key: cord-0797397-edvesfrm
authors: Ali, Muhammad Ashar; Ahmad, Asrar; Chaudry, Hafsa; Aiman, Wajeeha; Aamir, Sobia; Anwar, Muhammad Yasir; Khan, Anam
title: Efficacy and Safety of Recently Approved Drugs for Sickle Cell Disease: A Review of Clinical Trials
date: 2020-08-22
journal: Exp Hematol
DOI: 10.1016/j.exphem.2020.08.008
sha: 99fec8cfe5692e9b53fac4f8f8e656501ae7f588
doc_id: 797397
cord_uid: edvesfrm

Abstract Sickle cell disease is prevalent in several parts of the world. Most of the hospitalizations in these patients are related to pain crisis episodes. Moreover, the levels of hemoglobin are lower in sickle cell disease patients as compared to the general population. Complications related to sickle cell disease are managed with blood transfusions, hydroxyurea, and opioids. Despite these therapies, patients with sickle cell disease experience multiple pain crisis episodes leading to hospitalizations and end-organ damage. FDA has approved three new drugs, L-glutamine, voxelotor, and crizanlizumab, for the prophylaxis and treatment of complications related to sickle cell disease. This review aims to assess the efficacy and safety of recently approved drugs for the treatment of sickle cell disease. A comprehensive search was made on PubMed and clinicaltrials.gov to look for clinical trials reporting the efficacy and safety of recently approved drugs for sickle cell disease. Based on the results of clinical trials, L-glutamine, voxelotor and crizanlizumab were well tolerated by sickle cell disease patients. L-glutamine and crizanlizumab reduced the number of sickle cell crisis episodes, while voxelotor improved the level of hemoglobin in sickle cell disease patients. These drugs were effective alone and in combination with hydroxyurea.

Sickle cell disease (SCD) is caused by mutation of beta-globin gene alleles with the involvement of at least one sickle mutation. The patients may have; both sickle mutations, one sickle and one hemoglobin C mutations, one sickle and one thalassemia mutations, and other similar mutations with one sickle mutation in beta-globin genes. The sickle mutation is a substitution of nucleotide thymine (T) by adenine (A) at 17 th nucleotide (sixth codon) in exon 1 of the beta-globin gene that reflects as a replacement of glutamic acid by valine at 6 th amino acid in the beta-globin chain.

This mutation decreases the solubility of hemoglobin (Hb), leading to clinical symptoms. [1] .

SCD is the most prevalent genetic disease in the United States. Every twelfth African American is a carrier of sickle cell trait. Every year, 300,000 infants are born with SCD. Environmental factors (weather, air quality), fetal Hb levels, infections, and different genetic subtypes, play a key role in exhibiting this disease. However, the knowledge of the phenotypic expression of SCD is still limited [2, 3] .

Long term irreversible complications of SCD, for example, vaso-occlusion crisis (VOC) and hemolysis, are the most common causes of morbidity and death. Affected RBCs in SCD have a shorter life span leading to chronic hemolytic anemia. Chronic hemolysis leads to compensatory changes such as an increase in RBC formation and adjustment to lower Hb levels. These modifications are beneficial for the survival of SCD patients. VOC occurs due to multiple changes in the adhesion of sickle RBCs to the endothelial cells of vessels and the activation of inflammatory and hemostatic mechanisms. Hydroxyurea, RBCs transfusion and opioids are the commonly used treatments to manage these symptoms. [4] Hydroxyurea increases gamma-globin gene expression that causes a shift in gene expression away from the beta-globin gene. This shift in gene expression results in a higher level of fetal Hb (HbF: α 2 γ 2 ), and a reduction in the production of adult Hb (HbA: α 2 β 2 ). Patients taking hydroxyurea can have gastrointestinal toxicity such as nausea or anorexia, but the significant adverse effect is myelosuppression [5, 6] .

RBCs transfusion can be life-saving in VOC, red cell aplasia, or splenic sequestration. But RBCs transfusion has its adverse effects as well, e.g., excessive iron storage, alloimmunization, infections related to transfusion, and hyperviscosity. Curative treatment options for SCD are hematopoietic stem cell transplantation (HSCT) and gene therapy. [7, 8] .

