What evidence supports new disease-modifying drug therapies in sickle cell disease?

Introduction
Sickle cell disease arises from point mutations in the β-hemoglobin gene that leads to the production of sickle hemoglobin (hemoglobin S, HbS).1 Several types of sickle cell disease exist based on the underlying genotype. The most common form is HbSS (homozygous for HbS; also called sickle cell anemia), followed by HbSC (heterozygous combination of HbS and HbC) and HbS β-thalassemia (combination of HbS and β-thalassemia). For HbS, the mutation affects the structure of beta-globin chains in a hemoglobin molecule.2 In a deoxygenated state, HbS molecules can link together into long polymers that leads to deformation of the red blood cell into the sickle shape. Polymerization of HbS eventually leads to hemolysis, which releases free hemoglobin, creates oxidative stress, and initiates inflammation and activation of neutrophils, platelets, and endothelial cells.3 Adhesion of sickled red blood cells, neutrophils, and platelets to the endothelium of blood vessels results in vaso-occulsion. Vaso-occlusion can lead to tissue ischemia/reperfusion injury, acute and chronic pain, and organ damage.2,3 Clinical manifestations include acute vaso-occlusive crises, acute chest syndrome, and stroke, but the disease can affect almost any organ in the body. Acute pain episodes are the most common complication of sickle cell disease.1

Preventative treatment for vaso-occlusive crises
Traditional management
Management of sickle cell disease is multifaceted and includes both primary prevention measures and acute treatments to manage complications of the disease.1,3 Up until 2017, the only disease modifying drug available was hydroxyurea. Hydroxyurea increases the expression of fetal hemoglobin (HbF), which does not polymerize; increased expression of HbF reduces the concentration of HbS that allows less sickling to occur in low oxygen environments.2,3 It is also decreases neutrophils, increases the water content of red blood cells, increases deformability of sickled cells, and alters adhesion of red blood cells to endothelium.4 A 2014 guideline from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report recommends use of hydroxyurea to reduce or prevent sickle cell disease complications in most patients with sickle cell anemia.5 The drug reduces the frequency of painful episodes, acute chest syndrome events, and hospitalizations; long-term use also reduces mortality. Utilization in adults and adherence to hydroxyurea has lagged despite its established benefits.6,7 Medication adherence is notoriously low in sickle cell disease and early treatment discontinuation is common.7,8 However, hydroxyurea prescribing in children increased in recent years after publication of data showing the benefits of initiating hydroxyurea in infancy.6 Limitations of hydroxyurea include its need for frequent hematologic monitoring and its perceived safety profile.9 Long-term safety and efficacy are less defined, but the drug appears to be safe and efficacious as continuous therapy.9,10

New disease-modifying therapies
In the past 4 years, 3 new disease-modifying drugs for the prophylaxis and treatment of complications related to sickle cell disease have been approved by the Food and Drug Administration (FDA).11 L-glutamine was approved in July 2017 to reduce acute complications in patients with sickle cell disease.11,12 L-glutamine targets oxidative stress in the pathophysiology of sickle cell disease by increasing intracellular nicotinamide adenine dinucleotide (NAD) within sickle cells. In November 2019, the FDA approved both voxelotor and crizanlizumab for treatment of complications of sickle cell disease.11 Voxelotor binds to HbS to stabilize the molecule, increase its affinity for oxygen, and prevent HbS polymerization.2,13 This upstream mechanism helps reduce hemolysis and prolongs the survival of red blood cells. Crizanlizumab is a monoclonal antibody that binds P-selectin. P-selectin inhibition on the surface of activated endothelium and platelets blocks the interaction between endothelial cells, platelets, sickled red blood cells, and leukocytes.14,15 These interactions can mitigate vaso-occlusive events by blocking adhesions.

