Sickle Cell Disease: The Future Could be Less Sticky
Sickle cell disease (SCD) is a chronic disorder that affects hemoglobin in red blood cells, a molecule that carries oxygen throughout the body. There are more than 4 million people globally with sickle cell disease, which has a debilitating impact on the quality of their lives and life expectancy.1 SCD is an inherited condition caused by a single mutation, resulting in only one amino acid change (glutamic acid replaced by valine) in the hemoglobin protein. This atypical hemoglobin, called hemoglobin S, alters the round shaped red blood cells into a sickle, or crescent, shape. 2 Red blood cells that are shaped like sickles affect normal blood flow and cause multiple clinical symptoms that include: a low number of red blood cells (anemia), fatigue, frequent infections, painful attacks (in the legs, chest, arms, and lower back), and multiple organ damage due to poor oxygen delivery. SCD, similar to many other genetic diseases, clearly demonstrates how a discrete genetic mutation can result in multiorgan damage with complex pathophysiologic mechanisms.
“People living with SCD have limited pain-relieving alternatives, further exacerbated by recent increases in opioid restrictions due to opioid abuse: thus the treatment of individuals with SCD is becoming an increasing challenge. ”
The most common symptom of SCD is sudden severe attacks of pain called sickle cell crisis. These severe pain crises are caused by vaso-occlusion and lack of tissue oxygen. Patients usually experience sickle cell crises several times a year and often need to be admitted to emergency departments, resulting in hospitalization. In the US alone, every year over 75,000 emergency admissions are for patients experiencing sickle cell pain crises.3 These painful crises are treated symptomatically with opioid pain medications until the pain settles. People living with SCD have limited pain-relieving alternatives, further exacerbated by recent increases in opioid restrictions due to opioid abuse: thus the treatment of individuals with SCD is becoming an increasing challenge.
Although SCD has been known about for more than 100 years and is currently diagnosed by simple identification of hemoglobin S in the blood, there is still a lack of treatment and management. Current treatments are aimed at relieving symptoms and preventing complications, as the only potential cure is stem cell transplantation through matching bone marrow.
Development of investigational drugs that target cell adhesion, inflammatory pathways, hemoglobin sickling, clotting, and platelet activation are potential approaches to alleviate clinical symptoms and slow progression of multiple organ damage due to SCD.4 The pathophysiology of the intense pain associated with vaso-occlusion of capillary beds is believed to be due to the restriction of blood to local tissues. Clogging of capillaries with rigid and inflexible sickled red blood cells leads to adhesion of white blood cells to the inner wall of the blood vessels and the recruitment of platelets. These precipitating events result in occlusion (blockage), clogging, and restriction of blood flow. As such, drugs targeting selectin-driven red blood cell and white blood cell adhesion are attractive therapeutic modalities in treating SCD as multiple adhesive interactions have been demonstrated as contributing to vaso-occlusion in in vitro experiments and in vivo animal studies.5
An investigational drug that can be potentially used for treating pain due to vascular occlusion in SCD is a pan-selectin inhibitor, Rivipansel. Selectins are a family of molecules that play a key role in regulating cellular interactions within blood vessels. In SCD, there is an increased level of selectins, which makes blood cells more prone to sticking to the vascular wall and to each other. Rivipansel acts by reducing cell adherence and associated inflammation that contributes to reduced blood flow through the microvasculature during sickle cell crisis. Rivipansel is the first drug to interrupt the underlying cause of vaso-occlusion, potentially enabling patients to reduce the use of narcotic pain relief medications and be admitted from the hospital more quickly. Initial testing with Rivipansel showed a decrease in white blood cell adhesion in vitro and in vivo in the Townes mice. In addition, administration of Rivipansel showed signs of improved cerebral perfusion and an improvement of peripheral microvascular flow in the SCD mice.5
This new drug candidate was also tested in humans for its potential to reduce the stickiness of cells in the blood by measuring the duration of the pain crisis and hospital stay. A Phase 2 study examined the efficacy, safety, and pharmacokinetics of Rivipansel in SCD patients experiencing sickle cell crisis. 5 Patients treated with Rivipansel experienced a reduction in the duration of vaso-occlusive crisis, length of hospital stay, and the use of opioids. Both adult and pediatric patients demonstrated improvement with no side effects.
Unfortunately, the results of the Phase 3 clinical trial, RESET, failed to meet the primary endpoint of the study. The RESET study tested 350 people with SCD in the US and Canada, aged six and older who are hospitalized for a vaso-occlusive pain crisis. If this study had shown that Rivipansel has a beneficial effect on pain management, it would have been the first non-opioid based treatment available for patients with SCD. The goal was to enable a faster access to treatment for patients, therefore, Rivipansel received Orphan Drug and Fast Track status from the U.S. Food and Drug Administration (FDA), and this study was being conducted under a Special Protocol Assessment (SPA). Ideally, this status would have enabled fast approval and marketing of the drug if the Phase 3 clinical data was positive.
Rivipansel clinical investigations concluded in 2019, and a recent post hoc analysis of the RESET study showed that there were statistically significant improvements in the length of the hospital stay for patients experiencing a pain crisis when treated with Rivipansel. Those treated with a placebo had a much longer stay than those treated with Rivipansel.6 Further, biomarker data was collected by researchers that confirmed Rivipansel was in fact affecting the biological target of interest and supporting that E-selectin has a critical role in the development of vaso-occlusion, and thus painful crises.6
Options for the treatment of underlying causes of SCD are still very limited and the current practice is to manage the painful crisis with opioid medications and hospitalization. Given the need for repeated treatments, people with SCD may build a tolerance to these medications, requiring increased dose levels over time. In recent years, there has been an increase in clinical pharmaceutical research that uses different mechanisms of adhesion and inflammation in SCD; the current and past drugs in testing make it reasonable to expect that new treatments for SCD will soon become available. Novel medications like Rivipansel for the treatment of painful crises could dramatically reduce the use of opioids for pain management, as well as reduce consumption and potential dependence on opioids.
Mila Pastrak
Works Cited
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2. "What Is Sickle Cell Disease?". National Heart, Lung, and Blood Institute. June 12, 2015. Archived from the original on 6 March 2016.
3. Hematol Oncol Clin North Am. 2014 Apr;28(2):155-79. doi: 10.1016/j.hoc.2013.12.002. Epub 2014 Jan 22. Hemoglobin s polymerization and red cell membrane changes.
4. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Marilyn J. Telen. Blood 2016 127:810-819; doi: https://doi.org/10.1182/blood-2015-09-618553
5. Rivipansel: A Small Pan-Selectin Antagonist Improves Cerebral Perfusion and Inhibits Leukocyte Adhesion and in Murine Sickle Cell Disease Model. Reema Jasuja, Georgette Suidan, Sunita Patel Hett, Kunal Desai, Kevin X Le, Elizabeth Parks, Robert Bell, John E. Murphy, and Debra D Pittman. Blood 2016 128:270;
6. Dampier CD, Telen MJ, Wun T, et al. EFFICACY AND SAFETY OF RIVIPANSEL (GMI-1070) IN THE TREATMENT OF VASO-OCCLUSIVE CRISIS IN HOSPITALIZED PATIENTS WITH SICKLE CELL DISEASE: RESULTS FROM THE RESET PHASE 3 STUDY. JSCDH Journal of Sickle Cell Disease and hemoglobinopathies. 2020;VII. doi:10.14223
Cite This Article:
Pastrak M. Sickle Cell Disease: The Future Could be Less Sticky . Illustrated by S. Chen. Rare Disease Review. January 2022. DOI: 10.13140/RG.2.2.13086.66880
