Sickle Cell Disease Treatment: From Gene Therapies to New Drug Approvals

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This is a research-based article on World Sickle Cell Disease Day, written by Venkataramana Konda. Read his other article at https://journals-times.com/2024/05/06/cutting-edge-thalassemia-treatments-and-research/

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Sickle Cell Disease (SCD) is a prevalent, life-threatening monogenic blood disorder that is caused by a point mutation of the Beta Hemoglobin gene (HBB) that replaces glutamic acid with valine at amino acid position 6.

The genetic mutation of HBB causes the hemoglobin to form as long and stiff rods instead of a flexible, round shape. The shape of hemoglobin is sickle-shaped and named after the disease. These deformed cells are stuck in blood vessels, causing blockages that lead to vascular occlusions, irreversible end-organ damage, and shorter life spans.

Though the exact count of people living with SCD worldwide is not known, approximately 100,000 Americans are estimated to have this disease. The average life expectancy of an SCD patient is 20 years. Having this high mortality rate, SCD doesn’t have plenty of treatment options.

So far, only four drugs are approved by the FDA. Hydroxyurea (approved in 1998), l-glutamine (approved in 2018), crizanlizumab-tmca (approved in 2019), and voxelotor (approved in 2020).

Hematopoietic stem cell transplant (HSCT- bone marrow transplantation) was the sole curative treatment for Sickle Cell Disease (SCD) before the two cell-based gene therapies (Casgevy and Lyfgenis) got approved by the FDA in 2023 for patients 12 years and older.

Gene Therapies Development over time

Modifying genes in genetic diseases involves various mechanisms, including introducing modified or healthy genes, replacing mutated genes, or inactivating disease-causing genes.

Currently, a range of gene therapy products is available for treating genetic diseases, infectious diseases, and cancer. These products include viral vectors, where modified disease-free viruses serve as carriers for genetic material, bacterial vectors, where modified disease-free bacteria are used as carriers, plasmid DNA, consisting of genetically engineered circular DNA molecules for carrying genetic material, human gene editing technology, which allows for modification, deletion, or insertion of mutated genes, and patient-derived cellular gene therapy, where a patient’s own cells are genetically modified using viral vectors and then infused back into the patient.

Over the past twenty years, gene therapy with a lentiviral vector has shown potential in curing sickle cell disease (SCD) in both laboratory and clinical settings. The first SCD patient treated with this approach achieved a high level of healthy, non-sickling β-globin protein 15 months post-treatment. A modified lentiviral vector called LentiGlobin, which carries the anti-sickling β-globin gene, was tested in clinical trials for safety and effectiveness.

However, lentiviral vectors carry potential risks, such as creating a virus that could infect other cells unintentionally, and the possibility of the virus inserting into the wrong place in the DNA, leading to harmful cell growth and cancer. Although early results from gene therapy trials are promising, longer follow-up is necessary to confirm the long-term safety and efficacy of this treatment.

Casgevy and Lyfgenia

Casgevy, also known as exa-cel (exagamglogene autotemcel), is an FDA-approved new treatment for severe sickle cell disease (SCD) developed by CRISPR Therapeutics and Vertex. It uses the CRISPR-Cas9 technique to edit genes outside the body. Developed by CRISPR Therapeutics and Vertex, this therapy involves collecting a patient’s own cells, editing them to correct the sickle cell issue, and then reinserting them into the patient. This technology does not use viral vectors; instead, it acts as a tool to edit patients’ DNA.

Lyfgenia, also known as lovo-cel( lovotibeglogene autotemcel ), is another FDA-approved new treatment developed by Bluebird Bio. This treatment employs a lentiviral vector for genetic modification and is approved for patients aged 12 and older with sickle cell disease (SCD) and a history of vaso-occlusive events (VOEs). Both these treatments are one-time. Patients’ own cells are modified and inoculated back as part of HSCT.

Casgevy

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system acts as a precision scissor to cut the mutated DNA at a user-defined location within hematopoietic stem and progenitor cells (HSPCs). This system is derived from bacteria.

In SCD patients, this CRISPR Cas9 Nuclease system targets the erythroid-specific enhancer region of the BCL11A gene, which is responsible for suppressing the production of fetal Hemoglobin (predominantly found in Newborns). The bacterial vector carrying genetic material edits the BCL11A gene. It removes the ability to suppress fetal hemoglobin, resulting in elevated levels throughout the life of SCD patients.

Clinical Trials

In the Phase 3 study, a single-group, open-label design was employed to evaluate exa-cel in patients aged 12 to 35 years with sickle cell disease who had experienced at least two severe vaso-occlusive crises annually for two consecutive years before screening. CD34+ hematopoietic stem and progenitor cells (HSPCs) were edited using CRISPR-Cas9 technology.

Before exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary endpoint was achieving freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary endpoint was achieving freedom from inpatient hospitalization due to severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also evaluated.

Results

A total of 44 patients received exa-cel, with a median follow-up of 19.3 months (range: 0.8 to 48.1 months). Neutrophils and platelets engrafted in all patients. Among the 30 patients with sufficient follow-up for evaluation, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations due to vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers were reported.

