Celebrating Diversity Within the Sickle Cell Community: Commitment, Innovation, Practice

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Friday, October 12

3:15pm EDT

Effect Of Long Term Treatment With Sc411 On Sickle Cell Crisis Rate In Children With Sickle Cell Disease

Dr. Ofelia Alvarez- University of Miami, Dr. Ahmed Daak- SCI, Dr. Matthew Heeney- Dana-Farber / Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Dr. Beng Fuh- East Carolina University Department of Pediatrics, Dr. Carlton Dampier-Emory University School of Medicine, Dr. Julie Kanter- Division of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA, 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

Docosahexaenoic acid (DHA) is a bioactive omega-3 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 patients with SCD. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology® (ALT®)) that enhances DHA bioavailability. The SCOT trial is a phase 2 randomized placebo-controlled double-blinded study followed by an open label extension phase (OLE).
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 six months prior to screening were enrolled. Subjects received either placebo or one of three doses of SC411 (20 [12-26]; 36 [26-48] or 60 [51-72] mg/kg/day DHA) for two months. Subjects who consented to the OLE were rolled into the lowest dose level (20 mg/Kg). The annualized rates of SCC against baseline were analyzed using a Poisson regression model with a log-link and with treatment, baseline disease severity, age group, and hydroxyurea use as covariates, and subject as a repeated measure. The model uses the log of (days in the study / 365) as the offset variable to produce the annualized rates. The percentage of subjects who remained crisis-free for at least 300 days post-randomization at the time of this analysis, was also reported. Safety and tolerability are reported.
A total of 67 subjects, 34 of whom are female (50.7%), were randomized to one of the three active groups (n=50) or placebo (n=17). Subjects on HU treatment constituted 76% of total study population. Sixty-two subjects (93%) completed the blinded portion of the study. Forty-one subjects (66%) opted into the OLE. Of all subjects in the OLE, seven (17.07%) received placebo during the blinded part of the study. At the time of this analysis, thirty-eight subjects have completed at least 300 days in the study and thirteen patients have completed one year. No unexpected or treatment-related adverse events were reported.
The median annualized rate of SCC at baseline for the subjects who enrolled into the study (n=67) or the OLE (n=41) was 3.00. The rate ratios of SCC of the year post versus the year prior to randomization were 0.560 (95% confidence interval [CI]: 0.39 to 0.80; p=0.0016) for the group who was on active drug during the blinded part (n=34), and 0.53 (CI: 0.66 to 0.79, p=0.0017) for patients who were on active treatment for a period of at least 6 months (n=32).
300 days after randomization, 40% of the patients (15/38) remained crisis-free. Of the 13 patients that have completed over one year of treatment, five (38.46%) are crisis free.
The SCOT OLE study provides additional evidence that SC411 is safe and well-tolerated. Subjects on a dose of 20 mg/Kg DHA of SC411 experienced a significantly lower rate of sickle cell crises compared to the year prior to enrollment.

avatar for Beng Fuh

Beng Fuh

Associate Professor, East Carolina University Department of Pediatrics
Dr. Fuh is an Associate Professor of Pediatrics at East Carolina University in Greenville, NC.He was born in Cameroon, and attended Medical School at the Philipps University in Marburg, Germany. He completed his residency in Pediatrics at Howard University and Children’s National... Read More →

Friday October 12, 2018 3:15pm - 3:30pm EDT
Constellation C

3:15pm EDT

Strategies And Next Steps For Improving Sickle Cell Disease Care: Highlights From The Sickle Cell Disease Treatment Demonstration Program (SCDTDP)

