Sickle cell disease (SCD) is a genetic disorder in which deoxygenation produces polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing significant end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis) and other clinical complications that are under-recognized, under-treated, and associated with early death. GBT440 is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, thereby inhibiting hemoglobin polymerization. GBT440-007 is a Phase 2a study designed to assess the safety, pharmacokinetics (PK) and efficacy of GBT440 in pediatric SCD patients (HbSS or HbSβ0 thalassemia). This abstract reports the first evaluation of multiple doses of GBT440 in adolescents (12 to 17 years) with SCD. Methods: This ongoing study is being conducted in 2 parts, Part A: single dose of GBT440 at 600 mg in pediatric patients (6 to 11 years) and adolescents (12 to 17 years) and Part B: multiple doses of GBT440 at 2 dose levels, 900 mg/d and 1500 mg/d for 24 weeks in adolescents (approximately 12 patients at each dose). Part A PK data in adolescents was previously reported. The primary objective of Part B is to assess the effect of GBT440 on anemia. Secondary objectives include effect on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial Doppler ultrasound (TCD), daily SCD symptoms using a patient-reported outcome (PRO) measure and safety. The PRO Sickle Cell Disease Severity Measure (SCDSM) was developed following FDA guidance as a clinical outcomes assessment. Results: Enrollment in Part B of the 900 mg cohort is complete. As of 21July2017, 13 patients (7 females) have received GBT440 for up to 12 weeks. The median age was 13 years (range 12 to 17 years) and median weight 52 kg (range 30 to 96 kg); 92% were on hydroxyurea (HU); 38% had 2 or more painful crises (range 2 to 8) in the year prior to enrollment. Data for measures of hemolysis and TCD are available for 4 patients who received GBT440 for 12 weeks; all were receiving HU at study entry. Three of the 4 patients achieved hemoglobin (Hb) response of > 1 g/dl increase; one patient had a smaller Hb increase with documented non-adherence with study medication and associated lower GBT440 exposures. Clinical measures of hemolysis improved concordantly; median reduction in reticulocytes and indirect bilirubin were 34% and 27% respectively, consistent with previously reported results of GBT440 in adults with SCD. Preliminary data following multiple doses of GBT440 suggest that the PK in adolescents were similar to those observed in adults with SCD. Baseline TCD velocity ranged from 89 to 150 cm/s in 13 patients. One patient at 12 weeks had a decline in TCD velocity from baseline of 22 cm/s, and 3 patients showed small reductions. Empirical distribution functions of the SCDSM questionnaires indicate total symptom scores (TSS) trended lower post dose in comparison to screening . All treatment-related adverse events (AEs) were Grade 1 or 2 and there were no treatment- related serious adverse events or no drug discontinuations due to AEs. The most common treatment emergent AEs were Grade 1 nausea and diarrhea reported in 2 patients. Abstract source

Growth failure has been a well-known complication of sickle cell disease (SCD) since the 70s. More recent studies show that the proportion of underweight children with SCD has decreased significantly, thanks to modern treatments (in particular hydroxyurea and iterative transfusions), with a tendency towards overweight and even obesity. However, most studies have been carried out in high-income countries, while 80% of the affected children are born in sub-Saharan Africa, where the environment and the medical care are entirely different. We carried out a case-control study nested in a multinational African cohort to study the growth of sickle cell children and the possible factors influencing growth failure. Methods: We performed a case-control transversal study nested in the CADRE cohort that includes SCD patients from five African countries: Cameroon, Gabon, Côte d'Ivoire, Mali and Senegal. All children aged 5 to 21 years-old from this cohort were included in our study. Healthy controls were recruited among the patients’ siblings or the children of health workers from each center. The main parameters studied were: medical history, height, weight, blood pressure; hemoglobin phenotype (SS, Sβ0, SC or Sβ +); complete blood count; hemolysis markers (LDH and bilirubin); microalbuminuria; echocardiographic parameters. The primary endpoint was growth failure, defined as a weight, height or BMI below the 5th percentile of the WHO growth charts. We described the frequency of growth failure according to hemoglobin phenotype, age and sex. Then we assessed by multivariate logistic regression in two SCD phenotypic groups (SS or Sβ0 and SC or Sβ +) the association between growth failure and the biological characteristics or the history of SCD-related complications. Conclusion: In sub-Saharan Africa, growth failure occurs in more than half of the SCD children and concerns weight more than height. Its prevalence is particularly high in SS or Sβ0 patients and during adolescence, due to pubertal delay. Growth failure in SCD children is associated with male sex, anemia and high hemolysis markers independently of the hemoglobin phenotype, but is not independently associated with the occurrence of acute or chronic vascular complications of sickle cell disease, apart from microalbuminuria. However, the long-term consequences of growth failure in sickle cell disease should be evaluated in a longitudinal study. Abstract source

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