
In clinical trials, Bluebird Bio has fine-tuned the lovo-cel administration process. In results submitted to the FDA, 96.8% (31/32) of patients who received the adjusted administration experienced complete resolution of severe vaso-occlusive events (VOEs) during a 24-month follow-up. In recently reported results, 94.1% (16/17) of patients who received exa-cel were free of VOEs for at least 12 consecutive months.
Myeloablation with busulfan carries the risk of leukemia. Efforts are underway to develop a less toxic method. In July 2023, researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia reported positive findings in the journal Science for a messenger RNA approach to gene therapy that does not require myeloablation.
Health care experts stress that the long-term durability of these treatments will not be known for many years. For now, however, stories are circulating of patients who, after a lifetime of restricted activity and pain, now have a relatively normal existence and lifestyle.
Neither company has disclosed their intended pricing, although ICER suggested that a price of $2 million per dose for either lovo-cel or exa-cel could be cost effective compared with standard of care. But the lower the price, the more patients with severe SCD could receive this treatment, ICER noted.
Patients with SCD do have the option for a hematopoietic stem cell transplant (HSCT), although only an estimated 14% of patients have access to appropriate donors. HSCT does have some risks, including organ toxicity, graft-vs-host disease, graft rejection, and mortality. HSCT is recommended only for younger patients with less-advanced disease damage.
Other options for managing SCD include screening adults and potential parents for the sickle cell trait, Newman said. Individuals are often unaware of their status, she notes. “There are efforts being made to have a nationwide screening program," said Newman. "There are people who find out only in later life they have sickle cell trait or sickle cell disease, so it’s important as part of the public health effort to make sure people are aware of their status, but also become educated about it, so they can be empowered to make decisions for themselves.”
Further, preimplantation genetic diagnostic (PGD) testing at the embryo stage of development also is available for SCD, enabling parents to combine PGD with in vitro fertilization (IVF) to avoid giving birth to children who bear this inherited disease. It is unclear whether payers, including Medicaid, which covers 42% of births in the United States, will cover PGD-IVF. There are also ethical concerns about preselecting children using this process. The President’s Council on Bioethics has concluded that in the context of preventing life-threatening diseases, these technologies are appropriate.