GEN BiotechnologyVol. 2, No. 1 News FeaturesFree AccessHealth Equity in Sickle Cell Research and Access to TherapyAnjali SarkarAnjali SarkarE-mail Address: asarkar@genengnews.comSenior Science Technology Editor, GEN.Search for more papers by this authorPublished Online:15 Feb 2023https://doi.org/10.1089/genbio.2023.29077.asaAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Cutting-edge gene editing technologies and AI-driven discovery of small molecule drugs offer belated hope for patients living with sickle cell disease. Part II of this two-part series explores how the cost, portability, and accessibility to these novel therapies are severely restricted by the lack of equity in research, funding, and health care.Prime Minister of India, Narendra Modi, visits a child with sickle cell disease receiving blood transfusion at a health care center. Source: Ministry of Health and Family Welfare, Government of India.Although labeled a rare disease in the United States, the incidence of sickle cell trait (carriers of the sickle cell disease mutation) in the population is high, particularly among people of African, Middle Eastern, South Asian, and south European descent. In a proclamation issued by the White House in late August 2022,1 Biden affirmed that his administration is “committed to following science, delivering breakthroughs, eliminating health disparities facing communities of color and other underserved communities, and promoting the health and wellness of all Americans.” Passing the Sickle Cell Disease (SCD) Treatment Centers Act of 2022 will determine whether such political promises are channeled toward concrete measures.Heterozygous individuals with sickle cell trait rarely exhibit any overt symptoms and thus are mostly unaware that they carry the mutation unless tested. Health care and philanthropic organizations, and governments are escalating their efforts in spreading SCD awareness. Yet, >300,000 babies around the world are born with SCD every year—>75% in sub-Saharan Africa (SSA)—and nearly 90% of them die before their fifth birthday.2,3Whole genome sequencing shows that the sickle cell mutation arose ∼7300 years ago and is classically categorized into five haplotypes that are believed to represent independent emergence of the mutation: Arabian/Indian, Benin, Cameroon, Central African Republic, and Senegal haplotypes.4 This scattered origin is explained by genetic selection pressure where a single HbS allele promotes an individual's chances of survival and genetic propagation by conferring protection against severe malaria,5 whereas a double copy results in SCD.Julie Makani, Associate Professor of Hematology and Blood Transfusion at the Muhimbili University of Health and Allied Sciences in Tanzania.Problems with PreventionAlthough necessary, primary prevention through genetic counseling is complicated for SCD because the disease manifests over a severity spectrum depending on the presence of disease-modifying genetic alterations, unlike related blood disorders, such as β0-thalassemia, that have uniformly severe clinical manifestations.Julie Makani, a clinician and an associate professor of hematology and blood transfusion at the Muhimbili University of Health and Allied Sciences in Tanzania, said, “It is very difficult to tell someone with an SS pregnancy to consider termination. Nobody can say if a child with SS will have severe disease. With newborn screenings, and prevention of infections and complications in the first three years of life, mortality can be reduced to 30%. With the right care, you can live to be 50.” Makani has been working to promote newborn screening for SCD and strongly believes SCD patients should have simultaneous access to both disease-modifying and curative therapies.Global Access to Existing and Emerging TreatmentsEfforts to translate existing and emerging treatment options to regions of the world with high incidences of SCD are a daunting task but have seen rapid progress in recent times, thanks to intergovernmental and private initiatives.Once past patent restrictions, small molecule drugs offer the advantage of being more accessible in financially challenged areas of the world. In pricing the small molecule drug voxelotor, which prevents the abnormal polymerization of HbS, Ted Love, former CEO and president at Global Blood Therapeutics (GBT), was torn between trying to recoup the money that the company had invested in its development and providing an affordable treatment for patients.Prashanth Srinivas, Assistant Director of Research, and Health Equity Cluster Lead at the Institute of Public Health in Bangalore, India.The drug is currently priced at a list price of $125,000, per year. To balance a vision of global access to treatments for SCD patients with the practical obligation to fulfill their commitments to investors, GBT gives away 15% of its drug, in addition to accommodating a 23% discount for Medicaid.