Dr. Suzette O. Oyeku- National Institute for Children’s Health Quality (NICHQ) and Division of Academic General Pediatrics, Children’s Hospital at Montefiore/Department of Pediatrics, Albert Einstein College of Medicine, Dr. Ifeyinwa Osunkwo- Levine Cancer Institute, Carolinas HealthCare System, Dr. Allison King- Department of Pediatrics, Division of Pediatric Hematology/Oncology and Program in Occupational Therapy, Washington University School of Medicine, Ms. Lisa Shook- Division of Hematology, Department of Pediatrics, Cincinnati, OH Cincinnati Children’s Hospital Medical Center; Division of Pediatrics, University of Cincinnati, College of Medicine, Dr. Rosalyn W. Stewart- Departments of Internal Medicine and Pediatrics, Johns Hopkins University School of Medicine, Dr. Marsha Treadwell- UCSF Benioff Children's Hospital Oakland, Department of Hematology/Oncology; Center for Inherited Blood Disorders,
Dr. Julie Kanter- Division of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA, Dr. John Strouse- Division of Hematology, Department of Medicine, Duke University
Since the Sickle Cell Treatment Act of 2003, the Sickle Cell Disease Treatment Demonstration Program (SCDTDP), funded by the Health Resources and Services Administration (HRSA) has promoted best practice treatments, offered provider training, and increased access to high-quality care for individuals living with sickle cell disease in the US.
This session will highlight the impact and accomplishments of the 2013-2017 SCDTDP, lessons learned and recommendations as highlighted in programs 2017 Congressional Report to Congress. A panel including presenters from the National Coordinating Center and the five current Regional Coordinating Centers will share their collective results and describe their regional efforts to improve:
  • access to high quality knowledgeable care,
  • the use of disease modifying therapies (Hydroxyurea), and
  • and broaden knowledge base among providers for caring for patients, from childhood to adulthood with this disease.
Recommendations for SCD programs and initiatives, clinical care, and policy will be shared to bridge the program into its current iteration, introducing the additional 5th Regional Coordinating Center to join the project, covering the Southeast region of the United States.
Over the past three years, a regional model was established to increase: access to Hydroxyurea (a disease-modifying therapy); knowledgeable sickle-cell providers; and access to quality care. Regional learning collaboratives tracked progress through data collection and quality improvement efforts. Some brief highlights include:
Heartland Regional Coordinating Center (IA, KS, MO, NE) established telementoring programs for healthcare providers to address geographic disparities in care access.
Midwest Regional Coordinating Center (IL, IN, MI, MN, OH, WI) addressed gaps that affect care, including setting up satellite clinics that connected patients and local providers to staff and resources at larger medical systems with SCD expertise.
Northeast Regional Coordinating Center (DC, MD, NJ, NY, VA, PA, DE, WV, Virgin Islands, Puerto Rico) developed strong relationships with community-based organizations both in individual states and at the regional level to increase patient access to SCD care.
Pacific Regional Coordinating Center (AK, AZ, CA, ID, HI, OR, NV, WA, Guam) increased patient access to care with the opening of two new comprehensive centers for SCD care in key urban areas targeting larger concentrations of patients with SCD.
Southeast Regional Coordinating Center (AL, FL, GA, KY MS, NC, SC, TN), has been newly-funded for the 2017-2022 program cycle will be working to implement many of the lessons learned from their RCC colleagues as well as share innovation they are driving in the southeast region of the country.
The concerted efforts of SCDTDP have improved access to care, increased the use of Hydroxyurea among patients with SCD, and increased the number of providers knowledgeable about SCD. These efforts have led to the following accomplishments. Within this time, across the four regional learning collaboratives:
  • Nearly 11,000 patients with SCD are receiving care through SCDTDP regional networks, reflecting an increase of more than 3,000 from baseline
  • Nearly 7,000 patients with SCD are contributing information to electronic health registries
  • The number of patients reached increased by more than 3,000, hydroxyurea use increased across all regions, and
  • over 200 providers accessed telementoring services and strategies to improve care. The continuing national initiative builds off this previous work and increases the focus on ensuring the highest quality of care for patients living with sickle cell disease.
The regional collaborative approach has modest impact on meeting the overarching SCDTDP program objectives. Spread of innovative approaches identified in the SCDTDP to educate providers and enhance access to care are necessary to ensure continued improvements in the delivery of high quality care to individuals with sickle cell disease.


