Rate Of Vaso-occlusive Crises Research Articles

Clinical Burden and Health Care Resource Utilization Associated With Managing Sickle Cell Disease With Recurrent Vaso-occlusive Crises in England

PurposeSickle cell disease (SCD) is an inherited red blood cell disease caused by a mutation in the gene encoding the β-subunit of adult hemoglobin that leads to hemolysis, anemia, vaso-occlusive crises (VOCs), morbidity, and mortality. This study provides a real-world assessment of the clinical burden and health care resource utilization (HCRU) associated with SCD with recurrent VOCs in England. MethodsThis retrospective study linked primary care records from the Clinical Practice Research Datalink database with secondary care records from the Hospital Episode Statistics database to identify patients with SCD with recurrent VOCs between July 1, 2008, and June 30, 2018. A VOC was defined as SCD with crisis, acute chest syndrome, or priapism. Eligible patients had SCD, ≥2 VOCs/year in any 2 consecutive years after a diagnosis of SCD, and ≥1 year of follow-up data from the index date. Patients were exact matched with 5 controls from the general population in the databases. Demographics were assessed at index. Mortality, clinical complications, and HCRU were summarized during follow-up. FindingsAfter applying eligibility criteria, 1117 patients with SCD with recurrent VOCs and 5585 controls were included in the study. Mean age at index was 25 years in both groups. The proportion of deaths (3.67% vs 0.68%; P < 0.001) and mortality rate (0.78 deaths per 100 person-years vs 0.16 deaths per 100 person-years) were substantially higher in patients with SCD with recurrent VOCs versus matched controls. Mean (standard deviation [SD]) age of death in patients with SCD with recurrent VOCs who died during the follow-up period was 40.17 (14.09) years. The mean (SD) rate of VOCs for patients with SCD with recurrent VOCs was 5.84 (12.50) per patient per year (PPPY) during follow-up. Compared with matched controls, patients with SCD with recurrent VOCs had substantially higher mean [SD] rates PPPY of inpatient hospitalizations (7.59 [14.50] vs 0.32 [2.71]), prescriptions (31.06 [60.62] vs 7.58 [27.77]), and outpatient visits (9.60 [10.69] vs 1.78 [4.18]). Older patients and those with increased numbers of VOCs had increased mortality, frequency of clinical complications, and HCRU. ImplicationsDespite currently available care, patients with SCD with recurrent VOCs in England have increased mortality, substantial clinical complications, and significant HCRU driven by VOCs and hospitalizations. Elevated mortality and clinical complications in patients with SCD with recurrent VOCs highlight the need for novel therapies in this space.

Crizanlizumab in adult patients with sickle cell disease: a retrospective German analysis

IntroductionThe marketing authorization for crizanlizumab (Adakveo®), indicated for the prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell patients (pts) aged ≥16, was revoked by the European Medicines Agency (EMA) as the STAND study did not demonstrate a significant difference between crizanlizumab and placebo in annualized rates of VOCs.MethodsThis is a retrospective, monocentric analysis of adult pts with sickle cell disease (SCD) (age (median) 29 years, range 19-42, annual VOC rate 3, range 1-5, homozygous SCD (HbS/S) 50.0% (4/8)) receiving crizanlizumab as monotherapy at the University Hospital of Essen between Dec 2020 to May 2023 (observation time (median) 17.5 months, range 4.8-27.3). The results were compared to hydroxycarbamide (HC)-treated pts at maximum tolerated dose (MTD).ResultsAt 6, 9, and 12 months, mean VOC rate was 1.5 (range 0-3; N=6), 1.8 (range 0-3; N=5) and 4.0 (range 3-5; N=3), indicating a time-dependent increase in VOCs in crizanlizumab-treated pts (6-9 months: p=0.039; 6-12 months: p=0.008) (mean VOC rate in HC-treated pts: 6 months: 0.38, range 0-1 (N=8); 9 months: 0.50, range 0-2 (N=8); 12 months: 0.63, range 0-3 (N=8)). Serious adverse events were mandatory in 7 pts, resulting in 12 inpatient-admissions (acute chest syndrome (N=2), VOC-related pain crisis (N=9), infusion-related VOC (N=1)).ConclusionThese findings, together with the high economic burden of crizanlizumab in contrast to HC, do further support the revocation of crizanlizumab in Europe in our opinion. Physicians should consider the potential risks when making a therapeutic decision regarding the use of crizanlizumab outside of Europe.

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease: final results from the phase II SOLACE-adults study.

Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD). The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD. Phase II, single-arm, multicenter study. Patients with SCD aged 16-70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially. Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was -0.79 (-3.04, 2.01) in the 5.0 mg/kg group and -0.98 (-1.11, -0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab. Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs. NCT03264989.

Outcomes of Children with Sickle Cell Disease Born Outside Belgium Remain Different Compared to Those Born in Belgium Despite Similar Management

Sickle cell disease (SCD) is characterised by a multitude of phenotypic expressions that are influenced by the environment and genetics. The only well-established treatments are infection prevention, hydroxyurea (HU), chronic transfusions, and hematopoietic stem-cell transplantation (HSCT). Early strategies facilitated by neonatal screening programmes improve morbidity and mortality. In the context of an increasingly multiethnic society, not all our patients benefit from early intervention. This study aims to evaluate the overall outcomes of children with SCD born in Belgium (BiB) compared to those born outside Belgium (BoB) and receiving the same treatment upon arrival in Belgium. This cohort study is based on anonymized data extracted from the Belgian National Sickle Cell Registry (BNSCR). Prospective data were collected from the date of diagnosis (start of follow-up (FU) for BoB) until the last FU visit or death. Were included in this study: all SCD children born between 01.01.2000 and 31.12.2018, followed at the Hôpital Universitaire des Enfants Reine Fabiola till 31.12.2020 and registered in the BNSCR. Clinical and hematological data are compared between both groups. A total of 245 patients were identified, of which 186 BiB and 59 BoB (all born in Africa). No statistically significant differences were found in terms of sex, parents' origin and genotype between the two groups. The median age at diagnosis/start FU was significantly higher in BoB-patients while the median duration of FU was not statistically different in both groups. Expressed by 100 patient-years (PY), the rate of vaso-occlusive crises (VOC) was significantly higher in BoB-patients while the rate of acute chest syndrome was not (Table 1). BoB had significantly less acute anemic episodes and a trend toward less splenic sequestration. The rate of severe infections, stroke and death was similar in both groups (Table 1). At start of FU, BoB patients had a significantly higher neutrophil count (PMN) and lower fetal hemoglobin (HbF) while other hematological parameters didn't differ from BiB The prescribed rate of HU and the rate of HSCT was similar in both groups. However, BoB-patients were significantly older at the start of HU treatment or at the time of the HSCT (Table 1). Hematological values between BoB and BiB-patients after HU did not differ. Nevertheless, PMN and Hb levels seem to be higher in BoB-patients without reaching statistical significance (Table 2). BoB-patients have a median delay of 2 years to access to a comprehensive care program dedicated to SCD. At the same time, this group is 1.5-fold as likely to develop a VOC during FU. No clear explanation exists, but the start of HU at an older age might have an impact with reduced HbF response at distance of the physiological switch of Hb as observed in the BoB-group. In addition, children born in Africa are submitted to a different environment with a higher inflammatory burden as suggested by their higher PMN count at diagnosis. So far, the impact of early inflammation on the long-term outcome is not known and need to be investigated. These points could not be evaluated in this study. The BoB-group's lower rate of acute anemia and splenic sequestration is explained by the older age at start of FU as these potentially lethal complications occur in very young children and could not be recorded from birth of the BoB-group. This also raises the question of the bias presented by our BoB-patients as they don't represent the SCD population from the country they originate: 1) they survived infancy and early childhood, 2) they come from families economically privileged enough to finance the travel to Belgium. In conclusion, the outcomes between BiB and BoB-patients remain different even though the latter benefits from the same comprehensive care. It would be interesting to explore whether a deeper understanding of the underlying physiopathology in terms of genetics, inflammation/immunity, and nutritional status, could clarify the differences observed between our groups. A longer FU of the Registry will help enhance our findings.

