SCDAA 46th Annual National Convention

Abstract 

Authors:
Dr. Ogechukwu Egini- Interfaith Medical Center, Dr. Edouard Guillaume- Interfaith Medical Center, Dr. Eric Jaffe- Interfaith Medical Center, Dr. Xian-Cheng Jiang- SUNY Downstate Medical Center, Mrs. Stephanie Egini- Caters Plan for Healthy Living, Dr. Ugochi Ogu- Montefiore Medical Center, Ms. Miren Blackwood- Interfaith Medical Center, Dr. Antony Lixon- Interfaith medical Center

Background - Beside lipid-lowering effects of statins, they have been shown to decrease inflammatory markers in many trials. The PRINCE (Pravastatin inflammation/CRP evaluation) trial was a 24 week study in which volunteers were treated with Pravastatin and inflammatory markers were measured at end of study. A significant reduction in serum CRP levels in subjects was noted, independently of any changes in LDL cholesterol. Furthermore, simvastatin reduced vaso-occlusive pain and oral analgesic use in patients treated over months.
Objective - To determine whether Pravastatin reduced sickle cell adhesion to endothelial cells using mouse endothelial cells in culture.
Design - Randomized experimental study
Study subjects - 4 sickle cell anemia patients from Interfaith Medical Center sickle cell outpatient program and 3 normal controls were recruited from the outpatient clinic. Subject recruitment was approved by the Institutional Review Board.
Interventions - Demographic information and EDTA blood samples were collected. Red cells were centrifuged, washed and stained with Vybrant Dil fluorescent cell labeling solution. Mouse endothelial cells were cultured on well plates. They were then treated with either Pravastatin or placebo for 1 hour. Both normal and sickle red cells were then activated with 20nM epinephrine and then introduced into the endothelial cell culture medium treated with either Pravastatin or placebo. Incubation was done for 30 minutes.
Main measures - Comparison of the number of red cells adherent to the mouse endothelial cell membrane in culture.
Results - In the placebo and treatment groups, there was significant sickle red cell adhesion compared to normal cells (P value < 0.05). When adherent sickle red cells in both placebo and treatment groups are compared, there was significant sickle red cell adhesion to mouse endothelial cell membrane in the placebo group (p<0.05).
Conclusion - Pravastatin reduced sickle red adhesion to mouse endothelial cell membrane.