“Our goal has been to get our therapies to as many patients as we can around the world, recognizing that some people have insurance and other people have no capacity to pay. We want to step up and be able to provide the drug to those individuals free if required,” said Love.Global clinical adoption of gene therapies is largely restricted by the lack of infrastructure, up-to-date information, and current prohibitive costs, in addition to international political hypocrisy and administrative bureaucracy.Replacing ex vivo therapies in current clinical trials with in vivo gene editing therapies in the future, where precise base editors are directly administered in patients circumventing the need for transplantation, chemotherapy, and immunosuppression, will increase access to gene therapies worldwide but are still in the distant horizon.Beam Therapeutics is conducting nonhuman primate studies to explore in vivo approaches that infuse lipid nanoparticles to deliver base editors directly to alter patients' hematopoietic stem cells. “Potentially an in vivo approach could eliminate the need for transplantation. This treatment will not only help patients in developed countries but also in developing countries where transplants are difficult to achieve,” said Giuseppe Ciaramella, president and CSO at Beam.AsiaThe Asian SCD haplotype occurs against a genetic background characterized by high levels of fetal hemoglobin and widely varying frequencies of alpha thalassemia, which inhibit sickling.6 This is compounded by complexities arising from poor nutrition, malaria, and other infections, and limited public health resources.“A large proportion of SCD patients in India are in rural or remote areas. Often these are tribal populations that face various other social barriers in being able to access even general healthcare, let alone specialist care or services,” said Prashanth Srinivas, assistant director (research) and health equity cluster lead at the Institute of Public Health in Bangalore, India, and academic editor of PLOS Global Public Health. His team has assessed SCD studies in India7 and highlights an urgent need for SCD studies across individual, population, services, and systems levels that engage with inequalities in socioeconomic status, gender, geography, and other vulnerabilities among SCD patients.Despite India's large primary health care network, including community health officers and Accredited Social Health Activists, efforts to organize screening, diagnosis, treatment, and physical and psychosocial rehabilitation for SCD patients have been lacking. “Sadly, SCD has not received priority within [India's] overall healthcare agenda. Most SCD epidemiological work has been through NGOs (nongovernment organizations) or pilot initiatives.” Recently, the National Health Mission has begun an initiative to build a centralized database on SCD.The availability of hydroxyurea (HU) is limited across India. “In Karnataka, it is only select rural primary health care centers (PHCs) that systematically dispense HU and very few have local databases of SCD patients,” said Srinivas. “Providers in rural, remote, and tribal areas that I work in have never been made aware of other treatment options.”Anupam Aich, AI Project Manager at Leica Biosystems.Srinivas does notice a silver lining in the current dismal state of SCD health care in India. A startup from the Indian Institute of Science has developed point-of-care diagnostic kits for SCD. “Hopefully these diagnostics will be made available in remote and rural areas, which is currently not the case,” says Srinivas. He also sees an increase in focus on establishing hemoglobinopathy care registries at the district, state, and national levels, which, he believes, will be important in understanding and improving patient outcomes. Finally, Srinivas sees an opportunity arising through the recent deployment of community health officers in health and wellness centers across the country through the Indian government's Ayushmann Bharat Yojna (Healthy India Initiative).“This is a huge opportunity to tackle SCD and other chronic conditions. Unfortunately, even in tribal areas, SCD care is not yet prioritized at health and wellness centers. If this happens, there is some hope,” says Srinivas.“Mediterranean Arabia and India are centers of origin for SCD in Asia. However, SCD as a public health problem has long been ignored in these countries,” said Anupam Aich, a biomolecular engineer and currently an AI project manager at Leica Biosystems, who has spent over a decade in research focused on understanding molecular mechanisms, drug targets, and diagnostics of SCD, particularly how free heme affects the polymerization of HbS.“There has even been limited adoption of HU [hydroxyurea] in Asia,” said Aich, although it is part of the standard of care for SCD patients in the United States and Europe. “While there have been new treatment options approved by US FDA recently—l-glutamine, voxelotor, and crizanlizamb—these options are yet to be used to their full potential in Africa and Asia due to cost and other issues. Novartis is running a multicenter clinical trial for crizanlizumab efficacy in India.”Periodic blood transfusion, a necessity for severe SCD patients, is limited by cost, personnel, infrastructure, availability of technologies, and supportive care. Strategic modification of advanced curative therapies for low- and middle-income countries remains an unmet need, said Aich.Although gene and cell therapies are being heavily invested in and have had some success in early clinical trials, efforts to make these therapies available worldwide are still in their infancy. “It is imperative that access to improved care and low-cost drugs such as HU and l-glutamine be increased to these population along with low-cost newborn screening to reduce the disease burden in low resource settings,” said Aich.AfricaIn African countries, the frequencies of SCD are as high as 1–2% of the population. With ∼75% of all babies with SCD born in Africa, the continent remains the epicenter of the disease. Despite recent progress being made in small molecule drugs, gene editing strategies, and stem cell transplantation, the efforts to translate these advances to Africa have lagged.