A Phase 2, Open-Label Study to Assess the Pharmacokinetics, Pharmacodynamics and Safety of Orally Administered Epeleuton in Patients with Sickle Cell Disease

Background. Sickle cell disease (SCD) is a rare hereditary multi-system disorder that is caused by a single mutation in the beta allele of the hemoglobin gene, leading to the production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, resulting in red blood cell (RBC) sickling and membrane damage, ultimately leading to a cascade of events which include hemolysis, chronic anemia, inflammation, and vaso-occlusion. Despite recent progress, there is a need for additional disease-modifying therapeutic options. Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester, a novel synthetic second generation w-3 fatty acid which targets key drivers of hemolysis and multicellular adhesion. In preclinical studies in Townes humanized SCD mice and SCD patient RBCs, epeleuton acts as a disease-modifying agent by simultaneously decreasing (a) systemic and local inflammatory activation, (b) endothelial adhesion, (c) organ damage and (d) intravascular hemolysis and sickling. Epeleuton has been administered to 343 subjects in clinical trials, with a favorable safety and tolerability profile. Objective To evaluate the pharmacokinetics, pharmacodynamics and safety of orally administered epeleuton in patients with SCD. Study Design and Methods. This open-label, phase 2, multicenter study (NCT05861453) will enroll approximately 30 adult patients with a confirmed diagnosis of SCD (HbSS and HbSß0-thalassemia). Participants must have hemoglobin levels of 5.0-9.5g/dL at screening, 2-10 vaso-occlusive crises (VOCs) in the past 12 months, and a high adhesion index at screening defined as RBC laminin adhesion &amp;gt; 400 cells. Concomitant treatment with a stable dose of hydroxyurea is permitted during the study. Key exclusion criteria include receiving an RBC transfusion within three months of enrolment, receiving voxelotor, crizanlizumab or l-glutamine within six weeks of enrolment and, prior hematopoietic stem cell transplant. The trial has a 28-day screening period, followed by a 16-week treatment phase and a 30-day post-treatment follow-up period. Study participants will attend the clinic on 6 occasions at screening, baseline, weeks 4, 8 and 16 (end-of-treatment) and the week 20 post-treatment follow-up visit. Enrolled patients will receive epeleuton 2g BID (4g daily) for 16 weeks. Study endpoints include change from baseline in hemoglobin levels, hemolytic markers, assessments of RBC health, soluble adhesion molecules, RBC adhesion, whole blood adhesion and rates of VOC. Conclusion: Treatments that can simultaneously target hemolysis and cellular adhesion may have an important disease-modifying utility for patients with SCD. The results of this study are anticipated to confirm the potential of epeleuton to address multiple aspects of SCD and to guide the design and conduct of future studies in patients with SCD.

1307. Vaso-occlusive Crisis is Associated with Subsequent Osteomyelitis in Pediatric Sickle Cell Disease

Abstract Background Children with sickle cell disease (SCD) commonly develop microvascular infarcts of bone known as vaso-occlusive crisis (VOC) and are also at high risk of osteomyelitis (OM). VOC and OM can be challenging to distinguish due to overlapping clinical features. VOC might predispose to OM, or an initial misdiagnosis of OM as VOC might lead to delayed diagnosis of OM. This study aimed to test whether VOC was associated with subsequent development of OM in children with SCD. Methods A retrospective Pediatric Health Information System (PHIS) database study (2010-2021) was performed. ICD-code data related to common diagnoses in pediatric patients with SCD were extracted. The rate of VOC within 30 and 180 days preceding episodes of OM was compared to the rate preceding acute chest syndrome (ACS), another common diagnosis in children with SCD but unlikely to be anatomically related to OM. Odds ratios (OR) were used to evaluate the association between these diagnoses. Results Of 22,818 PHIS participants with SCD, 13,699; 450; and 7,327 had ≥ 1 episode of VOC, OM and ACS, respectively. The distribution of OM diagnoses was similar across pre-specified age groups (0-4, 5-12, and 13-18 years). The odds ratio of VOC preceding a diagnosis of OM vs. ACS was 2.15 within 30 days (95% CI: 1.82-2.54; p= 3.68 x 10-18), and within 180 days was 1.39 (95% CI: 1.20-1.62; p=2.04 x 10-5). VOC Preceding Osteomyelitis vs. Acute Chest Syndrome Conclusion VOC was significantly more common in the days preceding a diagnosis of OM than of ACS. The strength of association was stronger within 30 days prior to OM than 180 days. These results suggest possible misdiagnosis of OM since VOC might delay OM diagnosis in some cases, that recurrent VOC might be misdiagnosed as OM, or that VOC can directly contribute to risk of OM in some cases. Limitations of this study include possible incomplete adjustment for unmeasured variables which could confound the analysis. More research is needed to confirm and evaluate the mechanism behind this association. Understanding the relationship could lead to improved screening and treatment of both VOC and OM. Disclosures Joshua Wolf, MBBS, PhD, Karius Inc.: Grant/Research Support|Merck Inc.: Participation in industry-sponsored research Sandra Arnold, MD, Contrafect: Grant/Research Support|Enanta: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support

Over 4 Years of Safety and Efficacy with Voxelotor Treatment for Patients with Sickle Cell Disease: Updated Results from an Open-Label Extension of the Phase 3 HOPE Trial

