FDA approval of gene therapies for sickle cell disease: Q&A with NHLBI Director Dr. Gary Gibbons and NHLBI’s Division of Blood Diseases and Resources Director Dr. Julie Panepinto

The U.S. Food and Drug Administration approved two new gene therapies to treat sickle cell disease — one a gene-editing and the other a gene-addition approach. Nearly 100,000 people in the United States — and millions worldwide — have been diagnosed with this painful, life-threatening genetic blood disease. To help explain the historic importance of this medical milestone, we sat down with Gary Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), and Julie Panepinto, M.D., director of the NHLBI’s Division of Blood Diseases and Resources (DBDR).

Genetic therapies aim to treat or cure conditions by adding new DNA or changing existing DNA. Decades of basic research on sickle cell disease by scientists—including NIH-supported researchers— and selfless efforts by clinical trial participants have helped lay the groundwork for these novel genetic approaches. Researchers, patients, clinicians, and advocacy groups expect these new FDA-approved approaches to help people with sickle cell disease live longer, less painful, and more productive lives. “We have made some exciting research advances over the years and are ready to collect on our scientific investments in sickle cell research,” Gibbons said. “However, we must remember that these advances need to go hand-in-hand with scalable innovations that will ensure equitable access to life-altering care and that we must continue to engage in additional research endeavors that will minimize or eliminate potential risks that might be associated with these therapies.”

Q: Two companies, Bluebird Bio and Vertex Pharmaceuticals, just received FDA approval of their gene therapy protocols. How will FDA approval of these approaches impact the field? How will it impact patients?

Gibbons: There are few disease-modifying and life-extending therapies for those living with sickle cell disease, leaving patients burdened by chronic pain, high financial costs, health complications, and higher risk of early mortality. FDA approval of the gene therapy protocols will reduce acute care utilization and improve the overall health and wellbeing of those living with sickle cell disease.

Panepinto: Approval by the FDA of the first gene therapy for individuals living with SCD will provide a very effective disease-modifying treatment that has been shown to be life-changing for individuals living with SCD. It will provide a potential option for many individuals for the first time in their life.

Q: Can you briefly and in plain language describe how these two gene therapy approaches will work?

Panepinto: The two gene therapy trials recently approved for SCD use different ways to change the expression of an individual’s genes but both therapies result in an individual making more fetal hemoglobin, a type of oxygen-carrying blood protein present at birth. When increased in adults with SCD, fetal hemoglobin can reduce complications associated with the disease, including vaso-occlusive crises, a condition in which the blood vessels become clogged and causes severe pain and organ damage.

Q: Can you comment briefly about the potential risks involved in gene therapies and the long-term effects of the SCD?

Gibbons: We still need to better understand and address the potential risks of this curative option. For example, leukemia is a very rare complication of gene therapy in adults with SCD. NHLBI investigators are working to identify the molecular basis of, and advance possible solutions for, blood cancers associated with gene therapy.

Panepinto: We don’t know yet if the long-term or chronic complications of SCD will be prevented, such as damage to the kidneys, lung, and brain. And the therapy may not be 100% effective at preventing the most common acute complication, such as pain crises, for all individuals. In addition, the medicine that is needed to allow for the new gene expression can have serious side effects. But building on what is currently known, and working to improve on what we know, will help provide improved therapeutic options and will advance the field and improve the lives of individuals living with SCD.

Q: Can you talk about the cost of gene therapies for sickle cell disease?

Gibbons: The cost of gene therapies is concerning: by some estimates they could be as high as $2 million per patient. NHLBI has partnered across the Federal government to address the cost and coverage of these curative therapies, working closely with Centers for Medicare & Medicaid Service (CMS), for example, to increase the accessibility of gene therapies for Medicaid enrollees living with SCD. NHLBI is also working with CMS to identify and reduce barriers to uptake and to support readiness of patients and clinicians for gene therapies once available.

Panepinto: Although therapies such as gene therapy are costly, we have supported NHLBI research that show the lifetime medical costs of individuals living with SCD is also high, but when economic modeling is used, the cost of one-time gene therapy is likely to be cost-effective.

Q: Are there additional therapies (drugs, procedures, lifestyle changes) that can help patients with sickle cell disease until gene therapy becomes more widely available?

Gibbons: Fortunately, there are additional therapies that can benefit those living with sickle cell disease. For example, hematopoietic stem cell transplants can cure some but not all people with the disease, and there are a few medications—such as hydroxyurea and crizanlizumab—that can reduce pain crises and prevent complications. NHLBI is working to improve quality-of-life for those living with the disease through an all-hands approach that improves access to evidence-based care and addresses disparities, pain management, and accessibility.

Q: It has been said that “more shots on goal” are needed for sickle cell disease treatments. Can you comment on what is meant by that expression and give some examples of “more shots on goal”?

Gibbons: Relying on a single curative strategy against sickle cell disease is unlikely to be successful, hence the need for “more shots on goal”—in this case, parallel development of multiple therapies, each of which takes a different approach to correcting the sickle phenotype. For example, among the gene therapy options to address sickle cell disease are gene correction, gene addition, and gene editing, the latter two of which have been used in the Bluebird Bio and Vertex gene therapy protocols. There are a number of gene therapies for sickle cell disease that have advanced into clinical trials, including ones funded by NHLBI’s Cure Sickle Cell Initiative (CureSCi).

Panepinto: In science, there are generally always ways to improve upon our discoveries. In gene therapy for example, we need to better understand if the treatment is durable, meaning does it continue to “last” over time and be effective at preventing complications, such as pain, over the course of a lifetime. The research of NIH and others will give us more promising options in the future, or more shots on goal.

Q: What else needs to be done (by NHLBI and others) to advance the field of SCD gene therapy?

Gibbons: Over 75% of individuals who have sickle cell disease live in Africa, and over 30% of children will die before the age of 5 years. To this end, NHLBI’s Sickle In Africa Consortium works to address infrastructure needs and implement local standards of care to successfully deliver therapies in healthcare settings to those who need them the most. Thus, in addition to developing cost-effective curative therapies, we will continue to collaborate with the African community to support implementation science to improve access to life-saving treatment with newborn screening, vaccines and penicillin, along with working with the community on readiness for gene and cell therapy. Continuing to follow up on the health of patients who receive gene therapy is important as these and other therapeutic options become available.

Q: Where can people go to learn more?

The following resources provide additional information:

• To learn more about sickle cell disease treatment, visit https://www.nhlbi.nih.gov/health/sickle-cell-disease/treatment
• To learn more about sickle cell disease in general, visit https://www.nhlbi.nih.gov/health-topics/education-and-awareness/sickle-cell.
• To learn about The Cure Sickle Cell Initiative, visit https://curesickle.org/
• To read about the people living with sickle cell disease, clinicians, and the researchers working to find a cure, visit Today’s Faces of Sickle Cell Disease: https://www.nhlbi.nih.gov/todays-faces-sickle-cell-disease
• To learn about the sickle cell disease gene therapy education project, visit https://www.genome.gov/research-at-nhgri/Projects/Democratizing-Education
• To search for clinical trials related to sickle cell, visit https://clinicaltrials.gov/