The efficacy and safety of crizanlizumab was established in its phase 2 trial, which demonstrated a reduction in the annualized rate of sickle cell-related pain crises compared to placebo.16 The phase 3 trial for L-glutamine demonstrated that its use resulted in fewer acute pain episodes and hospitalizations.17 The phase 3 trial for volexotor was designed to evaluate a surrogate marker rather than reduction in pain crises.18 The trial found that volexotor increased hemoglobin levels and reduced markers of hemolysis. Table 1 further describes the clinical trials that garnered FDA approval for the respective drugs.16-18 It should additionally be noted that dropout rates were high among the longer-term trials. The dropout rates in the crizanlizumab and L-glutamine trials were 35% and 32%, respectively.16,17 For the L-glutamine trial the dropouts were not balanced between groups with 36.2% discontinuing treatment in the L-glutamine group compared to 24.4% in the placebo group.17

Table 1. Clinical trials establishing efficacy for new disease-modifying therapies in sickle cell disease.16-18
Study design and duration
Subjects
 
Interventions
Primary outcome
Notable secondary outcomes
Ataga 201716
 
SUSTAIN
 
MC, DB, PC RCT
 
Duration: 52 weeks (treatment phase)
198 patients with sickle cell disease (16 and 65 years of age) with 2 to 10 sickle cell-related pain crises in the last year
 
 
Crizanlizumab 2.5 mg/kg IV (n=66)
 
Crizanlizumab 5 mg/kg IV (n=67)
 
Placebo (n=65)
 
Doses given at week 0, week 2, then every 4 weeks thereafter
 
62.1% of patients received concomitant hydroxyurea
Median sickle cell-related pain crises rate per year was significantly lower with high-dose crizanlizumab vs placebo (1.63 vs 2.98; percent difference, -45.3%; p=0.01); the rate with low-dose crizanlizumab was 2.01 (p=0.18 vs placebo)
Median time to first crisis was significantly longer with high-dose crizanlizumab compared to placebo (4.07 vs 1.38 months; p=0.01)
 
Annual rate of uncomplicated sickle cell-related pain crisis was significantly lower with high-dose crizanlizumab than placebo (1.08 vs 2.91; percent difference, ‑62.9%; p=0.02)
 
Crizanlizumab had no impact on measures of hemolysisa
Niihara 201817
 
MC, DB, PC RCT
 
Duration: 48 weeks (treatment phase)
230 patients with sickle cell disease (≥5 years of age) with at least 2 sickle cell-related pain crises in the last year
L-glutamine 0.3 g/kg orally twice daily (n=152)
 
Placebo (n=78)
 
66.5% of patients received concomitant hydroxyurea
Number of pain crises through week 48 was significantly lower with L-glutamine compared with placebo (median, 3 vs 4; percent difference, 25%; p=0.005)
 
The number of hospitalizations for sickle cell-related pain was also reduced (median 2 vs 3, p=0.005)
 
Median time to first crisis was significantly longer with L-glutamine than placebo (84 vs 54 days; p=0.02)
 
Markers of hemolysis were not reported
Vichinsky 201918
 
HOPE
 
MC, DB, PC phase 3 RCT
 
Duration: 24 weeks
274 patients with sickle cell disease (12 to 65 years of age); Hb level between 5.5 to 10.5 g/dL; 1 to 10 VOCs in the last year
 
 
Voxelotor 1500 mg once daily (n=90)
 
Voxelotor 900 mg once daily (n=92)
 
Placebo (n=92)
 
65.3% of patients received concomitant hydroxyurea
Percent of patients with a Hb response (>1 g/dL increase in Hb at week 24 from baseline) was achieved by significantly more patients receiving voxelotor 1500 mg than placebo (51% vs 7%; p<0.001); 33% of patients in the voxelotor 900 mg group achieved a Hb response
 
Adjusted mean change in Hb from baseline to week 24 was 1.1 g/dL in the voxelotor 1500 mg group, 0.6 g/dL in the voxelotor 900 mg group, and -0.1 g/dL in the placebo group
 
Decrease in indirect bilirubin was significantly greater with voxelotor 1500 mg vs placebo (‑29.1% vs ‑3.2%; p<0.001)
 
Annualized adjusted incidence rate of VOCs (per person-year) was not significantly different between groups: 2.77, 2.76, and 3.19 in the voxelotor 1500 mg, voxelotor 900 mg, and placebo groups, respectively
aMeasures of hemolysis included lactate dehydrogenase, number of reticulocytes, haptoglobin, indirect bilirubin
Abbreviations: DB, double-blind; Hb, hemoglobin; IV, intravenous; MC, multicenter; PC, placebo controlled; RCT, randomized controlled trial; VOC, vaso-occlusive crisis.