Mary Brown

President & CEO, PSCRC, Sickle Cell Disease Foundation of California

Suzette Oyeku MD, MPH, FAAP

Director, Academic General Pediatrics Fellowship, The Children’s Hospital at Montefiore

Roslyn W. Stewart, MD, MS, MBA

SiNERGe, Johns Hopkins University, School of Medicine

Lisa M. Shook, MA, MCHES

Instructor, STORM, Cincinnati Children’s Hospital Medical Center

Ifeyinwa Osunkwo, MD, MPH

EMBRACE, Levine Cancer Institute Division of Hematologic Oncology, Atrium Health

E. Donnell Ivy, MD, MPH

eivy@hrsa.gov, Health Resources and Services Administration

Taniya Varughese, MSOT, OTR/L

Heartland Sickle Cell Disease Network, Washington University School of Medicine

Friday October 12, 2018 3:15pm - 4:15pm EDT

3:30pm EDT

Compassionate-Use Voxelotor (GBT440) For Up To 2 Years In Patients With Severe Sickle Cell Disease And Life-Threatening Comorbidities

Dr. Gershwin T. Blyden- Foundation for Sickle Cell Disease Research,
Dr. Kenneth R. Bridges- Global Blood Therapeutics, Dr. Lanetta Bronté- Foundation for Sickle Cell Disease Research
Objective: Voxelotor (GBT440) is a first-in-class, oral, once-daily therapy designed to modulate the affinity of hemoglobin (Hb) for oxygen and delay sickle Hb polymerization, thereby reducing consequent red blood cell damage and life-threatening complications from sickle cell disease (SCD). Seven patients with severe SCD ineligible for ongoing clinical trials because of high mortality risk from comorbidities, including renal dysfunction, frequent hospitalizations for vaso-occlusive crisis (VOC), extreme anemia, and multiorgan failure were provided compassionate-use access to voxelotor by US Food and Drug Administration single-patient international new drug application.
Methods: Once-daily voxelotor began at 900 mg with possible increase to 1500 mg. Baseline echocardiograms were performed. Initial assessments at 2 and 4 weeks were followed by routine evaluations at least monthly. Key data captured included Hb levels, reticulocyte count, indirect bilirubin, resting oxygen saturation, pain level on 0-10 scale, transfusions, and hospitalizations for VOC. Patient Health Questionnaire 9-item (PHQ-9) assessed depression.
Results: Four female and 3 male patients aged 22-67 years had severe comorbidities at baseline including iron overload in all patients, frequent transfusions in 5/7, severe fatigue in 4/7, chronic oxygen supplementation in 2/7, and progressive severe renal dysfunction or multiorgan failure in 1 each. In 5/7 patients, baseline Hb was ≤6.4 g/dL, with three <6 g/dL. Hb level increased in all 7 patients by 24 weeks of voxelotor, with 5 reaching ≥1.0 g/dL. Hb increase due to voxelotor was clearest in 3 patients who experienced 1.0 to 5.4 g/dL Hb rises without transfusion. The number of transfusions fell by 60% in the 7 patients. VOC hospitalizations fell by 67%. Baseline oxygen saturation improved to 98%-99% from <95% in 4 patients following voxelotor treatment, permitting 2 patients to discontinue long-term supplemental oxygen. Overall well-being improved, typically 2-3 weeks after treatment initiation, for all patients, and the PHQ-9 score registered reduced depression. Voxelotor was well-tolerated with no discontinuations during treatment periods of up to 2 years. There was 1 dose reduction because of grade 2 diarrhea. Two patients with advanced end-stage organ injury died of SCD complications unrelated to treatment.
Conclusions: Seven patients given compassionate-use voxelotor after exhausting all treatment options achieved substantial improvements in clinical and mental health parameters for as long as 2 years. Controlled clinical trials will be needed to confirm the benefit of voxelotor in patients with severe SCD and multiple comorbidities.

avatar for Kenneth R. Bridges

Kenneth R. Bridges

Clinical Scientist, Global Blood Therapeutics
Dr. Kenneth R. Bridges received the MD degree from Harvard Medical School, and subsequently trainedin internal medicine and hematology in Boston, at Massachusetts General and Brigham and Women’sHospitals, respectively. Following medical subspecialty training, Dr. Bridges worked... Read More →