Lyfgenia

Lyfgenia is a cell-based gene therapy that utilizes a lentiviral vector to transfer a gene into the patient’s blood stem cells, enabling them to produce HbAT87Q, a type of hemoglobin.

HbAT87Q functions similarly to hemoglobin A but with the added benefit of reducing the likelihood of sickling and blood flow obstruction in red blood cells. This allows the body to produce sufficient healthy hemoglobin, thereby alleviating the painful episodes known as sickle cell crises, a hallmark of sickle cell disease (SCD).

Clinical Trials

Eligible recipients of Lyfgenia medication include patients aged 12 years and older with SCD who have a history of at least four vaso-occlusive episodes in the past 24 months. Following treatment, patients receive the modified stem cells. Efficacy and safety data for lovo-cel came from the phase 1/2 HGB-206 clinical trial (NCT02140554). Cost, quality of life, and other clinical data were obtained from the HGB-206 trial and existing literature.

Analyses were conducted from U.S. societal and third-party payer perspectives. Uncertainty was evaluated using probabilistic sensitivity analysis and extensive scenario analyses.

Results

Patients undergoing Lyfgenia therapy have been observed to develop hematological malignancies, also known as blood cancer, as indicated on the medication’s label. Therefore, individuals using this treatment should undergo regular cancer screenings.

Despite this risk, Lyfgenia represents a potential paradigm shift in the management of SCD, offering a one-time therapy option capable of preventing sickle cell crises and improving overall health outcomes for affected individuals.

Analytical Assays for Cas9 and gRNA

The effectiveness of gene-editing tools, such as Cas9 nuclease and single guide RNA (sgRNA), significantly influences the quality of the resulting cellular product by affecting editing precision and efficiency.

To evaluate how the quality of Cas9 protein and sgRNA influences the formation, stability, and functional capabilities of a Cas9 ribonucleoprotein (RNP) complex, we devised a size exclusion chromatography technique. This method employs various detectors and an in vitro DNA cleavage assay conducted through anion-exchange chromatography.

There are several analytical assays to measure the purity, accurate sequence, and safety of these components, which is an expectation of the regulatory agencies. This is achieved by assessing various critical quality attributes (CQAs) such as appearance, sequencing, UV content, identity by LC-MS and HPLC, purity and impurities by HPLC, sodium content, water content by Karl Fisher, residual solvents by Gas Chromatography with headspace sampling (GC-HS), potency or assay, elemental impurities, endotoxin, and bioburden and validating those assays as per ICH guidelines and FDA requirements.

Navigating Affordability Challenges

“I don’t think we want to live, or I don’t want to live, in a world where only a few wealthy or connected people can get access to something like this,” Jennifer Doudna of the University of California, Berkeley, who shared the 2020 Nobel Prize in Chemistry with Charpentier for development of CRISPR-Cas9, the gene editing enzyme used in Casgevy told to STAT. (Cited: https://www.statnews.com/2023/11/16/crispr-vertex-sickle-cell-beta-thalassemia-casgevy-approval/#:~:text=But%20the%20biggest%20factor%20is,as%20multiple%20years%20of%20treatment)

Making this technology accessible to patients worldwide poses a significant challenge. Developing these specialized medicines for rare diseases requires extensive research, effort, and funding. Since gene therapies are one-time treatments, companies argue that the cost should reflect the expense of multiple years of treatment.

Additionally, issues like monopolizing intellectual property, public skepticism about genetic engineering, and unclear regulatory policies may hinder market growth. In traditional drug development, many compounds are discarded during the transition to clinical trials and commercialization.

The high failure rate of drugs in pre-clinical and early-phase trials often justifies the high prices of approved drugs, as companies need to recover the costs of failed projects. With increased state and federal funding for genome therapies, the financial risk has shifted from private companies to the public sector.

In a for-profit context, it makes sense for companies to deprioritize genomic therapies for rare diseases because commercialization is only feasible if it is economically viable. The small patient populations for rare genomic therapies mean that, even at high prices, the expected revenue may not justify the substantial upfront investment.

Given the challenges pharmaceutical companies face in advancing genomic therapies for rare diseases, alternative models of production are necessary to fulfill the potential of this technology.

For instance, Orchard Therapeutics secured a license to commercialize a gene therapy for SCID but returned the license to the University of California due to manufacturing issues. Similarly, Bluebird Bio developed therapies for SCD and beta thalassemia with positive regulatory outcomes but ceased operations in Europe, citing difficulties in achieving appropriate value recognition and market access.

Conclusion

In conclusion, the future of Sickle Cell Disease treatment holds promise and challenges in equal measure. As emerging therapies like gene editing and CRISPR/Cas9 technology offer hope for patients with beta-thalassemia, concerns over accessibility and affordability loom large.

While breakthroughs in science and technology pave the way for transformative treatments, the imperative remains to navigate the complexities of healthcare economics and ensure equitable access to these life-saving interventions. Collaborative efforts between stakeholders, including pharmaceutical companies, policymakers, and advocacy groups, are essential to address affordability challenges and realize the full potential of emerging therapies.

By fostering innovation, promoting transparency, and prioritizing patient welfare, we can chart a path towards a future where all thalassemia patients have access to effective and affordable treatments, ushering in a new era of hope and healing.

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