FDA has approved three novel drugs for the treatment of sickle cell complications in recent years. L-glutamine is the oldest one among the three drugs. FDA approved L-glutamine for the treatment of complications of SCD in July 2017. L-glutamine is an amino acid required in the production of NAD (nicotinamide adenine), which is a cofactor in the reduction-oxidation reactions in the body. Oxidative stress is proven to be a critical factor in the pathophysiology of SCD [9] . Therefore, it has been shown that supplementation with L-glutamine in patients with SCD increases the intracellular concentration of NAD within the sickle cells [10] .

FDA approved voxelotor and crizanlizumab for the treatment of complications of SCD in November 2019. Voxelotor is a hemoglobin modulator. It binds to the hemoglobin and increases its affinity for oxygen. Increased affinity for oxygen stabilizes the sickle cell hemoglobin and prevents polymerization [11] . FDA approved voxelotor for SCD patients above 12 years of age.

It is considered for patients refractory to hydroxyurea therapy, cannot tolerate hydroxyurea therapy, or as an additional therapy in patients with worsening anemia [12] .

Crizanlizumab is a humanized monoclonal antibody that binds p-selectin. P-selectin is the primary mediator of the vaso-occlusive crisis in SCD. P-selectin binds with its ligand P-selectin glycoprotein-1(PSGL-1), an adhesion molecule. They capture leukocytes, which then activate platelets and form aggregates with sickled erythrocytes. These aggregates block vessels and lead to sickle cell pain crisis. FDA approved this drug for patients above 16 years of age. [13] [14] [15] This review aims to assess the efficacy and safety of new drugs, i.e., L-glutamine, voxelotor, and crizanlizumab, for sickle cell disease.

A comprehensive search was performed on PubMed and clinicaltrials.gov with keywords "Voxelotor" OR "Crizanlizumab" OR "Glutamine" AND "Sickle Cell Anemia" by June 5, 2020.

One article was added through citation analysis-Supplementary table 1

All clinical trials providing efficacy (change in hemoglobin, change in reticulocyte count, change in vaso-occlusive crisis episodes, etc.) and safety (treatment-related adverse effects) were included. All preclinical studies, case reports, case series, reviews, meta-analysis and clinical trials not providing efficacy and safety of drugs in SCD were excluded.

Information regarding the efficacy (change in hemoglobin, change in reticulocyte count, change in indirect bilirubin, change in vaso-occlusive crisis episodes, etc.) and safety (treatment-related adverse effects) were extracted from the selected clinical trials.

Cochrane collaboration tool [16] was used by two researchers (M.Y and W.A) for the quality of bias assessment in randomized clinical trials. Disagreements were settled by a third researcher (M.A).

One hundred eleven articles were identified through a search on PubMed and clinicaltrials.gov.

A total of seven clinical trials (two phase III, three phase II, and one pilot study) with 976 participants were selected based on inclusion criteria.

The risk of bias was unclear in the trial by Niihara The results of the pilot study were reported in 1998 by Niihara et al. [17] . This study included only seven patients (age 19-60 years) who were administered 30g of L-glutamine orally each day for four weeks. The primary endpoints of this study were the change in NADH levels and NAD redox potential. The total NADH levels increased from 47.5 nmol/ml to 72.1 nmol/ml (p<0.01).

While the NAD redox potential also raised significantly from 47.2 to 62.1 (p<0.01). The mean hemoglobin levels were not significantly changed from baseline, the baseline Hb was 8.5 mg/dl, and it was 8.7mg/dl at four weeks for the study population. In addition to the change in these levels, the study also included some patient-reported outcomes. All patients reported an increase in energy level and a decrease in chronic pain levels. None of the patients reported any adverse events associated with L-glutamine.

In the phase II trial reported in 2014 [18] , outcomes were reported for a total of 62 patients (age 9-58 years) with SCD who had a history of painful sickle cell crisis. Of these patients, 33 were administered L-glutamine, while 29 were administered a placebo. The patients were followed up for 53 weeks, and the outcomes were reported at 48 weeks. At week 48, the mean number of events for the painful sickle cell crisis was 4.5 for the L-glutamine group and 10.8 for the placebo group with a p-value of 0.076 between the two groups. The study also reported a mean number of events for hospitalization for sickle cell pain, which was 1.5 in the L-glutamine group and 2.3 for the placebo group, and the p-value was 0.072. Treatment-related adverse events (TRAE) were 8.1% in the L-glutamine group and 9.1% in the placebo group.