Introduction: Sickle cell disease (SCD) is an inherited blood disorder caused by a homozygous or compound heterozygous mutation in the hemoglobin (Hb) subunit β gene, leading to sickle hemoglobin (HbS). Polymerization of HbS results in red blood cell sickling/damage and leads to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Hemolysis and low Hb put patients with SCD at risk of end-organ damage, increased morbidity, and early mortality. Voxelotor, a first-in-class HbS polymerization inhibitor, is approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. In the phase 3, randomized, placebo-controlled HOPE trial (NCT03036813), significantly more patients (aged ≥12 years) treated with voxelotor 1500 mg achieved a &amp;gt;1 g/dL Hb increase vs placebo (89% vs 25%, respectively) at any time up to Week 72. Hb increases were associated with reductions in markers of hemolysis (indirect bilirubin, reticulocyte percentage, and lactate dehydrogenase). To assess the safety and efficacy of long-term voxelotor use, we report an updated interim analysis of an open-label extension (OLE) of the HOPE trial. Methods: Patients who completed the HOPE trial were eligible to enroll in the multicenter, global OLE study (NCT03573882) and receive ongoing treatment with once daily voxelotor 1500 mg if they continued to derive clinical benefit and/or until voxelotor was available via an alternative source. Adverse event (AE) data were collected through 28 days after voxelotor discontinuation, and measurements of Hb and clinical markers of hemolysis were summarized through 168 weeks of treatment in the OLE. Central laboratory assessments were used for the US and Europe through Week 48; local laboratory assessments were used for the rest of the world throughout the study. The annualized rate of VOCs was calculated from events reported as sickle cell anemia with crisis or acute chest syndrome. Data presented are based on an interim data cut (Dec 31, 2022). Results: Of 199 patients who completed the HOPE trial, 178 (89.4%) were enrolled and dosed in the OLE. Median age at enrollment was 25 years (15.7% adolescents, 84.3% adults). At data cutoff, the median (range) duration of voxelotor exposure the OLE was 124.0 (1.9-205.9) weeks, and 81 patients were treated for ≥168 weeks. Of these 81 patients, 52 had previously received voxelotor in the randomized part of the study, for a combined duration of exposure of ≥240 weeks (4.6 years). In 17 patients previously treated with placebo who remained on study through 168 weeks, the mean (SD) Hb change from baseline (start of OLE) was 1.1 (1.51) g/dL. The mean (SD) Hb change from baseline for patients who previously received voxelotor 1500 mg was 0.5 (1.49) g/dL (n=18), indicating durability of response. Markers of hemolysis improved from baseline to 168 weeks in patients who received placebo in the HOPE trial (median decreases of 44.3% in indirect bilirubin [n=19] and 52.3% in reticulocyte percentage [n=14]). Patients who received 1500 mg voxelotor in the HOPE trial showed a stable response at Week 168 (median decreases of 25.2% in indirect bilirubin [n=17] and 53.3% in reticulocyte percentage [n=17]). The annualized incidence rate of VOCs was 1.1 (95% CI: 1.0-1.2) events per year across all patients. A total of 157/178 patients (88.2%) reported a non-SCD-related treatment-emergent AE (TEAE); the most commonly reported TEAEs were arthralgia, headache, pain in extremity, and upper respiratory tract infection (Table). Many TEAEs were reported during the COVID-19 pandemic; most were grade 1 or 2 in severity. AEs that led to treatment discontinuation occurred in 16 patients (9.0%). Eight deaths occurred, none deemed related to voxelotor treatment. Conclusions: In this updated analysis from the HOPE OLE,treatment with voxelotor 1500 mg resulted in improvements in Hb and clinical markers of hemolysis at Week 168 in patients who received placebo in the HOPE trial. Treatment with voxelotor 1500 mg showed durability of response in patients who received voxelotor in the HOPE trial. The safety profile in the OLE was consistent with findings from the HOPE trial, and no new safety signals were identified with exposure through a combined 240 weeks of treatment. Long-term use of voxelotor was well tolerated and effective at maintaining reductions in anemia and hemolysis, with a low rate of VOCs, in patients with SCD.

Efficacy, Safety, and Biomarker Analysis of 5 Mg and 7.5 Mg Doses of Crizanlizumab in Patients with Sickle Cell Disease: Primary Analyses from the Phase III STAND Study

Background: Crizanlizumab, a selective, humanized immunoglobulin G2 kappa anti-P-selectin monoclonal antibody, demonstrated positive clinical activity and general tolerability in patients (pts) aged ≥16 years (yrs) with sickle cell disease (SCD) in a phase II SUSTAIN trial at a dose of 5 mg/kg when compared to placebo (PBO). This primary analysis (cutoff: August 31, 2022) from the ongoing multicenter (at 65 sites in 21 countries), Phase III STAND study (NCT03814746) included the comparison of the efficacy, safety, and expression levels of biomarkers, of crizanlizumab (5 &amp; 7.5 mg/kg) vs PBO, over 1-year post randomization, in adolescent and adult pts with SCD. Method: Pts aged ≥12 yrs, with a history of ≥2 vaso-occlusive crises (VOCs), with/without concomitant treatment with hydroxyurea/hydroxycarbamide were randomized (1:1:1) to receive intravenous crizanlizumab 5 mg/kg, 7.5 mg/kg, or PBO, on Day 1 of weeks (wks) 1 and 3, followed by every 4 wks in addition to standard of care therapy. Adverse events (AEs) were evaluated based on MedDRA version 25.1 and severity on CTCAE v5.0. Levels of biomarkers such as soluble P-selectin (sPsel), were evaluated. Results: Overall, 252 SCD pts were enrolled: 85, 84 &amp; 83 pts received PBO, crizanlizumab 5 &amp; 7.5 mg/kg respectively. Mean (SD) age of pts was 27.8 (12) yrs, 54 (21.4%) were adolescents, and 139 (55.2%) were females. Treatment was discontinued in 27 (31.8%), 18 (21.4%), and 15 (18.1%) pts in PBO, crizanlizumab 5 &amp; 7.5 mg/kg arms, respectively, primarily due to pts' (n=30) and physicians' decisions (n=8). Protocol deviations (n=97) were comparable across all arms; deviations due to COVID-19 (n=80) were mostly attributed to missed visits and assessment/procedure changes during lockdown/quarantine of pts. Rate ratios of adjusted annualized rates of VOCs leading to healthcare visits, with crizanlizumab 5 &amp; 7.5 mg/kg vs PBO, were 1.08 (95%CI: 0.76, 1.55; P&amp;gt;0.999) and 0.89 (95%CI: 0.62, 1.27; P&amp;gt;0.999), respectively, indicating no statistically significant difference (Table 1A). Mean (SD) annualized rates of VOCs leading to healthcare visits were similar across PBO (2.1 [2.8]), 5 mg/kg (2.5 [3.0]), and 7.5 mg/kg (1.9 [2.3]) arms. Rate ratios of the adjusted annualized rates of VOCs managed at home and/or leading to a healthcare visit, with crizanlizumab 5 &amp; 7.5 mg/kg vs PBO, were 1.21 (95%CI: 0.87, 1.70) and 0.83 (95%CI: 0.59, 1.17), respectively, suggesting no statistically significant difference (Table 1B). Overall, AEs were reported in 77 (90.6%), 74 (88.1%), &amp; 77 (92.8%) pts with PBO, crizanlizumab 5 &amp; 7.5 mg/kg, respectively (Table 2), the most common being, pyrexia (22 [25.9%], 22 [26.2%], 19 [22.9%]), COVID-19 (17 [20.0%], 18 [21.4%], 27 [32.5%]), and headache (16 [18.8%], 21 [25.0%], 13 [15.7%]). Serious AEs (SAEs) and grade ≥3 AEs were less frequent with PBO (30.6%, 31.8%) and crizanlizumab 7.5 mg/kg (26.5%, 38.6%) than with 5 mg/kg (41.7%, 56.0%). Among AEs of special interest, infections, and infusion-related reactions (all categories) were the most frequent (Table 2). Treatment-related SAEs and AEs leading to discontinuation were rare (&amp;lt;4% pts, all arms). None of the 6 fatal SAEs were related to treatment. Levels of free and total sPsel were measured across time: At Wk 3 Day 1, free sPsel showed a relative change from baseline in geometric mean (CV%, range) of 1.01 (56.2, 0.201-7.37) with PBO vs 0.05 (88.9, 0.00507-0.225) and 0.06 (68.4, 0.0146-0.208) with 5 &amp; 7.5 mg/kg doses, respectively. Relative change from baseline in total sPsel remained close to 0% in the PBO arm at different study visits, while it increased in treatment arms from Wk 3 Day 1 onward, plateauing at Wk 15 Day 1. Conclusion: Unlike the previous phase II PBO-controlled SUSTAIN study, the STAND study did not demonstrate superiority of crizanlizumab (5 or 7.5 mg/kg) over PBO on its primary and key secondary efficacy endpoints, in pts aged ≥12 yrs. These results differ from the previous study results and may be due to various factors, such as geographic differences in healthcare utilization as well as the low VOC rates in all arms, possibly either due to selection of pts with less severe disease, or, more likely due to the lower reporting of VOCs during the pandemic. The safety results were consistent with the known safety profile of crizanlizumab in SCD pts with no new safety concerns. Both treatment arms showed reductions in free sPsel vs PBO, demonstrating crizanlizumab activity on this biological parameter.

Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease: Final Interim Analysis Results from the Phase 2 Solace-Adults Study

Background: Acute painful vaso-occlusive crises (VOCs), the hallmark of sickle cell disease (SCD), are associated with chronic and potentially life-threatening complications. The SOLACE-adults study (NCT03264989) interim analysis (cutoff date: August 1, 2020) demonstrated the long-term pharmacokinetic (PK) and pharmacodynamic (PD) properties, potential sustained efficacy (VOC reduction), and long-term safety of crizanlizumab 5 mg/kg and 7.5 mg/kg during ≥12 months' (mo) treatment in &amp;gt;80% of patients (pts) with SCD [Kanter J et al . Blood advances 2023]. Here we report the updated PK/PD, including ex vivo P-selectin inhibition, safety, and efficacy results from the final interim analysis of this study (cutoff date: June 1, 2022) for all pts who received crizanlizumab 5 mg/kg (~3.5 years [y]) and 7.5 mg/kg (~3 y). Methods: This is a phase 2, multicenter, open-label study in pts with SCD, aged 16 to 70 y, who had experienced ≥1 VOC (defined as pain crises and complicated SCD crises such as acute chest syndrome, priapism and hepatic or splenic sequestration) in the 12 mo prior to screening. Pts were enrolled into 5 mg/kg and then 7.5 mg/kg groups sequentially and received crizanlizumab by intravenous infusion over 30 minutes on day 1, day 15, and every 4 weeks (wk) thereafter. Pts receiving hydroxyurea/hydroxycarbamide (HU/HC) and/or erythropoietin-stimulating agents for at least 6 mo prior to screening were allowed to continue the same dose and schedule during the study. Results: Overall, 57 pts were enrolled: 45 received crizanlizumab 5 mg/kg (median age, 29 [IQR 22, 39] y) for a median of 191 (IQR 98, 210) wk, and 12 received 7.5 mg/kg (median age, 21 [IQR 18, 41] y) for a median of 167 (IQR 120,182) wk. At cutoff, 22 pts (49%) in 5 mg/kg group and 6 pts (50%) in 7.5 mg/kg group discontinued the treatment, primarily because of physicians' (5 mg/kg, n=6; 7.5 mg/kg, n=4) and pts' decisions (5 mg/kg, n=9). For both doses, serum crizanlizumab concentrations increased to nearly maximum levels (C max) at the end of the 30-minute infusion and remained steady for 6 hours after infusion. For each dose, C max at wk 1 and 15 was similar ( Table), indicating no significant accumulation. Crizanlizumab exposure increased almost dose proportionally from 5 mg/kg to 7.5 mg/kg. P-selectin inhibition was nearly complete throughout the dosing interval for both doses at steady state (5 mg/kg, 90% to 98%; 7.5 mg/kg, 86% to 96%), with consistent and stable pre-dose inhibition throughout the study ( Figure). All pts reported ≥1 adverse events (AEs) in both dose groups. The most common AEs were pyrexia (5 mg/kg, 14 [31%]; 7.5 mg/kg, 3 [25%]), headache and hypokalemia (5 mg/kg, 12 [27%]; 7.5 mg/kg, 2 [17%], each). Grade ≥3 AEs occurred in 27 pts (60%) in the 5 mg/kg group and in 6 pts (50%) in the 7.5 mg/kg group. At least one serious AE was reported in 22 pts (49%) in the 5 mg/kg group and 5 pts (42%) in the 7.5 mg/kg group; 1 was drug related in 5 mg/kg group (none in the 7.5mg/kg group). One pt in each of the 5 mg/kg (2%) and 7.5 mg/kg (8%) groups discontinued treatment because of drug-related AEs. One pt in each group died while on treatment, but the death was not considered related to crizanlizumab. Two pts in the 5 mg/kg group had severe crizanlizumab-related infusion-related reactions (IRR) (grade 2 pain [n=1], grade 3 IRR [n=1]), which resolved with treatment. No grade ≥3 treatment-related infections or bleeding events were reported. No pts developed antibodies against crizanlizumab. The median (IQR) annualized rate of VOCs leading to a healthcare visit in the 5 mg/kg group was 4 (1, 7) at baseline and 2.75 (1.03, 5.32) on treatment; absolute change from baseline, -0.76 (-2.94, 2.01). In the 7.5 mg/kg group, the corresponding rates were 2 (1, 4.5) and 1.09 (0.30, 3.36), -0.91 (-1.06, -0.50). Eight pts (18%) in the 5 mg/kg group and 2 pts (17%) in the 7.5 mg/kg group were VOC free during the entire treatment period. Conclusions: These long-term results for ~3.5 y in 5 mg/kg and ~3 y in 7.5 mg/kg groups demonstrate that serum crizanlizumab concentrations rose to a near maximum level shortly after infusion and remained steady 6 hours after infusion for both doses. Crizanlizumab with or without HU/HC was safe with no new/unexpected safety concerns and no apparent differences between the two doses in the frequency and severity of AEs. Consistent with previously reported results from SUSTAIN study, crizanlizumab reduced the annualized rate of VOCs leading to a healthcare visit from baseline.

