The disproportionate burden of the global pandemic on Black communities and recent wave of protests against police brutality during an election year have created the perfect storm for discourse on racial inequities in healthcare. Black Americans continue to suffer from higher morbidity and mortality rates at younger ages due to a nexus of structural disparities, which manifest conspicuously during outbreaks of infectious disease. Institutional policies and implicit biases have resulted in neglect at the point of care, higher rates of insurance loss, and a divestment of resources from diseases primarily impacting Black people. These inequities are evident in the past and present state of care in the US for sickle cell disease (SCD), an inherited blood disorder prevalent in those with sub-Saharan African or other malaria-endemic regional ancestry. While the growth of genetic engineering and biologics has ushered in an unprecedented rise in novel SCD therapeutics, several challenges bar equitable access to potentially curative genetic therapies and next-generation supportive medications. Indeed, a case study of SCD raises ethical questions surrounding the role of race and wealth in healthcare and medical research.

What causes SCD and who is impacted?

The HBB gene provides instructions for making the beta-globin subunits of hemoglobin, which binds and releases oxygen in red blood cells. Several abnormal variants of this gene have been documented, resulting in misfolded or suppressed levels of beta-globin. SCD encompasses a group of disorders in which at least one copy of the HBB gene encodes a “sticky” version of beta-globin that aggregates and distorts red blood cells into a sickle shape. These cells are inflexible and prone to premature cell death, resulting in pain crises when cells block small blood vessels, anemia, stroke, and susceptibility to infection from spleen damage. Complications from SCD significantly reduce life expectancy to 38 years for men and 42 years for women according to the most recent US study. While SCD is the most common inherited blood disorder in the US, it is important to note that it predominantly impacts Black or African-Americans, occurring in 1 out of every 365 Black or African-American births. Moreover, approximately 1 in 13 Black or African-American children carry one copy of the sickle cell HBB mutation, which they may pass on to their children, but are otherwise symptomless.

Current standard of care for SCD in the US and historical neglect

Current recommendations for children with SCD include genetic counseling, transfusions, penicillin prophylaxis to prevent pneumococcal sepsis in children, and an annual transcranial doppler (TCD)  ultrasound to predict risk of stroke. Despite the proven effectiveness of these procedures, only 18% of affected children receive antibiotics for at least 300 days out of the year, and more than half of children do not receive TCD screening. Though a near unanimous decision was sent to the Centers for Medicare & Medicaid Services (CMS) to include these metrics in the core set of pediatric measures, CMS declined to add either. Furthermore, SCD lacks extensive nationwide networks of comprehensive specialty care centers that exist for less common chronic conditions like hemophilia and cystic fibrosis (CF). To make matters worse, ER staff have a documented history of being dismissive and erroneously assuming opioid addiction for SCD patients experiencing pain crises, exacerbating the racial bias in pain management Black patients experience across the board.

There is neglect not only in the healthcare sector, but also in resource allocation for SCD research and drug development. A recent study highlighted the disparities in funding between SCD and CF, which are driven in large part by structural violence. NIH funding per person afflicted with CF was over 10 times greater, there were twice as many CF-related publications, and five new drugs were developed for CF over the study period while none had been discovered for SCD. Compared to the CF constituency in the US, which is primarily white, the SCD constituency consists mostly of racial minorities with overall lower median income and educational levels. The typical systems that fund scientific research are less likely to cater toward SCD-related interests, as such ventures are less likely to be profitable or called for by public opinion. To address these concerns, the NIH and the Gates Foundation recently each invested $100 million to accelerate the development of easy-to-administer gene-based interventions for SCD that restore normal levels of functional hemoglobin.

Challenges facing curative genetic therapies for SCD

With a cure rather than supportive treatment, SCD patients can avoid repeated transfusions and subsequent iron overload, multi-organ damage, and chelation therapy. The only approved curative option to-date is allogeneic bone marrow transplant, given a suitable donor. Genetic therapies obviate the need for a matched donor, as the modified cells can originate from the patient themselves. The most common strategies pursued in biotech center around (1) reactivating the fetal version of hemoglobin, which has anti-sickling properties, and (2) introducing a functional copy of the beta-globin gene. One notable example is Zynteglo, an ex vivo therapy produced by Bluebird Bio that restores a working copy of the HBB gene. In Europe, where Zynteglo is approved for use, the treatment costs $1.8 million not including hospital fees, making it one of the most expensive drugs in the world. The cost is prohibitive considering the SCD constituency within the US and globally, which is an unfortunate trend amongst genetic therapies.

Why are prices so high? The nature of drug pricing in the US is complicated. In general, genetic therapy development is estimated to be five times the average of traditional small molecule therapeutics. Moreover, ex vivo genetic therapies currently rely on an expensive process of extracting, modifying, and delivering live cells. Coupled with the typically limited customer base and reduced frequency of administration, the price quickly soars into the million-dollar range to recoup expenses. Some may assume that insurers should provide coverage regardless of the sticker price; however, healthcare funding is finite. David Whitrap of the Institute for Clinical and Economic Review (ICER) noted that insurers overpaying for treatments can lead to “rising premiums, individuals dropping insurance coverage, and ultimately greater health losses for the patients who can no longer afford the care they need.”

