Sickle Cell Disease (SCD) is major health problem in Tanzania. Every year, approximately 11000 babies are born with SCD1, and this number is expected to double by the year 2050. Tanzania has the fourth greatest number of annual SCD births in all of Africa, and the fifth greatest in the world. In addition, almost 20% of the Tanzanian population carries a copy of the sickle gene in a form of sickle cell trait (AS). Despite these staggering statistics, Tanzania has made progress in the fight against SCD over the past decade. In 2008, the Ministry of Health and Social Welfare by then, recognized SCD as a priority disease in the National strategy for Non-communicable disease 2009- 2015, calling for all sector to cooperate in combating the disease. A chapter on SCD was also included in the national Non-communicable Disease Treatment Manual. Hydroxyurea is useful in the management of individuals with SCD. It reduces the complications of SCD in infants, children and adults based on its ability to: o Increase haemoglobin F levels o Increase steady state hemoglobin counts o Lower WBC and PLTs hence moderate the chronic inflammation state in SCD Indications for starting hydroxyurea:  All children 9 months and above with proven SCD  Adolescents and adults with the following: o Recurrent VOC ( 3 or more severe episodes requiring admission in the last 12 months) o Severe and/or recurrent ACS (2 or more episodes in a lifetime) o History of stroke or abnormal TCD (≥199cm/sec) o Severe symptomatic chronic anemia that interferes with daily activities or quality of life o To reduce the risk of new or recurrent stroke where chronic transfusion therapy is not feasible. o Recurrent priapism o Patient with chronic kidney disease on erythropoietin to improve anemia #SickleCell disease#Indications for Hydroxyurea#Hamisi Mkindi#CKD#Investigations:  FBP - absolute neutrophil count (ANC) > 1,500/µl, platelet > 100,000/ul, Hb> 6g/dl.  If Hb is less than 6gm/dl do Reticulocyte Count[Do not start hydroxyurea in patients with Hgb< 6 g/dl AND absolute reticulocyte count (ARC)<100,000/µL]  Serum Creatinine - should be within normal range,  Serum ALT – should not be greater than twice the upper limit of normal,  Bilirubin Total and direct  Urine Pregnancy Test in women  HPLC - Quantification of HbF (if this test cannot be done, Hydroxyurea should be prescribed nevertheless and an elevated baseline HbF should not affect the decision to initiate hydroxyurea)

1. JOURNAL CLUB
Presenter:
Dr.Hamisi Mkindi,PGY2

2. CLINICAL QUESTION
• In patients with sickle cell disease, does
voxelotor 1500mg increase baseline
hemoglobin of patients?

4. Abbreviations and Definition of terms
Hb – Hemoglobin
SCD-Sickle Cell Disease
SSA-Sub Saharan Africa
VOC-Vaso oclusive crisis
CKD-Chronic Kidney disease
Phtn-Pulmonary hypertension
MSH-Multicenter Study Hydroxyurea

5. INTRODUCTION-SCD

6. Introduction-SCD
• SCD-Qualitative hemoglobinopathy, resulting from point
mutation in both genes coding for beta chain1.
• Results in decreased solubility in deoxy-form results in
polymer formation-Sickling.
• >66% of the 120 million people affected worldwide by SCD
live in Africa(WHO).
• In Tanzania,every year approximately 11000 babies are born
with SCD, and this number is expected to double by the year
20504.
• 20% of the Tanzanian population carries a copy of the sickle
gene in a form of sickle cell trait.
4.Hamza S, Makani J et al

7. INTRODUCTION
• Despite these staggering statistics, Tanzania has made
progress in the fight against SCD over the past decade.
• Recognized SCD as a priority disease in the National strategy
for Non-communicable disease 2009- 2015.

8. INTRODUCTION
• The unmet needs of the sickle cell disease population
are substantial.
• Despite previously available therapies, individuals with
sickle cell disease can continue to have persistent
haemolytic anaemia2.
• Lower Hb concentrations and increased haemolysis are
associated with increased morbidity due to acute and
chronic complications.(CKD,Phtn,Stroke)3

9. INTRODUCTION
• Chronic medical complications and early death in
persons with sickle cell disease remain a substantial
burden.
• Increasing haemoglobin concentrations and reducing
haemolysis are therefore crucial in preventing
complications in patients with sickle cell disease3.

10. INTRODUCTION
• Current standard of care
Hydroxyurea.
-Potent ribonucleotide reductase
inhibitor,increases HbF.
Exchange transfusion.
Blood transfusion.
Regular folic acid.

11. VOXELOTOR
• Orally available modulator and stabilizor of sickle cell
hemoglobin
• Covalently binds to N terminal Valine of alpha chain
of hemoglobin S.

12. VOXELOTOR

13. MECHANISM OF ACTION-VOXELETOR

14. RATIONALE
• To evaluate the efficacy and safety of voxelotor, as
compared with placebo,in adolescents and adults
with sickle cell disease.

15. METHODOLOGY
Design and Participants
• The HOPE trial is an international, randomised,
doubleblind, placebo-controlled, phase 3 trial done at 60
clinical sites.
• Patients with confirmed sickle cell disease.
• Haemoglobin concentration of 5·5–10·5 g/dL at
enrolment, and who had between one and ten vaso-
occlusive crises in the previous 12 months.