Preliminary Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a lifelong inherited disorder resulting in polymerization of sickle hemoglobin (HbS) and is characterized by chronic hemolytic anemia, vaso-occlusive crises (VOCs), and cumulative end-organ damage. Voxelotor is a first-in-class HbS polymerization inhibitor approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. GBT021601 is a next-generation HbS polymerization inhibitor with improved pharmacokinetic (PK) properties that increases hemoglobin (Hb)-oxygen affinity and stabilizes Hb in the oxygenated state to inhibit polymerization. GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden and improve clinical outcomes. Here we report preliminary safety, efficacy, and pharmacodynamic (PD) data from an ongoing phase 2/3 study of orally administered GBT021601 (NCT05431088) in patients with SCD. Methods: This is a 3-part, multicenter phase 2/3 study in SCD. Part A is a randomized, open-label, 12-week, dose-finding study of GBT021601 in adult participants. Part B is a placebo-controlled study in adult and adolescent participants. Part C is an open-label study in pediatric participants. Here, we report data at Week 12 from Part A, which enrolled participants aged 18-65 years with SCD (HbSS/HbSβ 0 genotype) and Hb 5.5-10.5 g/dL at screening. Eligible participants were randomly assigned 1:1 to GBT021601 100 mg or 150 mg and received a loading dose twice daily for 4 days followed by once-daily maintenance doses through to Week 12. The primary endpoint was change from baseline in Hb at Week 12; secondary endpoints included Hb response (increase from baseline &amp;gt;1 g/dL) and change from baseline in hemolysis markers at Week 12, PK, PD, and safety. Vascular cell adhesion molecule-1 (VCAM-1) levels are elevated during VOCs, with flow adhesion of whole blood on VCAM-1 previously reported as a prognostic biomarker for VOC risk. The effect of GBT021601 on adherent cells was evaluated using a microfluidic device coated with VCAM-1. Results: At data cutoff (June 20, 2023), 35 patients were treated in Part A; 28 had completed 12 weeks of treatment. The 100-mg group consisted of 17/35 patients (48.6%), with a mean (range) age of 29.1 (18-49) years; 7/17 patients (41.2%) were on hydroxyurea (HU). The 150-mg group had 18/35 patients (51.4%), with a mean (range) age of 30.2 (18-59) years; 9/18 patients (50.0%) were on HU. Most patients (32/35 [91.4%]) had the HbSS genotype. After 12 weeks of treatment, the mean (SD) increase in Hb from baseline was 2.67 (1.52) g/dL for the 100-mg group (n=12) and 3.17 (1.82) g/dL for the 150-mg group (n=11). A favorable trend towards reduction from baseline was observed in markers of hemolysis. Flow adhesion data showed patients taking GBT021601 had a reduction in adherent cells, which could correlate with a reduction in the probability of a VOC event (Figure). At data cutoff, the safety data showed GBT021601 was well tolerated. For 27 patients with ≥1 VOC at baseline, the baseline annualized VOC rate was 2.30 (95% CI 1.81-2.92), and the on-study annualized VOC rate was 1.16 (95% CI 0.55-2.43) with a median (range) on-study duration of 0.4 (0.03-0.41) years. Treatment-emergent adverse events (TEAEs), predominantly grade 1 and 2 (15/35 [42.9%]) and unrelated to treatment (14/35 [40.0%]), were reported for 22 patients (62.9%). Treatment-related TEAEs in 8/35 patients (22.9%) were headache (n=4), diarrhea (n=2), and abdominal discomfort, nausea, suspected seizure (uncoded), sickle cell anemia with crisis, upper abdominal pain, and urticaria (n=1 each). There was 1 TEAE, unrelated to treatment, that led to study discontinuation (sepsis, in the 100-mg group). One death deemed unrelated to GBT021601 was due to a cerebrovascular (CVA) event, in a patient with history of CVA and seizures, after new onset high fever and no change from baseline Hb 8.0 g/dL. Conclusions: Loading and daily doses of GBT021601 for 12 weeks were well tolerated in adult participants with SCD. Despite large increases in mean Hb levels, pain episodes did not increase and there was a reduction of adherent cells in a flow adhesion assay with VCAM-1, a potential biomarker for VOC risk. Data from Part A of this phase 2/3 study support the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD.

5572697 TRIALS IN PROGRESS: THE THRIVE STUDIES EVALUATING THE EFFICACY, SAFETY, AND LONG-TERM TREATMENT WITH INCLACUMAB, A P-SELECTIN INHIBITOR, IN PATIENTS WITH SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) is an autosomal recessive red blood cell (RBC) disorder caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerization within deoxygenated RBCs contributes to hemolysis, anemia, vaso-occlusion, and end-organ damage. Additionally, abnormal heterocellular adhesive interactions between RBCs and endothelial cells, leukocytes, and platelets play a central role in triggering painful vaso-occlusive crises (VOCs) in patients with SCD. Inclacumab is a recombinant, fully human monoclonal antibody directed against human P-selectin, a cell adhesion molecule produced by endothelial cells and platelets. Inclacumab interferes with the adhesion of sickle RBCs, platelets, and leukocytes to endothelium by binding P-selectin and preventing P-selectin binding to its ligands. This is the putative mechanism by which inclacumab may potentially reduce the incidence of VOCs. Aims: We aim to conduct two global, multicenter, phase 3 studies and an open-label extension (OLE) study to evaluate the safety and efficacy of inclacumab in individuals with SCD. Methods: THRIVE-131 (NCT04935879) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~240 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive intravenous (IV) inclacumab or placebo every 12 weeks for 48 weeks (Figure). The primary endpoint is the rate of VOCs during the 48-week treatment period. THRIVE-132 (NCT04927247) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~280 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive a single dose of IV inclacumab or placebo within 5 days of resolution of an index VOC that required admission to a healthcare facility and treatment with parenteral pain medication. The primary endpoint is the proportion of participants with readmission for a VOC within 90 days of randomization. After completion of their participation in THRIVE-131 or THRIVE-132, participants may enroll in THRIVE-133 OLE, in which the long-term safety of inclacumab will be investigated. In THRIVE-133 OLE, participants will receive IV inclacumab every 12 weeks as long as the clinical benefit of treatment outweighs the risk and until access to inclacumab from an alternative source (eg, through commercialization or a managed-access program) becomes available. Results: Recruiting for both THRIVE-131 and THRIVE-132 began in October 2021 and is ongoing. Summary – Conclusion: The THRIVE-131 and THRIVE-132 phase 3 studies will examine the efficacy of inclacumab in reducing the frequency of VOCs and readmissions due to VOCs, and the THRIVE-133 OLE study will examine the long-term safety of inclacumab in individuals with SCD. Funding: These studies are supported by Global Blood Therapeutics. Figure: Designs of the THRIVE Studies