“SCD remains largely neglected in terms of investment in prevention, care, and research,” noted Ambroise Wonkam, professor at the University of Cape Town, South Africa.Growing networks among SCD organizations across Africa is a welcome sign. In 2019, at the African Union conference in Ethiopia, the National Institutes of Health (NIH) and the Gates Foundation committed $100 million to make HIV and SCD gene therapies available in Africa. Although progress took a hit due to the pandemic, the organization hopes to enroll its first SCD patient in Africa into a clinical trial by 2023.Building Infrastructure for SCD TreatmentsMakani says there have been extraordinary developments in building infrastructure for SCD treatments in Africa. Sickle in Africa has established a registry of >20,000 individuals with SCD, with an aim to increase this number to 34,000. From this cohort, the group hopes to enroll patients in clinical trials.Work led by Solomon F Ofori-Acquah, associate professor of medicine at the University of Pittsburgh, who is part of the SickleGenAfrica Network has enrolled 7000 SCD patients from Ghana, Nigeria, and Tanzania and created a repository of their DNA samples.8 This is one of the largest SCD cohorts in the world with genotype and phenotype data. Wonkam and his colleagues at the University of Cape Town in South Africa have developed an ontology for SCD.9 This is a systematic controlled vocabulary for existing knowledge on SCD. It is currently being used to standardize phenotype data for comparative studies.“As members of the medical profession and of the human family, we must aim to remove barriers that are essentially financial: especially since countries with rich economies share a history of having exploited African countries,” wrote Lucio Luzzatto, and Makani, in a recent perspective. “We call on the Global Fund to supply hydroxyurea for all SCD patients; and we call on companies who produce ODs [orphan drugs] to donate, for every patient who receives an expensive OD [orphan drug] in a high income country, enough of the same drug, at a symbolic price, to treat one patient in Africa.”10Box 1 describes more coalitions tackling SCD.Access to SCD Treatments in AfricaAccess to HU remains a global challenge. “Either it's not being prescribed, or patients can't get it because of the healthcare system. For a long time, hydroxyurea was not used because it was myelosuppressive,” said Makani. In Africa, access to HU can be improved by manufacturing the drug in African countries to make the drug cheaper for patients.Box 1. African Coalitions for Sickle CellMuch of the sickle cell disease (SCD) networks in Africa are being shepherded by Sickle In Africa, a consortium of three initiatives—Sickle Africa Data Coordinating Center (SADaCC), Sickle Pan-African Research Consortium, and Sickle Cell Pan African Network—that aims to facilitate SCD research and the translation of this research into health care.“The global SCD network has become more interconnected in the past five years. Partnerships with SSA countries such as Ghana, Nigeria, Tanzania, and investigators in the US and Europe, have allowed transcontinental discussions about SCD treatments and care,” said Campbell. “These relationships have expanded access of patients to clinical trials so that we can test these new drugs in areas of the world where three quarters of the cases lie. We're trying to bridge that gap, so that clinical trials reach areas where even HU is out of reach.”Partnerships that start as clinical trials often increase access to care for SCD patients. Novartis runs 11 treatment centers in Ghana that administer hydroxyurea (HU) and plans to expand to Kenya, Uganda, and Tanzania. However, this is just a drop in the bucket says Albert Zhou and Mark Travassos in a recent perspective in the New England Journal of Medicine15 and urge the deployment of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) to support a multicountry program for SCD treatments in Africa. They believe PEPFAR's existing infrastructure could be leveraged to oversee the clinical administration of HU that requires periodic blood tests to titrate doses for safety and efficacy.