16. ETHICAL CLEARANCE
Trial done in accordance with:
• The International Conference on Harmonisation for
Good Clinical Practice guidelines
• The principles of the Declaration of Helsinki,
and all applicable country-specific regulatory guidelines.
• Written informed consent was obtained from patients
before enrolment.
• The study protocol was reviewed and approved by an
independent ethics committee at each participating trial
site.

17. RANDOMIZATION AND MASKING
Patients were randomly assigned (1:1:1) to receive either:
• voxelotor 1500 mg od
• voxelotor 900 mg od
OR
• placebo for up
to 72 weeks/until withdrawal from the study
• All individuals involved in the direct conduct of the study
were masked to individual treatment assignment.

18. Procedures
• Patients were assessed at the screening visit, the
baseline visit,
• Every 2 weeks (up to week 8), every 4 weeks (up
to week 24),
AND
• Every 12 weeks (up to week 72).

19. Procedures…
• Safety was monitored at every assessment
throughout the 72-week treatment period.

20. Primary Outcome
• The proportion of patients with a
haemoglobin response at week 24;
Defined as the proportion of patients who
had a haemoglobin change from baseline of >1
g/dL

21. Secondary outcome
• Change in haemoglobin concentration from baseline at week 24
• The change in markers of haemolysis at week 24
• The annualised incidence of vaso-occlusive
crises by treatment group
• The incidence of severe anaemic episodes, defined as having
haemoglobin concentrations less than 5·5 g/dL at any time
during the trial

22. STATISTICAL ANALYSIS
• Efficacy analyses included all randomized patients
(intention-to-treat population).
• Change from baseline in haemoglobin concentration
over time was analysed by use of a regression model
for repeated measures.
• All statistical analyses were done with SAS, version
9.4

26. MEAN/PEAK Hb AT WEEK 72

30. DISCUSSION
• Among persons with SCD, the 1500-mg dose of voxelotor
increased HB levels and reduced the incidence of
worsening anemia as compared with placebo.
• No significant improvements in the hemoglobin levels of
the recipients were recorded by L‐glutamine and
crizanlizumab therapy in different trials4.

31. DISCUSSION
• The increase in hemoglobin level and
reduction in hemolysis occurred within 2 weeks after
initiation of the trial drug.
• A clear relationship was observed between voxelotor
exposure and all hematologic measures of efficacy,
including lactate dehydrogenase level and absolute
reticulocyte count.

32. • Mean haemoglobin concentrations of
approximately 10 g/dL throughout the duration of
the study was observed.
• An important finding given the graded inverse
association observed between haemoglobin
concentration and end-organ damage5 .
5.Ataga KI et al 2020

33. DISCUSSION
• The incidence of vaso-occlusive crisis did not
differ significantly among the trial groups.
• In those with severe SCD (hb <6g/dl) and on
voxelator use,time to 1st VOC was 6
months(AlDallal et al)
• With HU MSH phase iii trial-time to 1st VOC
was 3 mo

34. DISCUSSION..
• Persons with sickle cell disease have abnormally elevated
blood viscosity(Schmalzer EA.et al)
• The absence of an increased incidence rate of VOC with
voxelotor despite significant increases in the hemoglobin
level suggests that voxelotor raises hemoglobin levels
without negatively affecting blood viscosity.

35. DISCUSSION
• Most patients(>70%) who received voxelotor had their
ulcers resolve within 24 weeks.
• HU and chronic BT are available for treatment of SCD
• There are no clinical data from systematic and controlled
trials demostrating their efficacy in treatament of leg
ulcers.

36. STRENGTH
• The double-blinded, randomised, placebo-
controlled,international design of the study.
• The 72-week efficacy and safety results for voxelotor
constitute the longest registrational trial of recently
approved therapies for SCD.

37. LIMITATIONS
• Although the distribution of SCD genotypes was
generally balanced across the three treatment
groups, the Hb concentration analyses were not
adjusted for sickle cell disease genotype.

38. TAKE HOME MESSAGE
• We owe our patients with SCA the opportunity to enjoy
healthy and productive lives with good quality.
• Voxelotor use provides significant, durable increases in
Hb concentrations and reductions in markers of
haemolysis and a favourable safety profile.
• Long-term use is appropriate to treat haemolytic
anaemia, thereby potentially mitigating the morbidity
and mortality of sickle cell disease

39. REFERENCES
1.Piel FB, Steinberg MH, Rees DC. Sickle
cell disease. N Engl J Med 2017;376:1561-73.
2.Kato GJ, Piel FB, Reid CD, et al. Sickle
cell disease. Nat Rev Dis Primers 2018;4:18010.
3.Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease.
Lancet 2017;390:311-23.
4.DeBaun MR, Armstrong FD, McKinstry RC, Ware RE, Vichinsky E, Kirkham
FJ. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood 2012;119:4587-96
5. Ataga KI, Gordeuk VR, Agodoa I, Colby JA, Gittings K, Allen IE.
Low hemoglobin increases risk for cerebrovascular disease, kidney
disease, pulmonary vasculopathy, and mortality in sickle cell
disease: a systematic literature review and meta-analysis
6.Gladwin MT. Cardiovascular complications and risk of death in sickle-cell
disease. Lancet 2016;387:2565-74.
7.Kato GJ, Steinberg MH, Gladwin MT.
Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin
Invest 2017;127:750-60.