One potential workaround may be adopting value-based alternative payment models, such as a subscription service model for curative SCD therapeutics negotiated between individual states and companies. In 2019, Louisiana formed such a deal with Asegua Therapeutics to finance hepatitis C cures for those on Medicaid and in the state correctional facilities. The payment model authorized an unlimited supply of medication over five years for a set price determined by the value brought to stakeholders by the drug. Considering that approximately 50% of SCD patients are covered under Medicaid and that Black Americans are overrepresented in the US correctional system, in which simply having the sickle cell gene is often weaponized against them, it is possible that this model would work well for SCD.

Another challenge to widespread use is the nature of ex vivo therapies. Once cells are harvested from the patient, they must be sent to an off-site facility that complies with good manufacturing-compliant policies for enrichment and gene modification. Moreover, prior to reimplantation, the patient must undergo chemotherapy to eliminate the native cell population containing the sickle cell mutation, which can cause infertility, long hospital stays, and infections. Additionally, the need for specialized personnel and facilities bars the treatment from being accessible in many of the regions of greatest need internationally. Courtney Stewart, a research fellow in the lab of associate investigator Vence Bonham at the National Human Genome Research Institute, studies the ethics of fairness and SCD curative therapies. Stewart emphasized that several institutions globally “have identified fairness and fair access as key in the development of curative genetic therapies.” In fact, the NIH/Gates Foundation collaboration specifically stated SCD genetic therapies should be administered “without needing to extract and modify cells from patients prior to reintroduction into the bone marrow.”

Dr. Ross Wilson, a professor at the Innovative Genomics Institute who studies the delivery of genome-editing enzymes, stated, “It would be transformative if these risky, labor-intensive, and expensive procedures could be avoided. SCD patients would be some of the greatest beneficiaries of in vivo genetic therapies targeting the blood-generating stem cells.” Due to the relatively short timeline for profitability of most biotech companies and few promising existing technologies for in vivo editing of cells in the human bone marrow, “the lion’s share of innovation takes place via academic research.” Given the historical neglect of SCD in healthcare and research communities, it is essential that actions are taken to ensure equitable access to clinical trials for novel SCD treatments. Bonham noted, “Most individuals living with [SCD] do not receive their care from quaternary research healthcare systems. Researchers must establish networks with community hospitals and hematologists so that individuals living with the disease in all regions of the country have access to participate in clinical trials.”

Next-generation pharmacological SCD treatments and efforts toward equitable access

While genetic therapies for SCD have yet to enter the US market, several next-generation supportive medications have been approved just last year. The associated drug development and distribution models provide concrete examples of how companies have attempted to foster equitable access to costly treatments both in the context of the US healthcare system and internationally. In terms of domestic outreach, Global Blood Therapeutics (GBT) provides a support program specifically for patients prescribed its hemoglobin polymerization inhibitor Oxbryta. Steven Immergut, head of GBT corporate communications, explained that GBT Source^TM is the first of its kind to be “specifically developed based on input from the SCD patient community” and includes assistance in financing and adhering to treatment regimens. Novartis released Adakveo around the same time, a biologic that prevents vascular occlusions. Michael Meo, director of global media relations at Novartis, stated that “Novartis continues to make progress in developing a child-friendly formulation of hydroxyurea,” the traditional treatment for SCD, and is actively “exploring clinical trials with [Adakveo]” in areas facing the greatest SCD burden globally. Moreover, Novartis recently expanded its Africa Sickle Cell Disease program, which aims to implement a comprehensive system of SCD care that addresses issues ranging from integrating diagnostics to building clinical research capabilities in sub-Saharan Africa.

Despite said efforts in improving accessibility, ICER asserted that both drugs would need to be discounted drastically from the list price to be cost-effective. Both GBT and Novartis disagreed with these findings, claiming ICER’s methodology failed to accurately estimate therapeutic benefits given existing scientific evidence and to capture the holistic benefits for the SCD community. Moreover, Immergut stated that GBT found even “the decision to conduct such a value assessment of novel treatments for SCD” to be problematic, as such an assessment may have an adverse impact on SCD patients given the nascent stage of investment in SCD therapies. Whitrap countered such concerns, stating that the assessment “is more likely to spur future investment and innovation in the pharmaceutical pipeline for this disease.” He pointed out a key takeaway from the report was that truly transformative medications “would warrant very high prices” and “policymakers may be willing to ‘overpay’… given the systemic racism that has delayed adequate investment” in SCD historically. ICER has since indefinitely postponed their public meeting on SCD therapies amid the COVID-19 pandemic.

In summary, SCD has been neglected in the US in large part due to the race and wealth of the affected constituency. While recommended procedures have proven effective in improving quality of life for children with SCD, most are not receiving said care, and little has been done to increase compliance with preventative measures. Decades of stagnation in SCD treatment development recently drew to a close with the advent of potentially curative genetic therapies and next-generation supportive medications. Given the long track record of divestment from SCD in the US, it is imperative that these novel treatments be made accessible for those most affected. In terms of genetic therapies, this will likely require a major shift from ex vivo to in vivo administration and innovative financing programs to mitigate the cost of treatment. The lifetime cost of chronically administered medications is likely even greater than their curative counterparts, and debate over pricing remains an unresolved issue between third party value assessment agencies and drug manufacturers.

Amy Guo, BS, is a Bioengineering PhD Student in the University of California, Berkeley – University of California, San Francisco Joint Program