In 2018, a phase III study [19] was conducted to assess the efficacy of L-glutamine in improving SCD. In this randomized controlled trial, a total of 230 patients (age 5-58 years) were assigned in a 2:1 to L-glutamine (n=152) or placebo (n=78) with most of the patients receiving concomitant hydroxyurea as well. The patients in the L-glutamine group were administered 0.3 g/kg of glutamine powder twice daily. The total treatment duration was 48 weeks, and the overall trial duration was 53 weeks. This trial showed statistically significant results. The mean number of pain crises in the L-glutamine and the placebo groups were 3.2 and 3.9, respectively, with a pvalue of 0.005, proving the results to be statistically significant. While the mean number of hospitalizations for sickle cell-related pain was 2.3 in the L-glutamine group and 3.0 in the placebo group with a p-value of 0.005, proving this difference between the two groups to be statistically significant. The improvement in hemoglobin levels, hematocrit levels, and the reticulocyte count between the drug and the placebo groups was not significant statistically.

TRAE was higher in the placebo group as compared to the L-glutamine group showing that it is safe to administer L-glutamine- Table 1 Voxelotor:

In phase I/II trial by Howard et al. 2019 [20] , different doses of voxelotor were used in 54 SCD patients of 18-60 years of age. In 28 days follow up (N=16), the median change in hemoglobin was 0.4 g/dl with 1000 mg voxelotor dose, 0.7 g/dl with 700 mg voxelotor, 0 with 500mg voxelotor and -0.1 g/dl with placebo. The difference was statistically significant. For markers of hemolysis, the median changes in the percentage of reticulocyte count, unconjugated bilirubin, and LDH were -49.9%, -56.3%, and -12.4%, respectively with 1000mg voxelotor vs. changes in the placebo group were 9.0%, -3.6% and -6.6%. The difference in changes in reticulocyte count and unconjugated bilirubin between 1000mg and placebo was statistically significant. In voxelotor, vaso-occlusive episodes were reported when the patients were off-treatment. No grade 3 side-effects were reported in this trial.

In phase III, placebo-controlled, double-blinded trial by Vinchinsky et al. 2019 [21] on SCD treated with different doses of voxelotor, aged 12-65 years with a follow up of 24 weeks (N=274). Least square (LS) mean of changes in hemoglobin was 1.1g/dl, 0.6 g/dl, -0.1g/dl in 1500 mg voxelotor (N=90), 900 mg voxelotor (N=92) and placebo (N=92) groups, respectively (p<0.001). Among markers of hemolysis, LS mean of changes in the percentage of reticulocyte count, indirect bilirubin and LDH were -19.9%, -29.1% and -4.5%, respectively in 1500mg voxelotor group, LS mean of changes were -1.3%, -20.3% and 1.4%, respectively in 900mg voxelotor group, and LS mean of changes were 4.5%, -3.2% and 3.4%, respectively in the placebo group. The difference was significant in the mean changes in reticulocyte count, and indirect bilirubin among 1500 mg voxelotor and placebo groups. The difference in vasoocclusive crisis episodes in the three groups was not significant. Treatment-related adverse events in 1500mg, 700mg, and placebo groups were reported in 94%, 93%, and 89% of participants, respectively- Table 1 Crizanlizumab:

A phase II, double-blinded, placebo-controlled study was performed by Ataga et al. [22] on efficacy and safety of crizanlizumab. The total population (N=198), median age 29 , and 55% were Females. 62% of participants had concomitant hydroxyurea use. Total population (N=198) is divided into high dose crizanlizumab (group 1 n= 67), low dose crizanlizumab (group 2 n=66) and Placebo (group 3 n=65). Of 198 participants, 129 completed the trial. A total of 36% of participants in group 1, 18% of participants in group 2, and 17% of participants in group 3 had no vaso-occlusive crisis during the treatment phase. The median crisis rate was 1.04 vs. 2.18 in group 1 and group 3, respectively (p=0.02). The median rate of days hospitalized was 4/yr in group 1 vs. 6.87/year in group 3 (p=0.45). The median time to first crises was 4.07months vs.

