Sickle Cell Disease oral posters from ASH

In this article, we will share with you the most important results of the American Hematology Society (ASH) oral poster results.

Characterization of Two Anti-P-Selectin Monoclonal Antibodies (mAbs): Crizanlizumab Shows Comparable or Stronger Effects Versus Inclacumab across Cell Adhesion Assays in Vitro

While the SPR/Biacore data suggested higher P-selectin binding affinity for inclacumab compared with crizanlizumab, there was a stronger inhibition of P-selectin-mediated cell adhesion with crizanlizumab vs inclacumab in other well-characterized functional in vitro assays. The data from healthy volunteers will be complemented by data from SCD patients for the WBA and PLA assays. Ultimately, clinical data are required to evaluate potential differences in the profiles and efficacy of crizanlizumab and inclacumab as treatments for SCD patients.

Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports

Although rare, based on review of PM data, healthcare professionals should be aware of the possibility of IRRs presenting as pain events during or after any crizanlizumab infusion. Crizanlizumab labels have been/are being updated by Novartis to provide information on monitoring for S/S of IRRs presenting as pain events, and guidance on management/prevention of subsequent IRRs, including a statement recommending caution when using corticosteroids in SCD pts. Given the limited data regarding IRRs and predictability of complications, Novartis is committed to further understanding these events.

Crizanlizumab Therapy Is Associated with Lower Levels of Circulating Extracellular Vesicles in Sickle Cell Disease Patients

Crizanlizumab therapy may modulate EV levels in the plasma of SCD patients and provide, for the first time, data to support exploring the use of extracellular vesicles as biomarkers to monitor the clinical response to this drug in patients. Further studies on EV expression of P-selectin and how crizanlizumab interacts with EVs and platelets may help clarify this particular effect of this drug.

12 Initial Safety and Efficacy Results from the Phase II, Multicenter, Open-Label Solace-Kids Trial of Crizanlizumab in Adolescents with Sickle Cell Disease (SCD)

Initial analysis of SOLACE-kids shows crizanlizumab 5.0 mg/kg is safe and well tolerated in pts aged 12–<18 yr, consistent with the established profile of crizanlizumab in adult pts. No new safety signals were identified. Compared with BL, crizanlizumab 5.0 mg/kg treatment led to a median reduction of 1 VOC leading to a HC visit/year in this pt population.

Pharmacokinetics of L-Glutamine (Endari) in Pediatric and Adult Sickle Cell Disease Patients: A Phase 4, Open-Label, Single-Center Study

This is the first multi-dose PK study of L-glutamine (Endari) for SCD. Daily dosing was overall well-tolerated, with rapid absorption of 0.1 and 0.3 g/kg doses and no drug accumulation. The highest 0.6 g/kg dose was limited by palatability and featured slower and saturable absorption, so further dose escalation is likely not feasible. Ongoing analyses include possible food-drug interactions and PK-pharmacodynamic (PK-PD) studies to identify salutary effects on erythrocytes. Our findings will help inform the proper dosing of L-glutamine for patients with SCD, and potentially permit individualized PK-guided dosing to maximize treatment benefits.

The Evaluation of Transfusion Data from the Phase 3 Clinical Study of L-Glutamine in Sickle Cell Disease

The post-hoc analyses of the L-glutamine phase 3 clinical study in SCD indicated that, of patients requiring RBC transfusions, those assigned to L-glutamine required approximately 43% fewer units of RBCs compared to those assigned to placebo over the 48-Week period. The recurrent event-time analysis showed a favorable trend in the fewer number of RBC transfusion episodes for those receiving L-glutamine as compared to placebo. These observations are significant when considering the fact that 66% of participants in both arms of this study were on hydroxyurea therapy.

A Method to Measure Voxelotor Exposure in People with Sickle Cell Disease Using Capillary Zone Electrophoresis

Using the following equation (uM voxelotor = -99.13 + 7.10*%HbF +12.52*%VarA2), can be used to detect the presence of voxelotor and estimate its whole blood concentration. This will allow clinicians to have a better understanding of how their patients are using voxelotor. Additionally, higher calculated whole blood concentrations correlated with higher increases in Hb. It was previously shown that patients who receive higher doses of voxelotor have on average larger increases in Hb. If it could be shown that increasing concentration in an individual on voxelotor is associated with an increased Hb for that individual, then our method could also be used to help clinicians select and adjust doses of voxelotor in a similar manner to how HbF is used in hydroxyurea dosing.

Long-Term Safety and Efficacy of Voxelotor for Patients with Sickle Cell Disease: Results from an Open-Label Extension of the Phase 3 HOPE Trial

In this OLE study, treatment with voxelotor 1500 mg resulted in improvements in Hb and clinical measures of hemolysis at 48 weeks in patients who received placebo in the HOPE trial. Treatment with voxelotor 1500 mg showed durability of response in patients previously treated with voxelotor of any dosage in the HOPE trial. The safety profile in the OLE was consistent with the findings from the HOPE trial, and no new safety signals were identified with exposure through a combined 144 weeks of treatment. Based on these results, long-term use of voxelotor is safe, well tolerated, and effective in reducing anemia and hemolysis, with a low rate of VOCs, in patients with SCD.

Real-World Experience of Voxelotor for the Management of Complications in Sickle Cell Disease

In real-world practice, voxelotor increased Hb by ≥1 g/dL, consistent with the HOPE trial. Data suggest statistically significant reductions in transfusions, VOCs, all-cause and VOC-related hospitalizations after voxelotor use. This real-world evidence provides additional support for the use of voxelotor in the treatment of hemolytic anemia and the management of its associated complications.

Model-Predicted Clinical Factors Impacting Patient-Specific Response of Sickle Cells to Voxelotor in a Microfluidic Platform

The analysis quantified patient-specific differences in the blood flow response to voxelotor, showing a wide variability in response despite treatment by the same drug concentration. Genotype-specific multivariable models that take into account easily measurable clinical variables such as the CBC have the potential to explain the variability in patient response to voxelotor treatment. In HbSC samples, the WBC, platelet, and reticulocyte counts were highly correlated and strong predictors of response to voxelotor, which may point to markers of hemolysis and inflammation being useful in determining patients that can be optimally treated with this drug. In HbSS, response to voxelotor was mainly inversely correlated with HbA levels, which is a surrogate marker for blood transfusions, indicating that the effect of voxelotor is lessened for patients who are receiving transfusions. However, the low R2Y of this model highlights the clinical variability in this SCD genotype and consequent need for additional biomarkers of disease severity. In conclusion, our hybrid experimental-computational approach is able to identify clinical factors that highly impact the response of patient blood samples to treatment with voxelotor for HbSC patients, and highlights the need for precision therapy recommendations in SCD.

Real-World Experience of Patients with Sickle Cell Disease Treated with Voxelotor: A Multicenter, Retrospective Study

RETRO is the first multicenter, retrospective study to examine the real-world effectiveness of voxelotor and describe the observed changes in laboratory and clinical outcomes after ≥2 weeks of therapy. This study shows that voxelotor treatment was associated with increased Hb levels and decreased hemolytic markers. The safety data are consistent with those from the HOPE trial. Further evaluation is needed, with additional data from all 10 sites, and will be presented later.

To learn more about SCD, click here.