Friday October 12, 2018 3:30pm - 3:45pm EDT
Constellation C

3:45pm EDT

Crizanlizumab 5.0 Mg/Kg Increased the Time to First On-Treatment Sickel Cell Pain Crisis (SCPC) and the Likelihood of not Experiencing SCPC While on Treatment: Subgroup Analyses of the Phase 2 Sustain Study

Dr. Julie Kanter, Division of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA , Dr. Abdullah Kutlar, Sickle Cell Center, Medical College of Georgia, Augusta University, Augusta, Georgia, US, Dr. Darla Liles, Division of Hematology–Oncology, East Carolina University, Greenville, North Carolina, USA , Dr. Rodolfo Cancado, Department of Hematology–Oncology, Santa Casa Medical School of São Paulo, São Paulo, Brazil, Dr. Andreas Bruederle,  Novartis Pharma AG, Basel, Switzerland, Dr. Michael Shi, Novartis Pharma AG, Basel, Switzerland, Dr. Zewen Zhu, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, Dr. Kenneth Ataga, Division of Hematology–Oncology, University of North Carolina, Chapel Hill, North Carolina, USA , Dr. Menaka Bhor, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA        

Objective: In the 52-week SUSTAIN study, crizanlizumab 5.0 mg/kg significantly reduced frequency of SCPCs versus placebo (1.6 vs 3.0, P=0.01) and increased time to first on-treatment SCPC (4.1 vs 1.4 months, P=0.001) in patients with sickle cell disease (SCD). Objectives of this study included evaluating time to first SCPC in patient subgroups and likelihood of not experiencing SCPC for the duration of the trial using post hoc analyses.
Methods: SUSTAIN was a randomized, double-blind, placebo-controlled, phase 2 study (NCT01895361). Inclusion criteria were: SCD patients aged 16-65 years; 2-10 SCPCs in previous 12 months; concomitant hydroxyurea use permitted if ≥6 months and stable dose for ≥3 months. Patients were randomized 1:1:1 to receive intravenous crizanlizumab 5.0 mg/kg, 2.5 mg/kg, or placebo. Study treatments were administered on days 1 and 15, then every 4 weeks to week 50, with the final assessment at week 52. Median time to first SCPC after first dose was summarized for crizanlizumab 5.0 mg/kg or placebo in these subgroups: 2-4 or 5-10 SCPCs in previous 12 months; SCD genotype; and hydroxyurea use at baseline. Hazard ratios (HRs) for crizanlizumab 5.0 mg/kg versus placebo were calculated based on Cox regression analysis, with treatment as a covariate. Descriptive statistics were used to summarize frequency of patients who were SCPC event-free for the duration of the study by prior SCPC events, SCD genotype, and hydroxyurea use at baseline.
Results: 67 patients received crizanlizumab 5.0 mg/kg and 65 received placebo. There was a meaningful delay in time to first SCPC with crizanlizumab 5.0 mg/kg versus placebo observed in the entire study population. The effect was present in both SCPC subgroups, and the largest treatment difference was observed in HbSS SCD versus other genotypes (4.1 vs 1.1 months; HR: 0.50). In patients taking hydroxyurea who experienced 2-10 SCPCs in the previous year, time to first on-study SCPC was longer with crizanlizumab 5.0 mg/kg versus placebo (2.4 vs 1.2 months; HR: 0.58). A greater proportion of patients treated with crizanlizumab 5.0 mg/kg were SCPC event-free versus placebo in each of the analyzed subgroups. One third of patients who were taking hydroxyurea and treated with crizanlizumab 5.0 mg/kg were SCPC event-free during the study versus 17.5% with placebo, possibly suggesting an additive effect.  
Conclusions: With crizanlizumab 5.0 mg/kg, there was a clinically meaningful delay in time to first SCPC and an increased likelihood of being SCPC-free versus placebo in all subgroups investigated, including patients taking hydroxyurea who had still experienced 2-10 SCPCs in the previous year, indicating that P-selectin inhibition provided additional beneficial treatment effect compared with hydroxyurea alone.


avatar for Julie Kanter, MD

Julie Kanter, MD

Lifespan Hematologist, Medical University of South Carolina
Dr. Julie Kanter is a lifespan hematologist specializing in sickle cell disease.  She is an associate professor of Pediatrics at the Medical University of South Carolina and runs the first all-ages, Lifespan Comprehensive Sickle Cell Center.  Dr. Kanter works closely with national... Read More →