5589320 FOLLOW-UP RESULTS OF A PHASE 2 STUDY ASSESSING THE SAFETY AND EFFICACY OF MITAPIVAT TREATMENT, AN ORAL PYRUVATE KINASE ACTIVATOR, FOR UP TO 60 WEEKS IN SUBJECTS WITH SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) is a devastating red blood cell (RBC) disorder. The root cause of SCD is polymerization of sickle hemoglobin (HbS) upon deoxygenation, resulting in poorly deformable sickled RBCs with shortened lifespan. 2,3-diphosphyglycerate (2,3-DPG), a glycolytic intermediate in RBCs, promotes deoxygenation by lowering hemoglobin (Hb)-oxygen affinity. Mitapivat (AG-348) is an oral allosteric activator of pyruvate kinase (PK), a key enzyme in RBC glycolysis generating adenosine triphosphate (ATP) and reducing 2,3-DPG levels. Aims: To report follow-up data of the safety and efficacy of mitapivat treatment in subjects with SCD (ESTIMATE study; www.trialregister.nl NL8517; EudraCT 2019-003438-18). Methods: The ESTIMATE study is a phase 2, investigator initiated, open-label study. Subjects ≥16 years with SCD (HbSS, HbS/β0 or HbS/β+), 1-10 vaso-occlusive crises (VOCs) in the prior year and/or prior SCD-related complications, a Hb level >6.1 g/dL and ≤11.1 g/dL, and no chronic transfusions are eligible and treated with mitapivat after obtaining informed content. In the 8-week dose finding period, initial dosing is 20 mg twice daily, escalated to max. 100 mg twice daily, and followed by an up to 52-week fixed dose extension period (FDEP). Primary endpoints are safety, based on adverse events (AEs), and efficacy of mitapivat treatment on RBC sickling (Point of Sickling (PoS), oxygen gradient ektacytometry). Key secondary endpoints are changes in Hb level, markers of hemolysis, ATP/2,3-DPG levels, and Hb-oxygen affinity (p50, Hemox Analyzer). Results: Until Jan. 2022, 9 subjects were treated with mitapivat. Baseline characteristics were: median age 22 years (range 16-59 years), 6/9 (67%) female, and 6/9 (67%) used hydroxyurea. 7/9 (78%) had HbSS, 1/9 (11%) had HbS/β0, and 1/9 (11%) had HbS/β+. One subject with a non-treatment related serious AE (SAE) of a urinary tract infection (grade 4), was lost to follow-up shortly after first dosing. No other SAEs or treatment-emergent AEs (TEAEs) grade ≥3 occurred. The remaining 8 subjects had a median treatment duration of 38 weeks (range 11-60 weeks). 6/8 (75%) took 100 mg mitapivat twice daily in the FDEP, and 2/8 (25%) took 50 mg mitapivat twice daily after a single dose reduction because of progressive transaminase increase. The most common TEAEs were (n>2 subjects): ALT or AST increase (both 5/9, 56%; all grade 1), and headache (4/9, 44%; grade 1-2). Three VOCs occurred: one related to excessive alcohol consumption with no need for hospitalization, and two in subjects with documented noncompliance the week before hospitalization. Mean annual VOC rate and SCD-related hospital admission days were, respectively, 1.5±1.3 and 5.9±7.1 days at baseline, and reduced to 0.5±0.7 and 1.6±3.1 days when weighting cases by follow-up duration (p=0.021 and p=0.134, respectively). Table 1 summarizes mean changes in parameters of primary and key secondary endpoints of scheduled visits in the FDEP compared to baseline. Hb level significantly increased, accompanied by a decrease in markers of hemolysis (absolute reticulocyte count, total bilirubin, lactate dehydrogenase). Mean PoS decreased, and p50, 2,3-DPG level and ATP/2,3-DPG ratio significantly improved. Conclusion: Treatment with mitapivat for up to 60 weeks in subjects with SCD showed no treatment related TEAEs grade ≥3. Improvements in anemia, markers of hemolysis, oxygen affinity, 2,3-DPG level and ATP/2,3-DPG ratio were seen.

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease.

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N= 45) and 7.5 mg/kg (N= 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained exvivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was-0.88 (-14.7 to 13.3) and-0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

Occult ischemic bone lesions in children with sickle cell disease: A study of prevalence.

Avascular necrosis (AVN) is a severe complication of sickle cell disease (SCD) and involves principally the femoral head. Few data exist about the prevalence of lesions in other segments. In this cross-sectional study, 42 children (20 males and 22 females) underwent a magnetic resonance imaging (MRI) of the spine, upper arms, and femurs. The primary outcome was to define the prevalence and locations of bone infarcts. Forty-two patients completed the study; the total median age was 11.9 years (interquartile range=9.5-13.9). Eleven patients (26.2%) were positive for altered bone findings for a total of 32 lesions. Most of the lesions were in the humerus 17 (53.1%), 11 (34.4%) in the femurs, and 4 (12.5%) in the vertebrae. The median number of vaso-occlusive crises (VOCs) was two and four for patients without and with bone lesions, respectively (p=.01). The annual rate of VOC is the best marker for the positive MRI (odds ratio=82.6; p=.03), and it is correlated with the number of sites involved (p=.02). Our study highlights that the prevalence of skeletal lesions could be underestimated, and it provides the basis for clinical reasoning and tailored therapy in SCD children.

