Addressing Sickle Cell Disease A Strategic Plan and Blueprint for Action (2020) / Chapter Skim
Currently Skimming:
7 Developing and Delivering the Next Generation of Therapies
7 Developing and Delivering the Next Generation of Therapies
Pages 303-352
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Chapter Summary • After decades of relatively little progress being made in therapeutic innovations for sickle cell disease (SCD) , an influx of pipeline products has been introduced in recent years.
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Testing new treatments in clinical trials will require a different set of considerations, including strategies for encouraging participation in trials and determining which endpoints to use as measures of success. Once novel therapies are approved by the U.S.
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The findings revealed that patients were more likely to have a positive attitude toward gene therapy when there was better education, prior participation in clinical trials, and perceived benefit. Persaud and Bonham (2018)
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When deciding whether to pursue allogenic hematopoietic stem cell transplantation (HSCT) , for example, patients were primarily influenced by the disease burden (particularly when it reached a critical point)
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As of December 2019, hydroxyurea (HU) , L-glutamine, voxelotor, and crizanlizumab are disease-modifying drugs available for those with SCD, and HSCT is the only established non-experimental curative therapy (Bernaudin et al., 2007; FDA, 2019; Hsieh et al., 2009; Kutlar et al., 2019; Strouse et al., 2008)
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sickling in the phenotype has not been challenged, but multiple complex and interlinked downstream mechanisms have been identified, in large part -- and in some cases exclusively -- based on preclinical evidence. Thus, compounding hemoglobin polymerization, cellular hyperadhesion, endothelial activation, hemolysis, hemostatic activation, oxidant stress, sterile inflammation, and hyperviscosity are now all recognized as critical determinants of the phenotype (Du et al., 2018; Kalpatthi and Novelli, 2018)
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. Clinical trials in adults and children have shown reduced hemolysis and improved hemoglobin, although these changes were not accompanied by a statistically significant reduction in VOEs (Vichinsky et al., 2019)
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. Rivipansel has shown clinical benefit in a Phase II trial, where it reduced cumulative intravenous opiate requirements by 83 percent in patients hospitalized with VOEs (Telen et al., 2015)
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Both reactive oxygen and nitrogen species are elevated and natural antioxidant mechanisms are depleted in the plasma and tissues. Enzymatic sources of reactive oxygen species (ROS)
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. Clinical trials are ongoing with efforts to modulate specific mediators of inflammation, which could potentially lead to drugs with more limited and predictable side-effect profiles.
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NO therapeutics, including inhaled NO, L-arginine, and sildenafil (a phosphodiesterase inhibitor) , have been tested in clinical trials.
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. Stem Cell Transplant Since the 1990s, stem cell transplant has offered the potential for an SCD cure.
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Unrelated-donor stem cell sources are actively sought to expand access to transplantation in SCD and other benign and malignant hematological conditions. While the probability of identifying fully matched donors in the bone marrow registry is low for African Americans (19 percent)
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Thus, the side effects of stem cell transplantation need to be assessed in the context of the patient's individual experience with SCD and projected disease course. With matched sibling transplantation, the side effects are relatively modest, and long-term, disease-free survival is the norm.
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. It is important to frame the discussion of the reproductive risks of stem cell transplantation (Xue et al., 2019)
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. Several clinical trials of haplo-identical transplantation with improved conditioning regimens or posttransplant immunosuppression are under way (Limerick and Fitzhugh, 2019; Tanhehco and Bhatia, 2019)
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Decisions concerning transplantation opportunity and timing will become even more complex once the new biological therapies under development become available. A future is foreseeable where multiple medications used sequentially or in combination may significantly mitigate the phenotype to the point that stem cell transplantation offers no added value.
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Since the 1990s, the use of viral vectors has allowed ex vivo gene therapy (via the insertion of genes into autologous hematopoietic stem cells)
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. Ethical Issues and Other Considerations Gene therapy shares some of the concerns surrounding stem cell transplantation because it requires a conditioning regimen, with the attendant risks of infertility and secondary malignancies, particularly when myelo ablative regimens are employed, as in ongoing gene therapy approaches.
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Finally, similar to the situation with stem cell transplantation, the SCD community has lower risk tolerance for gene therapy due to the availability of effective alternative therapies and the absence of long-term outcomes data for most patients. Thus, it is paramount that gene therapy trials receive the appropriate oversight by both an FDA-appointed and a non-FDA panel of experts.
