Fulfilling the Promise of Sickle Cell Gene Therapy

Dr. Jingyi Liu, clinical fellow in medicine, Brigham & Women’s Hospital

Two gene therapies for sickle cell disease, CRISPR/Vertex’s exa-cel and Bluebird Bio’s lovo-cel, are being reviewed by the FDA and are likely to win US approval for sale by the end of the year.

While it will take more time to fully establish long-term safety and efficacy of these therapies, they offer a glimmer of hope for a cure.

This is the culmination of a decades-long scientific journey. In 1957, molecular biologist Vernon Ingram’s discovery revealed the genetic basis of sickle cell disease — a single amino acid substitution in the hemoglobin beta chain. Since then, investments in sickle cell disease research trailed behind other genetic disorders, resulting in limited progress and treatment options. Current treatments like hydroxyurea, Endari, Adakveo, and Voxelotor manage but don’t cure sickle cell disease, leaving patients with an average life expectancy of just 50 years. Bone marrow transplants offer a cure, but they come with life-threatening risks.

Exa-cel and lovo-cel offer the potential for transformative change. These therapies target the genetic root of the disease, potentially functioning as cures that would alleviate fatigue, excruciating pain crises and cardiovascular complications.

Recent data releases suggest that these therapies are breakthroughs from standard of care.  31 of the 32 evaluable patients who had received lovo-cel had resolution of severe vaso-occlusive crises through 24 months of follow-up. Similarly, 16 of 17 evaluable patients who had received exa-cel were free of severe vaso-occlusive crises for at least 12 consecutive months.  For context, the median number of severe vaso-occlusive events among these patients in the 2 years preceding enrollment was 3 to 4 events per year.

However, approval is only the initial step towards realizing the promise of sickle cell gene therapy.

Physicians and patients are about to confront some thorny issues around cost and access. Prices are sure to be in the sticker-shock range of $1 million and up.

Sick Cells, a patient advocacy group, asks a pressing question: “Will eligible patients have full access to coverage to utilize these therapies?”

Historical barriers to care for sickle cell disease are complex, encompassing socioeconomic, geographic, informational, and racial factors. About 100,000 people in the US are thought to have sickle cell disease, but only one in four patients has access to standard oral medications.

The cost of sickle cell gene therapy will be substantially higher than with oral pills. Gene therapy will also require substantially more monitoring and support. Patients must commit to a multi-month process that involves hospitalization, chemotherapy, and an extensive recovery process. While there is the potential for a long-term cure with gene therapy, this isn’t exactly as simple as a one-and-done procedure.

Through interviews with the SCD community, including patient groups, physicians and payors, I compiled a few ideas on how to improve the accessibility of sickle cell gene therapy post FDA approval:

1. Care Navigation and Coverage of Supportive Services. Individuals undergoing gene therapy treatment bear significant physical, mental and financial burdens during the treatment course. Patients and physicians in the sickle cell disease community believe that that addressing associated challenges like fertility preservation, mental health support, transportation and lost income during the treatment process are vital to helping patients complete the gene therapy treatment course. According to Sick Cells, “A key factor to accessing gene therapies will be the consideration of wrap-around services such as mental health services, transportation, and fertility preservation, which at this time, is still not accessible to many. Although there are organizations dedicated to ensuring access to fertility preservation for sickle cell patients, those resources are not yet widespread.” To navigate the multidisciplinary care pathway required for gene therapy, sickle cell disease patients also mentioned the importance of care coordination programs staffed with case managers and patient advocates. Historically, care coordination programs for rare diseases have improved outcomes and been cost effective. Coordinators can also help streamline the administrative burdens of applying for gene therapy through developing prior authorization standard operating procedures.
2. Establish National Coverage Standards. Another potential hindrance to gene therapy access may be varying criteria set by different payors. Most individuals with sickle cell disease receive healthcare through disabled or . While Medicaid is mandated to cover all therapies (unlike commercial payors), each state’s Medicaid agency establishes its own eligibility criteria. This variation in coverage is already present for bone marrow transplants and will likely continue for sickle cell disease gene therapy. Dr. Mohammad Dar, Senior Medical Director at MassHealth (Massachusetts’ Medicaid) says that establishing a national perspective for evaluating and accessing rare therapies can offer a more equitable solution for access. A national eligibility standard would be particularly beneficial for patients residing in states that have historically enacted stricter eligibility criteria and to prevent undue financial burdens on individual states. For rare and costly therapies such as sickle cell gene therapy, federal legislation payment policy and support, and on access eligibility criteria may be the most equitable solution.
3. Data, Data, Data. Unsurprisingly, the sickle cell disease community yearns for more extensive, long-term follow up data concerning the safety and efficacy of gene therapy from the initial pivotal trials. Patients seek reassurance against the risk of secondary malignancy. Additionally, anticipation builds for data from upcoming trials in expanded patient populations. More concrete data from expanded populations will help payers widen the circle of who they can approve the medication for in otherwise gray spaces.

As we celebrate the imminent approval of sickle cell gene therapy, it’s vital to remember that the true relevance of this milestone will depend on what comes next – how many patients receive the treatment and its benefits. If some of these roadblocks aren’t smoothed out, it could create more healthcare disparities, said Dr. Maureen Achebe, a hematologist at the Brigham and Women’s Hospital and the Dana Farber Cancer Institute. 

Science has made great advances against sickle cell disease. But realizing the potential of gene therapy for sickle cell disease will require a fundamental overhaul of our healthcare system’s approach to financing and distributing these groundbreaking treatments. We have more work to do to fulfill the promise of sickle cell gene therapy for eligible patients.

Disclosures

• Dr. Achebe’s opinions do not necessarily reflect those of the Brigham and Women’s Hospital or the Dana Farber Cancer Institute.
• Dr. Achebe has been a consultant for GBT (Pfizer), Fulcrum Therapeutics, Forma Therapeutics.
• Dr. Dar’s opinions do not necessarily reflect those of any Medicaid or other government agency or any provider system.