Abstract


Authors:
Dr. Regina Graul- Ironwood pharmaceuticals, Dr. Bina Tejura- Ironwood pharmaceuticals, Dr. José Trevejo- Ironwood pharmaceuticals, Dr. Courtney Walls- Ironwood pharmaceuticals, Ms. Meghan Bratton- Ironwood pharmaceuticals, Dr. Jennifer Chickering- Ironwood pharmaceuticals, Ms. Oluwafunke Ojo- Ironwood pharmaceuticals,Dr. Joshua Field- Froedtert and Medical College of Wisconsin
BACKGROUND: STRONG-SCD is an ongoing randomized, double-blind, placebo-controlled, Phase 2 study of the sGC stimulator, olinciguat (IW-1701), in patients with stable sickle cell disease. Olinciguat is an oral sGC stimulator that enhances NO-sGC-cGMP signaling. Intracellular cyclic guanosine monophosphate (cGMP) produced by soluble guanylate cyclase (sGC) in response to nitric oxide (NO) binding plays an important role in regulating vascular tone, smooth-muscle proliferation, fibrosis, and inflammation. Low NO bioavailability in SCD has been proposed to contribute to marked vascular inflammation, cellular adhesion, and vasoconstriction, which may propagate vaso-occlusive crisis and other complications of SCD. In preclinical studies in relevant animal models, olinciguat decreased biomarkers of intravascular inflammation, leukocyte-endothelial cell interactions, and neutrophil extravasation both alone and in combination with hydroxyurea.
METHODS: The clinical program with olinciguat includes completed Phase 1 single ascending and multiple ascending dose (MAD) studies in healthy volunteers and STRONG-SCD, the ongoing Phase 2 study. STRONG-SCD is a multicenter, randomized, double-blind, placebo-controlled study evaluating 12 weeks of treatment with olinciguat in SCD patients (NCT03285178). Its primary objective is to assess the safety and tolerability of 3 dose levels of olinciguat. Exploratory objectives include evaluation of plasma biomarkers of disease progression, as well as health-related patient-reported outcomes. In particular, daily symptoms of SCD will be assessed via eDiary using the Sickle Cell Disease Symptom Assessment Form (SCD-SAF). The SCD-SAF is a fit-for-purpose instrument designed to reflect the most important and relevant SCD symptoms that impact patients with SCD. The STRONG-SCD study is enrolling patients 16-70 years old with HbSS, HbSC, HbSβ0-thalassemia, or HbSβ+-thalassemia who have had 1 to 10 pain crises in the past year and who meet all protocol defined eligibility criteria. Patients may be on stable therapy of hydroxyurea and other approved SCD medications. An independent data monitoring committee will review safety data. Target enrollment is 88 patients across sites in the US.
RESULTS: Multiple doses of olinciguat were well tolerated across the dose levels tested in the Phase 1 single and multiple ascending dose studies, with olinciguat showing target engagement as evidenced by reductions in blood pressure and increases in circulating cGMP concentrations. The most common adverse event (AE) reported was headache (22% in pooled treatment groups compared to 5% in placebo). Patients for the STRONG-SCD are still being enrolled.
CONCLUSION: Results of preclinical and clinical data supported the clinical development of olinciguat in SCD, with the STRONG SCD study initiated in initiated in 2017. Completion is expected in 2019.

Abstract 

Authors:
Dr. Ahmed Daak- SCI, Dr. Matthew Heeney- Dana-Farber / Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Dr. Carlton Dampier- Emory University School of Medicine, Dr. Beng Fuh- East Carolina University Department of Pediatrics, Dr. Julie Kanter- Division of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA, Dr. Ofelia Alvarez- University of Miami, Dr. Vandy Black- University of Florida College of Medicine, Dr. Melissa Mcnaull- University of Mississippi Medical Center, Dr. Michael Callaghan- Children's Hospital of Michigan, Dr. Alex George- Texas Children’s Hospital