“There is a lot to be done but there has been an explosion of efforts—a lot of this through Sickle in Africa cohort, SADaCC, and providers like Dr. Julie Makani from Tanzania, Dr. Ambroise Wonkam from the University of Cape Town and Dr. Kwaku Ohene-Frempong who pioneered efforts that led to multi-country newborn screening,” said Campbell.In 2011, as part of the Human Heredity & Health in Africa (H3Africa) project, five African countries got together to build the infrastructure needed to deliver treatments for SCD. This included Ghana, Nigeria, Cameroon, Congo, and Tanzania. In 2017, the group received funding from the National Institutes of Health (NIH) as part of the SCD network in Africa. This prompted work in Ghana, Tanzania, and Nigeria with a data coordinating center in South Africa and a clinical coordinating center in Tanzania. Added funding enabled the inclusion of Mali, Uganda, Zimbabwe, and Zambia, in the second phase of the H3Africa funding. In 2018, the network received funding as part of SickleGenAfrica to look into genomic factors responsible for hemolysis in SCD. This study is currently underway in Ghana, Nigeria, and Tanzania. In 2020, the network started working with the global coalition for SCD and the global gene therapy initiative, through Sickle CHARTA, the consortium of health, advocacy, and training in Africa.A white paper written by the H3africa team launched in 2011 in a collaboration with the Welcome Trust in the NIH and the African Society of Human Genetics under the leadership of Charles Rotimi, scientific director at National Human Genome Research Institute, and late professor Bongani Mayosi, dean of the faculty of health sciences at the University of Cape Town, SCD was recommended as one of the model diseases for gene therapy. Through its “Cure Sickle Cell Initiative,” the NIH is striving to develop safe and effective genetic therapies and exploring machine learning applications to predict organ function decline in SCD patients.Although evidence shows HU does not work as well in individuals with a Central Africa Republic haplotype, Makani encourages all SCD patients to be on HU, as haplotyping all SCD patients is just not a feasible approach and the drug does not increase risk of complications.Bone marrow transplantation remains beyond reach in SSA countries due to high cost and lack of required infrastructure, but Egypt, Nigeria, and countries in east Africa are beginning to develop resources needed for curative therapies. “You need a well-established teaching hospital that has negative pressure rooms to decrease the risk of infections,” said Andrew Campbell, director of the Comprehensive Sickle Cell Disease Program at Children's National in Washington DC. “When you get these curative therapies, your bone marrow is wiped out, and that puts you at risk for infection.”Risk of infection and high costs are deterrents for access to curative therapies in SSA, but Campbell is confident that with the establishment of the requisite infrastructure, and reduction in the price of these therapies through government and private commitments, patients in SSA can have access to cutting-edge curative therapies.“The NIH has put in a lot of money toward curative initiatives and the Bill and Melinda Gates Foundation has initiatives to bring curative therapies to sub-Saharan Africa,” said Campbell, who feels hopeful for SCD patients in Africa.In addition to detailed proposals, pilot programs, close monitoring, and mentoring to develop infrastructure, cellular and genome processing centers, Campbell believes it is also crucial to invest in people. “You also have to invest in health care providers and expertise on the ground so that when you're doing bone marrow transplant or gene therapies you can prioritize safety and efficacy,” said Campbell.Technology, including point-of-care molecular diagnostics and cell phone communication, has increased newborn screening for SCD in Africa. “Dr. Baba Inusa and others have led many efforts in newborn screening in Nigeria that have led to the establishment of satellite clinics.”Andrew Campbell, Director of the Comprehensive Sickle Cell Disease Program at Children's National Health System in Washington DC.Early identification through newborn screening, more treatment options, together with antibiotics, vaccinations, and antimalaria treatments, will improve the chances that children with SCD in Africa do not die during the first 5 years of their lives.“Transplant is curative,” said Makani. “There are two problems with transplant. One, only 25% sickle cell patients will have matched sibling donors—the ones who will have the best outcome. Two, you must have toxic myeloablation and post-transplant, you have to be on immunosuppression for long periods. This involves complications of GVHD [graft-versus-host disease]. But outcomes are improving.”These limitations in bone marrow transplant have led Makani to focus on making gene therapy available for patients in Africa, ever since Bluebird Bio used gene therapy to successfully cure the first SCD patient in 2017.