ASCENT1: A Phase 2 Trial to Evaluate the Efficacy and Safety of Oral Decitabine-Tetrahydrouridine (NDec) in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is driven by the polymerization of mutated hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) mitigates the effects of HbS polymerization, but the HbF gene expression is silenced in infancy by DNA methyltransferase 1 (DNMT1). Decitabine induces HbF expression by direct inhibition of DNMT1. NDec is an innovative combination treatment with decitabine, the active component, and the pharmacokinetic enhancer tetrahydrouridine (THU). Hydroxyurea (HU), the current standard of SCD care, indirectly induces HbF by inducing bone marrow stress. As the indirect effect of HU on HbF is clinically variable, the direct HbF induction of NDec is hypothesized to provide a sustainable treatment option for patients with SCD. In a previous trial in high-risk patients with SCD by Molokie R et al. (2017), oral decitabine (0.16 mg/kg) and THU vs placebo significantly increased total Hb, HbF, proportion of HbF-enriched RBCs (%F-cells) and improved RBC health markers, without triggering grade ≥3 non-hematologic toxicity. NDec formulations were further investigated in 2 phase 1 trials in healthy people. The ASCENT1 trial (NCT05405114) aims to study the efficacy and safety of once- or twice-weekly NDec vs placebo in patients with SCD. This study will provide proof of concept and determine the optimal dose for future trials. Study design: ASCENT1 is a randomized, placebo-controlled phase 2 trial with an additional exploratory open-label HU block (Figure). To ease the operational aspects for patients and sites, trial design, visit schedule and trial materials were developed together with patient groups, study nurses and coordinators. The HU non-eligible block will include those who are HU-naïve or who cannot be treated with HU for any reason. Participants randomized to NDec in the HU active block will discontinue HU during a 4-week washout period. Study population: All SCD genotypes are eligible for inclusion; other criteria are ≥18 years of age, 2-10 documented vaso-occlusive crises (VOCs) ≤12 months before screening, Hb ≥5.0-≤10.5 g/dL and reticulocyte count >1.5x upper limit of normal at screening. HU active participants are eligible only if deemed inadequately controlled by investigators despite being prescribed HU in the preceding 6 months and being on a stable dose >3 months. Exclusion criteria include chronic transfusion therapy or treatment 28 days before screening/during trial with hematopoietic growth factors and treatment with voxelotor, crizanlizumab or L-glutamine 12 weeks before signing informed consent. Study treatment and endpoints: HU non-eligible (n=60) and HU active (n=24) participants will be randomized 1:1:1 to NDec once weekly, NDec twice weekly (2 consecutive days) or placebo/open-label HU. The trial consists of a main and extension phase (24 weeks each). NDec will be administered orally, with a meal, according to body weight intervals to attain a decitabine dose level of 0.16−0.25 mg/kg and THU dose level of 8−12.5 mg/kg. The primary endpoint is change in total Hb (g/dL) from baseline (BL) to Week 24. Secondary efficacy endpoints include change in HbF (g/dL and %HbF of total Hb), change in %F-cells of total RBCs, and change in hemolysis markers from BL to Week 24. Secondary efficacy endpoints also include numbers of VOCs, acute chest syndrome and transfused RBC units from BL to Week 48. The secondary safety endpoint is the number of adverse events (grade ≥3) from BL to Week 52. Changes in patient-reported outcomes from BL to Week 48 will be assessed using 5 validated questionnaires for SCD. Statistical analysis: The primary endpoint will be analyzed using an ANCOVA model with treatment, historical VOC rate and sex as fixed factors, and BL Hb as covariate. Treatment policy estimand will be used to handle intercurrent events. Considerations: In this trial, VOCs are defined as ≥1 predefined clinical events requiring a medical visit, including home and telemedicine visits, for those with limited regular access to medical management at a clinic/hospital. NDec and HU both induce HbF and will not be given together due to a theoretical potentiation of hematologic toxicity. The exploratory HU active block enables preliminary comparisons of the efficacy and safety between NDec and HU. The extension phase allows for analyses that may require longer follow-up to show clinical benefits and sustainability of NDec in SCD. The recruitment to ASCENT1 started in summer 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TRIALS IN PROGRESS: THE THRIVE STUDIES EVALUATING THE EFFICACY, SAFETY, AND LONG-TERM TREATMENT WITH INCLACUMAB, A P-SELECTIN INHIBITOR, IN PATIENTS WITH SICKLE CELL DISEASE

Sickle cell disease (SCD) is an autosomal recessive red blood cell (RBC) disorder caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerization within deoxygenated RBCs contributes to hemolysis, vaso-occlusion, and end-organ damage. Additionally, abnormal heterocellular adhesive interactions between RBCs and endothelial cells, leukocytes, and platelets play a central role in triggering painful vaso-occlusive crises (VOCs) in patients with SCD. Inclacumab is a recombinant, fully human, monoclonal antibody directed against human P-selectin, a cell adhesion molecule produced by endothelial cells and platelets. Inclacumab interferes with the adhesion of sickle RBCs, platelets, and leukocytes to the endothelium by binding P-selectin and preventing P-selectin from binding to its ligands. This is the putative mechanism by which inclacumab may potentially reduce the incidence of VOCs. We aim to conduct 2 global, multicenter, phase 3 studies and an open-label extension (OLE) study to evaluate the safety and efficacy of inclacumab in individuals with SCD. The THRIVE studies (THRIVE-131, THRIVE-132, THRIVE OLE) are being conducted in approximately 75 sites worldwide, including 13 sites in Brazil. Of the Brazilian sites, 2 are currently activated. THRIVE-131 (NCT04935879) is a randomized, double-blind, placebo-controlled, multicenter trial in which 240 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive intravenous (IV) inclacumab or placebo every 12 weeks for 48 weeks. The primary endpoint is the rate of VOCs during the 48-week treatment period. THRIVE-132 (NCT04927247) is a randomized, double-blind, placebo-controlled, multicenter trial in which 280 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive a single dose of IV inclacumab or placebo within 5 days of resolution of an index VOC that required admission to a healthcare facility and treatment with parenteral pain medication. The primary endpoint is the proportion of patients with readmission for a VOC within 90 days of randomization. After completion of their participation in THRIVE-131 or THRIVE-132, participants may enroll in THRIVE-133 OLE in which the long-term safety of inclacumab will be investigated. In THRIVE-133 OLE, participants will receive IV inclacumab every 12 weeks as long as the clinical benefit of treatment outweighs the risk and until access to inclacumab from an alternative source (eg, through commercialization or a managed-access program) becomes available. Recruiting for both THRIVE-131 and THRIVE-132 began in October 2021 and is ongoing. The THRIVE-131 and THRIVE-132 phase 3 studies will examine the efficacy of inclacumab in reducing the frequency of VOCs and readmissions due to VOCs, and the THRIVE-133 OLE study will examine the long-term safety of inclacumab in individuals with SCD. The phase 3 THRIVE studies are expected to provide valuable data on the safety and efficacy of inclacumab as a potential therapy for VOCs associated with SCD. These studies are supported by Global Blood Therapeutics.

O-04: INCIDENCE OF VASO-OCCLUSIVE CRISES IN PATIENTS WITH SICKLE CELL DISEASE (SCD) AND A HIGH BASELINE DISEASE BURDEN TREATED WITH CRIZANLIZUMAB IN A REAL-WORLD SETTING: RESULTS FROM A MANAGED ACCESS PROGRAM (MAP)