Introduction:
Blood cell membranes of patients with sickle cell disease (SCD) have low docosahexaenoic acid (DHA) levels. DHA is a bioactive fatty acid known to have potent anti-inflammatory, anti- blood cell adhesion and anti-oxidant properties. There is evidence that treatment with DHA reduces the rate of sickle cell crises (SCC) and ameliorates the chronic inflammation, oxidative stress and hypercoagulable state observed in SCD patients. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology® (ALT®)) that enhances DHA bioavailability. The SCOT trial investigated three different doses of SC411 in children with sickle cell disease.
Methods:
Children with SCD (HbSS, HbSC or S/β°‑thalassemia) aged 5-17 years (n=67), who had ≥2≤10 documented Sickle Cell Crises (SCC) during the 12 months prior to screening, and either had not received or who were on hydroxyurea (HU) for at least 6 months prior to screening, were enrolled. Subjects received either placebo or one of three increasing doses of SC411 (20; 36 or 60 mg/kg/day DHA, respectively) for two months. The effect of treatment with three dose levels of SC411 on selected clinical and biochemical parameters was investigated. Analysis was conducted under the Intention-To-Treat (ITT) population.
Results:
Sixty-seven (n=67) subjects were randomized, 50 to active treatment. Fifty-one (76%) were on HU treatment. Sixty-two patients (93%) completed the double-blinded phase of the study.
The analysis of the primary endpoint showed a mean percent increase from baseline in DHA and EPA concentration of 108.0 [CI: (49.5, 166.6)], 194.1 [CI: 145.8, 242.5)], 179.2 [CI (126.7, 231.6) and 15.4 [-42.8, 73.6)] in 20, 36 and 60 DHA mg/kg day and placebo, respectively, after 4 weeks of treatment.
After 8 weeks post-treatment, significant changes against placebo were observed in D-dimer (p=0.025) and sE-sel (p=0.0219) on patients exposed to 36 mg/kg. Significant increase in hemoglobin (Hb) against placebo was observed in those who received 20 mg/kg (p=0.039). Positive non-significant directional changes against placebo were observed in plasma hs-CRP, LDH, sVCAM and WBC count.
The adjusted eDiary-recorded incidence rate ratios (IRRs) of pooled active versus placebo were 0.65 (95% CI: 0.46, 0.93; p=0.02) for sickle cell crises, 0.75 (95% CI: 0.62, 0.92; p=0.0054) for analgesic use at home and 0.41 (95% CI: 0.31, 0.56; p=0.0001) for opioid use at home. The odds ratio of days absent from school because of sickle cell pain of active groups pooled versus placebo was 0.28 (95% CI: 0.19, 0.39; p=0.0002).
The rate of clinical SCC was 53% lower in the active groups pooled against placebo (rate ratio, 0.47; 95% confidence interval [CI]: 0.20 to 1.11; p=0.07).
Conclusions:
SC411 significantly reduced eDiary recorded sickle cell crises, analgesic and opioid use at home for sickle cell pain, and days absent from school due to sickle cell pain after two months of treatment. In addition, a non-statistically significant reduction of pain episodes and improvements in markers of inflammation, adhesion and coagulation were observed. These findings support further evaluation of the safety and efficacy of SC411 for SCD treatment in a phase 3 clinical trial

Abstract

Authors:
Dr. Lori Luck- Pfizer Inc., Collegeville, Pennsylvania, Dr. Krupa Sivamurthy- Pfizer Inc., Collegeville, Pennsylvania, Dr. Frank Shafer-Pfizer Inc., Collegeville, Pennsylvania, Dr. Carl Kollmer- Pfizer Inc., Collegeville, Pennsylvania, Ms. Amanda O’brien- Pfizer Inc., Collegeville, Pennsylvania, Mr. David Readett- Pfizer Inc., Collegeville, Pennsylvania

Objectives: Acute therapy for a sickle cell vaso-occlusive crisis (SCD-VOC) remains limited to symptomatic relief predominantly with opioids, which fails to address the underlying pathophysiology of VOC. Preclinical studies have demonstrated a reduction in white blood cell (WBC)-endothelial cell adhesion, in addition to a decrease in secondary capture of sickle red blood cells (sRBCs) through selectin inhibition (Wun T, et al. PLoS One. 2014;9[7]:e101301). This suggests that inhibition of selectin-mediated cell adhesion to vascular endothelium may provide a therapeutic approach that would target the underlying cause of VOC. We describe the clinical development of rivipansel, a pan-selectin inhibitor, for the acute treatment of SCD-VOC.
Methods: We report on the clinical development of rivipansel from Phase 1 to Phase 3 investigation. Phase 1 studies were performed in healthy volunteers and individuals with SCD not experiencing a VOC. The Phase 2 multicenter, randomized, double-blind, placebo-controlled trial that followed enrolled and treated 76 individuals with SCD who were 12 – 60 years of age and hospitalized for a VOC. Subjects received a loading dose and a maximum of 14 maintenance doses of rivipansel or placebo. The primary efficacy endpoint was resolution of VOC and secondary endpoints included cumulative opioid use, length of hospital stay and adverse events (Telen MJ, et al. Blood. 2015;125[17]:2656-64). The subsequent ongoing randomized, double-blind Phase 3 clinical trial will include approximately 350 SCD subjects, 6 years of age and older, admitted to the hospital for VOC. The study design largely mirrors the Phase 2 study but the primary endpoint is time to readiness-for-discharge, defined as the difference between the time of readiness-for-discharge and the start time of the first infusion of study drug. Secondary endpoints include time to discharge, cumulative IV opioid consumption, time to discontinuation of IV opioids and adverse events. Subjects in the Phase 3 study also have the option of entering an open label extension study following their participation in the double blind study (ClinicalTrials.gov identifier: NCT02187003).
Results: The Phase 1 investigations demonstrated safety and tolerability in addition to identifying a Phase 2 starting dose for intravenous rivipansel. The subsequent Phase 2 trial revealed shorter median time to resolution of VOC and time to hospital discharge, as well as lower mean cumulative IV opioid (mg/kg morphine equivalent units) use in the rivipansel group compared to the placebo group. (Table 1) All causality and treatment-related adverse event (AE) rates, including serious AEs in the rivipansel group were comparable to the placebo group (Telen MJ, et al. Blood. 2015;125[17]:2656-64). These encouraging results prompted further investigation of rivipansel in a randomized, double-blind Phase 3 study (ClinicalTrials.gov identifier: NCT02187003) which is ongoing.
Conclusions: The clinical development of rivipansel as an acute therapy for SCD-VOC is based on selectin inhibition that is expected to decrease the adhesion between WBCs, endothelial cells and sRBCs, a key event in the evolution of sickle cell vaso-occlusion. Initial clinical studies have shown encouraging results leading to the ongoing randomized, double-blind Phase 3 study.