1.38months (p=0.001) in groups 1 and 3, respectively. In the high dose crizanlizumab group, the rate of uncomplicated crisis per year was 62.9% lower as compared to the placebo group. Serious adverse events occurred in 26%, 33%, and 27% of participants in groups 1, 2, and 3, respectively. The difference in changes in hemoglobin levels and markers of hemolysis were not statistically significant between the drug and the placebo group. 

There are 11 ongoing clinical trials on these drugs, with 1288 participants registered on clinicaltrials.gov [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] . Four of them are phase III clinical trials- Table 2 

Hematopoietic stem cell transplantation (HSCT) with fully matched donors is the most effective treatment available for SCD, especially for patients refractory to hydroxyurea. However, the complications of stem cell transplantation, unavailability of suitable donors, financial burden, and insufficient stem cell transplant centers in certain parts of the world limit the use of HSCT [35] [36] [37] . Therefore, almost all new therapies and further avenues of exploration are directed towards the reduction of adverse events encountered in SCD to improve the quality of life. The main aim is to reduce the pain crises, the number of hospitalizations as well as improvement of hemoglobin levels in these patients.

In the past, hydroxyurea was the only drug available for SCD, along with supportive therapy (hydration, opioids) and blood transfusions. Hydroxyurea was approved in 1998. Although it has clinical efficacy and reported incidence of decreased hospitalizations to 47% and pain crises to 43% [38] , adherence to hydroxyurea always remained a challenge [39] . Moreover, patients taking hydroxyurea still experience end-organ damage, crisis episodes, and decreased life expectancy [40] .

The trials on L-glutamine use in SCD patients paved the way for L-glutamine to be approved by the FDA. In preclinical studies, it was found that sickle RBCs transport three-fold increased glutamine as compared to reticulocyte controls [41] . Similarly, in a trial on PK/PD of oral glutamine supplementation, increased glutamine and arginine levels in RBCs were noted [42] .

In the pilot study in 1998, although it was not randomized, and the sample size was quite small, almost all the patients reported an improvement in the quality of life. There was a statistically significant improvement in NADH levels in the participants using L-glutamine. And hence laid the foundation of further trials to investigate the efficacy of L-glutamine. In phase II clinical trial, the reduction in the mean number of hospitalizations was statistically significant in the Lglutamine drug group as compared to the placebo group at 24 weeks follow up. Although there were a decrease in the hospital admissions and painful sickle cell crisis events at 48 weeks follow up, there was no statistically significant difference between L-glutamine and the placebo groups.

It was possibly due to the smaller sample size in that study. In the phase III clinical trial, the difference in sickle cell crisis episodes between the L-glutamine group and the placebo group was statistically significant. Most of the patients in this trial were administered concomitant hydroxyurea, as its benefits are well documented and proven [43] . Subgroup analysis with and without hydroxyurea also showed a statistically significant difference between L-glutamine and the placebo groups regardless of the hydroxyurea usage.

As far as the safety profile is concerned, L-glutamine has shown promising safety results in all these trials. There were no serious adverse events reported in any of the trials that could be attributed to L-glutamine use. But, patients with co-morbidities were not included in these clinical trials.

In phase I/II clinical trial, voxelotor has shown a substantial, durable, and rapid reduction in hemolysis in the limited number of patients. The affinity of oxygen, hemoglobin levels, and markers of hemolysis showed improvements in a dose-dependent fashion. The reduction in hemolysis was independent of hydroxyurea use. The maximum dose used was 1000mg. The adverse events in voxelotor groups were comparable to placebo without any safety concerns. In the phase III trial, an increased dose of 1500mg was used. The increased dosage of voxelotor has shown better outcomes as compared to low doses without causing any severe side effects.

Anemia was improved irrespective of baseline hemoglobin levels or the use of hydroxyurea. The improvement in hemolysis was consistent with the impact of voxelotor on HbS polymerization.

In phase I/II trial, vaso-occlusive episodes were seen in patients when they were not taking voxelotor, but the results were inconclusive. However, in the phase III trial, it was clear that the incidence of vaso-occlusive crisis episodes did not increase with voxelotor use. An abandoned SCD drug, senicapoc, was also a hemoglobin polymerization inhibitor. Senicapoc prevented polymerization by inhibiting Gardos channels of sickle cell RBC, which resulted in increased viscosity of blood and an increase in vaso-occlusive pain episodes [44] . In contrast, voxelotor acts by causing allosteric changes in hemoglobin, leading to increased affinity on sickle cell

RBCs. This mechanism does not lead to an increase in viscosity or increase in vaso-occlusive episodes. [22] . Also, no significant changes were observed in hemolytic variables between crizanlizumab and placebo.