“With gene therapy, we don't have to deal with myeloablation. They don't need to have matched donor because they're their own donors,” said Makani. “We can't deal with transplant in Africa long term or for many patients.”Makani finds it frustrating that African countries are denied opportunities for access to curative gene therapies on the pretext that patients in Africa do not yet have access to HU. “When we want to participate in gene therapy trials as a country in Africa, we're told you need to go and make sure all your patients are on hydroxyurea or have facilities for x, y or z, when patients in other countries are not on HU or have those facilities,” says Makani.Makani strongly believes SCD patients in Africa should have simultaneous access to both disease-modifying agents and curative therapies. “I don't see why I should tell somebody to continue to take drugs for the rest of their life if they can get a transplant from a matched sibling donor, or if they can get gene therapy,” says Makani.Inclusion in Genetic Studies and Clinical TrialsGenetic counselors cannot advise a termination of HbSS pregnancies because genetic modifiers of the disease are not yet fully understood. An impediment in identifying such clinically relevant genetic modifiers of SCD is the lack of inclusion of individuals from diverse gene pools in genetic studies.Wonkam laments that too few Africans are enrolled in genome wide association studies, which in turn undermines gene therapy initiatives. Despite Africa being the origin of our species, with genetic diversity that supersedes any other continent, <2% of human genome analyses are African.11Wonkam believes, a multicenter prospective longitudinal SCD cohort in Africa will not only improve the mechanistic understanding of SCD pathophysiology and its determinants, but it would also open avenues for novel therapeutic innovations. “The time has come for an ambitious global genomic-research program to uncover more genomic keys to sickle-cell disease therapy,” noted Wonkam.12“There are currently over 30 ongoing clinical trials for SCD gene therapies around the world and none are happening in Africa,” emphasizes Makani at the 2022 American Society of Human Genetics Conference.13 “The barriers for gene therapy trials for SCD in Africa involve issues of ethics, equity, expertise and experience.” Malkani hopes the integration of health care, advocacy, and research and training, will change this scenario.Another obstacle to African participation in clinical trials arises when funders in the United States insist patients travel to the United States or other countries in the global north to receive treatment. Makani believes sending patients out of Africa for transplant or gene therapy is not a practical strategy. “COVID demonstrated that you can't send people outside of your country. You need to build up strength and capacity in your own country,” said Makani.When refused direct funding for gene therapy trials in African countries, Makani has now decided to settle for participating in such trials through subcontracting agencies in the global north who receive the same funds that African countries are denied on direct application. “That's really frustrating but beggars can't be choosers,” says Makani with a wry smile.Legislation and Health EquityResearch on SCD has been historically underfunded compared with other rare genetic diseases, which has contributed to the current lack of treatment options for patients.“Most of us think it was because these patients are Black, Brown and poor. That was part of the reason I got excited about building an organization which rallies around helping people that desperately need help and had been ignored,” said Love. “We've been focused on leveraging science to make great medicines, but the social impact has never been lost on us—the desire to come in and try to correct for years of underinvestment.”In 2018, President Trump signed the Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act into public health law (No. 115-327). However, this has not had any significant impact on research funding for SCD, Love observes.The Sickle Cell Disease Treatment Centers Act, introduced in September 2022, and sponsored by representative Barbara Lee, directs the department of health and human services to award grants for establishing SCD treatment centers to networks comprising health care organizations and community-based organizations.14 The bill was referred to the subcommittee on health on September 18, 2022.Love said, “We will continue to be involved in the Sickle Cell Treatment Act that we hope to get before our legislators. This would appropriate $535 million each year to build high quality sickle cell treatment centers.”With such investments, SCD patients might eventually receive medical care with the same level of clinical insight, consistency, and cordiality as patients suffering from other rare diseases, such as cystic fibrosis, have been receiving all along.“In addition to bringing great therapies to treat SCD patients, we want to fix the whole ecosystem of healthcare for these patients, which has been inadequate,” said Love.The recent success of companies such as Bluebird and Beam in developing gene therapies and of companies such as GBT (now Pfizer) in developing easily accessible small molecule drugs, has appeared to have attracted the attention of several pharmaceutical and biotech companies, who aspire to replicate and further these efforts.If the current trend in SCD drug development and global community outreach continues, we might expect to see the establishment of well-equipped SCD treatment centers in the United States and around the world over the next decade. It is clear that breakthroughs in biotechnology, health care, and economy alone will fall short in ensuring access to treatment for SCD patients worldwide without an earnest commitment to social justice.The Current State of Sickle Cell Disease Treatments [Part I] was published in the December 2022 issue of GEN Biotechnology.
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