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New Drug Shows Promise for Preventing Painful Sickle Cell Crises

December 6, 2016
Crizanlizumab, a new monoclonal antibody under development, could be an effective treatment for preventing sickle cell-related pain crises in patients.

Sickle cell-related pain crises are a significant issue for patients suffering from sickle cell disease,1 but a new therapy in development could cut the rate of attacks in half.  In a phase 2 trial, researchers found crizanlizumab, a novel humanized monoclonal antibody, was effective at significantly reducing the rate of pain crises found in sickle cell disease patients, regardless of whether they were taking concomitant hydroxyurea (Hydrea, Droxia).2

The research, which has been published in The New England Journal of Medicine, could be a major breakthrough for clinicians treating patients with sickle cell-related pain crises, noted Forest Tennant, MD, editor in chief of Practical Pain Management. "The pain of sickle cell crises has long been a burden to patient and practitioner. Crizanlizumab is a most welcome scientific discovery that hopefully will soon be available to practitioners and patients. This agent is reported to be an antibody against the adhesion molecule, P-selectin, which is apparently up-regulated in endothetial cells and platelets which contributes to the sickle cell interactions that produce vaso-occlusion and pain," noted Dr. Tennant.

While crizanlizumab is preventive, it will not eliminate the current need for acute and chronic pain care, he added.  Hopefully, over time, it will decrease acute and chronic morbidity. "Unfortunately, sickle cell and other genetic connective tissue and metabolic diseases such as Ehlers-Danlos, Marfan’s, and porphyria are caught up in the opioid-restriction frenzy," said Dr. Tennant. "It is apparently not well appreciated that these genetic, connective tissue metabolic diseases may cause progressive, tissue, and neurologic degeneration that often results in horrible, intractable pain and the need for high-dose opioids."

See additional commentary on study by Leonard Goldstein, DDS, PhD here.

Sickle cell-related crises, or vaso-occlusive crises, are a hallmark of the disease, and a typical cause of emergency department visitis and hospitalization. With every acute episode a patient suffers, their condition worsens. Over time, sickle cell disease can permanently damage vital organs, including the heart, lungs, kidneys, and spleen.3 Not only are these patients at an increased risk of death,4 but their quality of life significantly lessens, as well.5

Sadly, up to this point, doctors have had a sparse armamentarium of therapies for treating the complications related to sickle cell, especially sickle cell-related pain crises. Hydroxyurea, an antineoplastic, was approved by the US Food and Drug Administration (FDA) in 1998, and has been the only drug to have been shown to modify the progression of sickle cell disease—until now.6

 

Blocking Vaso-Occlusive Crises with Crizanlizumab

Crizanlizumab is a novel therapeutic agent in development that works by binding to P-selectin, a key component in the inflammatory process during vaso-occlusive crises.

P-selectin is a cell adhesion molecule (CAM) found in resting endothelial cells. As it translocates to the cell surface, sickle erythrocytes adhere to blood vessels blocking blood flow.7-10 For a while, researchers have noticed that by blocking P-selectin, it may be possible to pharmacologically prevent sickle erythrocytes and leukocytes from adhering to the endothelium, and perhaps even increase microvascular blood flow.10-12

In a new multicenter, randomized, double-blind, placebo-controlled Phase 2 trial, 198 patients with sickle cell disease were recruited from 60 centers in the US, Brazil, and Jamaica. Patients were split into 3 groups: a high-dose crizanlizumab group (n=67), a low-dose crizanlizumab group (n=66), and a placebo group (n=65).

After 52 weeks of treatment, researchers found patients in the intention-to-treat population taking crizanlizumab showed nearly half the median rate of pain crisis per year compared to placebo, at 1.63 (high-dose crizanlizumab) versus 2.98, a 45.3% lower rate, respectively (P = 0.01). Patients taking low-dose crizanlizumab also showed a 32.6% lower median rate of pain crises compared to the placebo group, at 2.01 versus 2.98, respectively (P = 0.18).

Strong Efficacy Data for High-Dose Crizanlizumab

Regardless if patients were taking concomitant hydroxyurea, those taking high-dose crizanlizumab showed a clinically significant reduction in sickle-related pain crises over the course of the treatment year.

The therapy appeared to be especially effective for patients who had had 2 to 4 crises within the previous 12 months prior to starting treatment. Their median crisis rate was 1.14 after taking high-dose crizanlizumab, 43.0% lower than patients on placebo, whose median crisis rate was 2.00.

This trend was even more significant for patients who had had 5 to 10 crises in the previous 12 months, where their median crisis rate was 1.97 while on high-dose crizanlizumab, 63.0% lower than the placebo group, whose median crisis rate was 5.32.

Furthermore, 24 out of 67 patients (36%) taking high-dose crizanlizumab had a crisis rate of 0 during the treatment phase, compared to patients taking low-dose crizanlizumab (12 of 66; 18%) or placebo (11 of 65; 17%).

Fifty-five patients reported serious adverse events during the trial, but this was evenly distributed throughout the 3 treatment groups (n=17 high-dose crizanlizumab; n=21 low-dose crizanlizumab; n=17 placebo group). Other adverse events reported in 10% or more of the patients in the high- or low-dose active treatment groups included:

  • Headache
  • Back pain
  • Chest pain
  • Musculoskeletal pain
  • Pain in upper and lower limbs
  • Arthralgia
  • Nausea
  • Urinary tract infection
  • Upper respiratory tract infection
  • Pyrexia
  • Diarrhea
  • Pruritus
  • Vomiting

According to researchers, patient safety data indicates the treatment presents no significant differences in adverse events or serious adverse events. None of the patients in the trial appeared to develop a detectable antibody response to the crizanlizumab treatment. Further ongoing research will help doctors better determine if patients possibly could develop an antibody response to the drug, especially in the context of long-term treatment courses that extend past 12 months.

This study was supported by Selexys Pharmaceuticals, as well as by grants to the company by the National Institutes of Health and the Food and Drug Administration. A full disclosure of the authors’ conflicts of interest, as well as a full text version of the original study, can be found at NEJM.org.

Last updated on: February 1, 2017
Continue Reading:
Prevention of Acute Sickle Cell Crisis: Review of the NEJM Report

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