Place in therapy for new disease-modifying drugs
Overall, there are no head-to-head comparisons of the various disease-modifying drug therapies to help direct their place in therapy. Both crizanlizumab and L-glutamine act to modify the consequences of hemolysis and have demonstrated improvements in reducing the frequency of sickle cell-related pain crises.16,17 Voxelotor works further upstream in the pathophysiology to prevent hemolysis and its phase 2 data demonstrated an improvement in hemoglobin levels and markers of hemolysis.18 The positive results for this surrogate marker need to be further explored to determine if voxelotor can reduce the frequency of pain crises and long-term morbidity.

Hydroxyurea remains the most studied and well-established option for patients with sickle cell anemia (HbSS). L-glutamine, crizanlizumab, and voxelotor present additional therapy options, particularly for those who cannot tolerate hydroxyurea or require additional treatment despite use of hydroxyurea. The trials evaluating these therapies allowed concomitant use of hydroxyurea and combination therapy represented about two-thirds of study population.16-18 The trials also included patients outside of the HbSS type, which is notable as there is not randomized controlled data supporting hydroxyurea in these other disease types (ie, HbSC, HbSβ).1 In the crizanlizumab and volexotor trials, approximately 25 to 30% of the population was represented by genotypes other than HbSS.16,18 In the L-glutamine trial, 90% of the population had HbSS, with HbSβ0 representing the most of the other participants.17 Some experts have suggested use of crizanlizumab as a first-line therapy in patients with heterozygous disease.1

Considerations for these new disease modifying-drugs are summarized in Table 2. Additionally, it should be noted that these therapies are expensive, and it is is unclear if the incremental benefits for these therapies justify these costs.19

Table 2. Notable considerations and characteristics for disease-modifying therapies in sickle cell disease.12-14
L-glutamine
VoxelotorCrizanlizumab
Approved indication
 
Reduce acute complications of sickle cell disease in patients ≥5 years of age
Treatment of sickle cell disease in patients ≥12 years of ageaReduce the frequency of vasoocclusive crises in sickle cell disease in patients ≥16 years of age
Administration
Oral powder twice daily
Oral tablet once daily
Intravenous infusion every 4 weeks (after initial doses at weeks 0 and 2)
Clinical benefits from trials
Reduction in number of sickle cell crises
Increase in hemoglobin
Reduction in sickle cell-related pain crises
Safety considerations or limitations
Most common AEs (>10%) in its phase 3 clinical trial were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain
 
High discontinuation rates in the L-glutamine arm in the clinical trial highlight potential tolerability concerns
Most common AEs (≥10%) in the HOPE trial were headache, diarrhea, abdominal pain, nausea, fatigue, rash, and fever
 
Serious hypersensitivity reactions have occurred in <1% of patients
 
Potential drug interactions with CYP3A4 inhibitors and inducers
Most common AEs (≥10%)  in the SUSTAIN trial were nausea, arthralgia, back pain, and fever
 
Infusion-related reactions occurred in 3% of patients in clinical trials
aapproved under accelerated approval based on increase in hemoglobin
Abbreviations: AE, adverse event; CYP, cytochrome P450.

Conclusions and future research
Disease-modifying drug therapies available for sickle cell disease have greatly increased in the last few years. Three additional options are now available that can be used in patients who cannot otherwise take hydroxyurea or used as an adjunct to hydroxyurea in patients with continued symptoms or anemia. Additional research questions remain including the long-term impacts on morbidity and mortality with these new therapies. Further, more data are needed to better characterize treating patients with less common disease types, as patients with HbSS represent the majority of the literature and hydroxyurea is only approved for use in patients with sickle cell anemia. Additional therapies are currently in the pipeline, so there is promise of additional options that can target different processes in the sickle cell disease pathophysiology.

References

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  3. Osunkwo I, Manwani D, Kanter J. Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease. Ther Adv Hematol. 2020;11:2040620720955000. doi: 10.1177/2040620720955000
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  19. Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: Effectiveness and Value. Institute for Clinical and Economic Review. March 12, 2020. Updated February 9, 2021. Accessed April 26, 2021. https://34eyj51jerf417itp82ufdoe-wpengine.netdna-ssl.com/wp-content/uploads/2021/02/ICER_SCD_Evidence-Report_031220-FOR-PUBLICATION.pdf

Prepared by:
Samantha Spencer, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2021

The information presented is current as April 28, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.