Abstract 

Authors:
Dr. Grammati Sarri- Evidera, London, United Kingdom, Dr. Menaka Bhor- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, Mr. Seye Abogunrin- Evidera, London, United Kingdom, Dr. Caroline Farmer- Evidera, London, United Kingdom, Dr. Savita Nandal- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, Dr. Dennis A. Revicki- Evidera, Bethesda, Maryland, USA

Objective: Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs) that result in repeated hospital admissions and can negatively impact patients’ health-related quality of life (HRQL). Most SCD randomized clinical trials (RCTs) are designed to evaluate efficacy relative to changes in the number of VOCs and their impact on HRQL. The objectives of this study were to conduct a systematic literature review (SLR) to identify patient-reported outcome (PRO) and health care resource utilization (HCRU) instruments used in RCTs and real-world studies and to evaluate their psychometric properties.
Methods: A SLR was conducted to identify and summarize validated PRO instruments used by patients with SCD in the United States and their caregivers. MEDLINE and EMBASE were searched using terms synonymous with SCD and psychometric properties of PRO instruments for articles published in English between 1997 and March 2017, focusing on pediatric patients, their caregivers, and adults. Studies were included if results assessed psychometric properties of PRO instruments and if the studies were interventional or observational in design. The quality of PRO instruments in the included studies was assessed using the COSMIN checklist.
Results: 21 studies assessing 10 child and 15 adult PRO instruments in SCD were included in the review. No validated PRO instruments measured caregiver burden in SCD and no validated HCRU instruments for any SCD population were identified. The most commonly reported instrument was the Pediatric Quality of Life Inventory; most of the adult instruments (9/15) evaluated self-efficacy/self-esteem and pain in relation to SCD. Only 1 instrument, the Adult Sickle Cell Quality of Life Measurement, evaluated HRQL in adults. Of the 25 PRO instruments reviewed for both children and adults, 3/10 and 5/15 instruments, respectively, were specifically developed for these age groups with SCD, and minimally important differences were not assessed for any of the reviewed instruments. Most instruments (9/15) identified for adult populations had strong internal reliability; however, there was often insufficient information to assess the content or construct validity, responsiveness, and test-retest reliability of the instruments identified for both populations.
Conclusions: Limited evidence on the psychometric properties of PRO instruments used in patients with SCD was identified. None of the reviewed instruments were found to sufficiently capture all the PRO aspects of SCD and their complications on patients’ HRQL for use as key trial endpoints. Further research should validate, or develop if no instrument is in existence, PRO instruments to assess HRQL of patients with SCD, PRO instruments for caregivers, and HCRU instruments.