The safety profile is comparable with crizanlizumab and placebo therapy. The incidence of serious infections was similar in crizanlizumab and placebo groups in both analyses. But the trial only included patients without any co-morbidity.

VOC episodes lead to multiple acute and chronic complications that are associated with increased mortality. Similarly, the improvement in hemolysis and hemoglobin level is crucial in preventing end-organ damage. Hemolytic anemia is associated with stroke, renal failure, silent infarcts, pulmonary hypertension, and early mortality. Therefore, all three drugs can decrease the mortality in SCD [45] [46] [47] . However, the completed trials did not assess the effect of these drugs on other complications, i-e., priapism, gall stones, nephropathy. Also, the trials did not assess the efficacy and safety in pregnancy or comorbid patients.

Trials on other drugs with a similar mechanism like prasugrel, sevuparin, rivipansel, and senicapoc have not shown any clinically significant improvements in SCD patients in phase II/III clinical trials [48] [49] [50] [51] .

L-glutamine, crizanlizumab and voxelotor did not significantly increase the treatment-related adverse events. The target of action of these drugs is also different from each other, so there is a possibility to add the three drugs together with hydroxyurea, especially for patients who experience sickle cell complications with a two-drug combination.

SCD drugs have low compliance due to the daily dosing schedule [39] . Crizanlizumab has the benefit of a single dose in 4 weeks that can increase the compliance of this drug. However, the drug can only be given in the form of a 30 minutes long infusion. The compliance for crizanlizumab can be increased if a simpler form of administration is formulated. In epidemics or pandemics like COVID-19, crizanlizumab can help reduce the number of pharmaceutical visits.

L-glutamine, voxelotor, and crizanlizumab, are almost 20-50 times more expensive than hydroxyurea that can be a hurdle in the extensive use of these drugs, especially in the case of crizanlizumab and voxelotor. Although the reduction in hospitalization can compensate for the expenses of these drugs, reduction in the cost of crizanlizumab and voxelotor is needed for these drugs to be used as primary treatment options for SCD [52, 53] . Haploidentical HSCT and gene therapy are currently under test, and a limited number of fully matched donors are available, the best possible treatment is pharmacological management with drug combinations. Gene therapy has the potential to become a major curative option for SCD patients in the future. Still, it will take a certain amount of time to train the professionals with new techniques, obtain long term outcomes and make gene therapy cost-effective and widely available.

With gene therapy and haploidentical HSCT still under experiment, pharmacological management is the best available treatment for patients who are unable to find matched HSCT donors. All three drugs, L-glutamine, voxelotor, and crizanlizumab, are well tolerated without any alarming adverse effects. L-glutamine was tested in ≥5 years old, voxelotor in ≥12 years old, and crizanlizumab in ≥16 years old participants. L-glutamine and crizanlizumab reduce the number of vaso-occlusive crisis episodes and hospitalizations, regardless of hydroxyurea use.

However, these two drugs do not improve hemoglobin levels. On the other hand, voxelotor improves hemoglobin levels and prevents hemolysis in SCD patients regardless of hydroxyurea use. In the trials on voxelotor, the increase in hemoglobin levels was not associated with an increased number of VOC episodes. More multicenter, randomized, double-blind clinical trials are needed to determine the efficacy and safety of these drugs in all age groups and participants with different health conditions.

Only one randomized clinical trial with low risk of bias was available. In the trials on Lglutamine and crizanlizumab, a significant number of participants left the treatment without reaching the end phase. Moreover, different clinical trials tested the efficacy and safety at different doses in a specific age group. Despite these limitations, our review is able to provide a comprehensive assessment of the efficacy and safety of L-glutamine, voxelotor, and crizanlizumab in sickle cell disease.

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gov Voxelotor OR GBT440 AND sickle cell anemia = 13 Crizanlizumab OR Seg101 AND sickle cell anemia = 7

Glutamine AND sickle cell anemia = 5