Purpose: Vaso-occlusive crises (VOCs) are the hallmark of SCD and can lead to serious complications. P-selectin is a cell adhesion protein that plays a key role in the multicellular interactions that lead to VOCs. Crizanlizumab, a first-in-class humanized monoclonal antibody that blocks P-selectin, is approved in several regions to prevent/reduce VOCs for SCD patients aged ≥16 years. Since June 2018, patients in some countries have received crizanlizumab before health authority approval via a MAP (NCT03720626). Materials and methods: The MAP was designed to provide access to crizanlizumab for patients with a serious or life-threatening disease (SCD) for which no comparable or satisfactory alternative to crizanlizumab was available in their country. Other eligibility criteria included: aged 16–70 years (18–70 years in Italy); history of VOCs as determined by the treating physician (including recurrent VOCs while taking preventative therapies eg hydroxyurea [HU]); and ineligibility for a crizanlizumab clinical trial. Patients’ disease burden during the baseline period was provided by the treating physician. This analysis describes the rate of VOCs and use of opioids for VOC-related pain relief 12 months before crizanlizumab initiation (baseline period) and after ≥12 months of crizanlizumab treatment in patients with SCD participating in the MAP, overall and stratified by genotype and prior HU use (in countries where publication of these data is allowed). Results: As of February 2022, 188 patients have received crizanlizumab in the MAP; 87 have been treated for ≥12 months (Brazil, n=79 [91%]; Italy, n=5 [6%]; Spain, n=2 [2%]; Israel, n=1 [1%]). Median (interquartile range [IQR]) age of the 87 patients was 33 (25–40) years, 57% were female, 45% were African American, 8% Caucasian, 20% Hispanic and 28% of ‘other’ ethnicity; 82% had an HbSS genotype. Prior HU use was reported for 41/56 (73%) patients with available data. During the baseline period, 85% (n=74/87) of patients were hospitalized for a total of 220 SCD-related complications. Crizanlizumab led to a median (IQR) absolute reduction from baseline of –3.0 (–6.0 to –1.0) home-managed and –2.0 (–4.0 to 0) healthcare-managed VOCs after ≥12 months of treatment. Similar reductions in VOC rates post- versus pre-crizanlizumab were observed when stratifying the data by SCD genotype/prior HU use (Figure), although some groups only contain a small number of patients. Opioids were taken for VOC-related pain relief by 95% of patients (n=83/87) at baseline and by 69% (n=60/87) in the 12 months after crizanlizumab treatment. Adverse events were consistent with those reported in other crizanlizumab studies. Conclusion: Patients in the crizanlizumab MAP had significant disease burden at baseline, as evidenced by the high rate of home- and healthcare-managed VOCs, proportion of patients with SCD-related complications and use of opioids for VOC-related pain relief, despite many patients reporting prior HU use. Crizanlizumab led to clinically relevant reductions from baseline in the median annualized rates of home- and healthcare-managed VOCs and use of opioids in this real-world setting, consistent with results from SUSTAIN.L. DEBONNETT declares a conflict of interest: Stock shareholder: Employee and stock shareholder in Novartis Pharmaceuticals

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

AbstractThe phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

PB2213: EFFECTIVENESS OF CRIZANLIZUMAB IN REDUCING VASO-OCCLUSIVE CRISIS IN PATIENTS WITH SICKLE CELL DISEASE IN BRAZIL: STUDY PROTOCOL FOR AN OBSERVATIONAL, RETROSPECTIVE, MULTICENTER, NATIONAL STUDY

Background: Sickle cell disease (SCD) is a genetic condition resulting in a structurally abnormal hemoglobin, that leads to a cascade of physiologic consequences, including erythrocyte rigidity, vaso-occlusion, chronic anemia, hemolysis, and vasculopathy. Its management can be intensive, time-consuming, and costly. Few effective treatment options are currently available for these patients, specially to control the vaso-occlusive crisis (VOC). In March 2020, crizanlizumab, a monoclonal antibody drug, was approved by the Brazilian Health Regulatory Agency (ANVISA) to reduce the frequency of VOCs in patients with SCD. Crizanlizumab has been provided through Novartis Managed Access Program (MAP), classified in Brazil as Expanded Access Program (EAP), as an alternative therapy for SCD patients with an immediately life-threatening condition or serious disease. So far, limited evidence is available on crizanlizumab effectiveness and safety profile in Brazil and no real-world evidence study was conducted in the country. In this scenario, real-world studies present an essential role on complementing efficacy and safety data from pivotal and randomized studies in a much broader population profile. Aims: To describe the study design and rationale for investigation for the first real-world study assessing crizanlizumab in SCD patients in Brazil. The study aims to describe the effectiveness and safety profile of crizanlizumab treatment in patients with SCD in Brazil. Methods: This is an observational, retrospective, multi-center study based on secondary data of SCD patients treated with crizanlizumab in Brazil. In total, 98 patients treated with crizanlizumab within the Novartis MAP (EAP) will be screened for the study. Patients aged ≥ 16 ≤ 70 years old, diagnosed with SCD and with documented history of at least one VOC episode up to abstraction data initiation will be included in the study. Patient known to be participating in an interventional study at any point of the two-year study period and/or on a chronic transfusion program will be excluded. Data will be retrospectively abstracted from medical chart, considering one-year prior to crizanlizumab onset and up to one year of crizanlizumab treatment to assess the pattern of VOCs. The annual rate of VOC experienced by the patient and leading to a healthcare visit within the preceding 12-months prior to crizanlizumab initiation and 12-month after will be assessed and compared as the primary outcome. Secondary outcomes include the overall effectiveness of crizanlizumab over 1 year of treatment; time to next VOCs in SCD patients; safety aspects – including the frequency of adverse events of interest, e.g.: arthralgia, nausea, back pain, pyrexia, abdominal pain and infusion-related reactions in SCD patients during crizanlizumab treatment; clinical parameters in SCD management as well as demographics and clinical characteristics of SCD patients who were treated with crizanlizumab. Results: Study in progress. Results not yet available. Image:Summary/Conclusion: This is the first real world study to assess the effectiveness and safety of crizanlizumab in Brazilian SCD patients. It is expected that the assessment of SCD patients under MAP in Brazil will provide valuable information closer to what is expected in the real-world scenario. The availability of more robust evidence can support decision-making process, from clinical assessment by providers, to implementation of public healthcare policies.

Real-world effectiveness of voxelotor for treating sickle cell disease in the US: a large claims data analysis

ABSTRACT Background Sickle cell disease (SCD) is a genetic disease that impacts patients’ quality of life, healthcare costs, and life expectancy. Elevated sickle hemoglobin (HbS), which readily polymerizes, causes red blood cell sickling, leading to chronic hemolytic anemia and complications often requiring hospitalization and transfusions. In 2019, voxelotor, which inhibits HbS polymerization, was approved for SCD treatment. Objectives This study uses real-world evidence to assess voxelotor’s effectiveness in SCD patients in typical clinical practice from 2019 to 2021 using a national medical claims database (N = 3128). Results After initiating voxelotor, 60.8% of patients with available hemoglobin (Hb) laboratory data (n = 74) showed a Hb increase >1 g/dL. Mean transfusion rate per patient-year dropped 52% in patients with ≥1 transfusion before treatment (n = 190). In patients with ≥1 of the corresponding events (n = 1065), decreases were observed in mean vaso-occlusive crisis (VOC) frequency (–23%); mean VOC-related hospitalizations and length of stay (LOS) time (–34% and –30%, respectively); mean all-cause hospitalization and LOS time (–37% and –23%, respectively); outpatient visits (–10%); iron chelation use (–46%); and prescribed opioids (–13%). Conclusion These data align with randomized controlled trial results showing voxelotor improvements and support that voxelotor may lower transfusion and VOC rates in clinical practice.