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clinical trials of SCD drugs will inevitably require large percentages of African Americans among the trial participants, but African Americans have many reasons to distrust the health care system. First, the history of human experimentation in the United States has been marked by racism and inequality, as epitomized by the infamous U.S.
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Compounding the issue of mistrust, decreased access to care among African Americans and a lack of clinicians specializing in caring for patients with SCD have resulted in a lack of awareness of new therapies and clinical trials among SCD patients. In response, ASH has recently developed several initiatives to increase access to care, educate providers across the nation, and bolster research infrastructure, including developing a clinical trial network (Michaelis, 2019)
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. In an effort to inform the field, ASH partnered with FDA to conduct work to identify clinical trial endpoints.
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The consensus is that the endpoints traditionally used in SCD clinical trials are limited and poorly represent the heterogeneity of the disease. Well-characterized biomarkers and relevant surrogate endpoints are scarce.
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. In response, the primary care and hematology departments partnered to create a multidisciplinary high-risk clinic to deal with advanced SCD patients.
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Criteria for use of these new therapies would help address this problem, for example, reducing the number of "marginal" cases where patients may or may not benefit would help mitigate overuse, even if the curative therapies are not bundled. It may be tempting to believe that curative therapy would eliminate the need for intensive, coordinated care, but this may not be the case.
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If so, then access to specialists will limit therapy availability. Among commercially insured SCD patients, less than half see a specialist in a given year; that rate is less than one-sixth for Medicaid patients (Dampier et al., 2017)
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It is difficult to predict how curative therapies for SCD will be priced, but the relevant factors will include the size of the eligible patient population and the expected take-up, the expected rate of treatment response, and the extent of irreversible sequelae (e.g., organ damage)
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. Clinical trials will always feature endpoints likely to satisfy regulators.
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The International Society for Pharmacoeconomics and Outcomes Research published guidelines in 2015 recommending that collecting cost data should be fully integrated into clinical trials (Ramsey et al., 2015)
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Spark Therapeutics prices its gene therapy for childhood retinal dystrophy at $850,000. Given the uncertainty about its long-term effectiveness and its high price tag, the company has proposed an outcomes-based pricing contract that offers a partial refund if the patient's eyesight deteriorates (Richards, 2019)
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Innovative Payment Models for Curative or High-Cost Therapies The examples above touch on a few of the numerous possible alternative payment mechanisms for curative therapies. Annuity-style payment models allow health plans to spread out payments for treatments over time through installments up to a contractual ceiling (Carr and Bradshaw, 2016)
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The pool could be administered by a nonprofit third party, the government, or the reinsurer, and it could be supported partially by the government to ensure patient access to high-cost treatments. Enabling Innovative Contracting Arrangements While there are a handful of innovative payment models, the idea remains nascent in the U.S.
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, efforts to advance medical science are still marred by historical exploitation. Yet, many are also willing to participate in clinical trials, and, somewhat paradoxically, there is evidence that recruitment efforts lag for this population.
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Conclusion 7-5: Gene therapy advances and clinical trials are proceeding at a fast pace. Education and patient-facing materials on the risks and benefits of gene therapy are urgently needed, as is research to elucidate the long-term implications of gene therapy.
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2001. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease.
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2007. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease.
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2019. Familial haploidentical stem cell transplant in children and adolescents with high-risk sickle cell disease: A Phase 2 clinical trial.
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2019. Pain and opioid use after reversal of sickle cell disease following HLA-matched sibling haematopoietic stem cell transplant.
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2017. Alternative do nor hematopoietic stem cell transplantation for sickle cell disease.
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2017. Sickle cell disease: An international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.
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2019. Updated results from the HGB-206 study in patients with severe sickle cell disease treated under a revised protocol with lentiglobin gene therapy using plerixafor-mobilised haematopoietic stem cells.
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2019. Choice of donor source and conditioning regimen for hematopoietic stem cell transplantation in sickle cell disease.
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2011. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity.
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2019. Lentiglobin gene therapy in patients with sickle cell disease: Updated interim results from HGB-206.
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2017. Gene therapy in a patient with sickle cell disease.
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2016. Nonmyeloablative stem cell transplantation with alemtuzumab/low-dose irradia tion to cure and improve the quality of life of adults with sickle cell disease.
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2019. Hematopoietic stem cell transplantation and cellular therapy in sickle cell disease: Where are we now?
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2005. Stem cell therapy for sickle cell disease: Transplantation and gene therapy.
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Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 95(6)
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