Friday October 12, 2018 3:45pm - 4:00pm EDT
Constellation C

4:00pm EDT

Parent and Youth Barriers to Hydroxyurea Adherence in Adolescents with Sickle Cell Disease

Dr. Arlene Smaldone, Columbia University School of Nursing, Dr. Deepa Manwani, The Children's Hospital at Montefiore,  Dr. Nancy S. Green, Columbia University Medical Center  

Objective:  The purpose of this study was to examine the effect of a community health worker (CHW) intervention on reduction of self-reported barriers to hydroxyurea (HU) adherence in a sample of poorly adherent youth ages 10-17 years who participated with their parent in the Hydroxyurea Adherence for Personal Best in Sickle Cell Disease "HABIT" feasibility trial. Dyads randomized to the intervention worked with CHWs to develop a HU habit reinforced by daily personized text messages.
Methods: We modified the Adolescent Medication Barriers Scale (AMBS) (17 items) and its parent counterpart, Parent Medication Barriers Scale (PMBS) (16 items) for use with HU by adding 9 items regarding HU beliefs.  Three subscales (Disease frustration, Regimen adaptation, Ingestion Issues) are common to both scales; the parent scale has an additional subscale (Reliance on parent reminders). Youth and parents completed the measure at 0, 3 and 6 months in either Spanish or English. Youth and parent proxy reported generic (PedsQL) and disease specific (PedsQL Sickle Cell module) HRQL were measured at the same intervals. Data were analyzed using Cronbach's alpha, descriptive statistics, spearman correlation coefficients and linear growth models controlling for group assignment and time.
Results: 28 parent youth dyads (50% Latino, youth 43% female, age 14.3 ± 2.6 years) participated. Internal reliability was high for both parent (alpha=0.88) and youth (alpha=0.91) total scales and all subscales except the parent ingestion subscale (alpha=0.30). On average, parents and youth acknowledged 3.5±3.2 and 5.0±3.9 total barriers (possible score 0-25 youth; 0-26 parents) respectively. Adherence barriers most frequently reported by parents were child overreliance on parent reminders [42.9%]; adolescent frustration (child tired of living with SCD [35.7%]); regimen adaptation problems (finding it hard to stick to a medication schedule [28.6%]); and HU beliefs (parent concern about possible adverse HU effects on fertility or on a fetus [25%]). Youth most frequently reported barriers were related to adolescent frustration (tired of living with SCD [57.1%]; being forgetful and not always remembering to take HU [53.6%], tired of taking HU [39.3%], not wanting to take HU at school [28.6%], and not wanting to be seen taking HU [25%],); ingestion issues (HU hard to swallow [25%], too many pills to take [39.3%], dislikes HU taste [35.7%]); and regimen adaptation problems (not organized about when and how to take HU [28.6%]). Parent and youth responses were moderately correlated for the total scale (r=0.50, p<0.001) and all subscales except HU beliefs (r=0.08, p=0.51). Greater number of barriers were associated with lower generic (parent r=-0.43, p=0.03; youth r=-0.44, p<0.001) and disease specific (parent r=-0.53, p=0.005; youth r=-0.53, p<0.001) HRQL. Controlling for group assignment and time, intervention parents demonstrated a trend in less reported adolescent frustration (p=0.18) at 6 months whereas for adolescents assigned to the intervention group, ingestion related barriers significantly declined (0.17/month, p=0.02) over 6 months. Total barriers and other subscales did not significantly change. 
Conclusions: Barriers to adherence are prevalent, multi-faceted and perceived differently by youth prescribed HU and their parents. Greater barriers were associated with poorer youth and parent-proxy reported generic and disease specific HRQL. Some barriers, e.g. problems with ingestion, are potentially modifiable. A CHW delivered intervention helped youth reduce their ingestion barriers to HU use. To derive the full value of HU in youth with SCD, barriers to its use must be addressed with both youth and parents.

avatar for Arlene Smaldone, PhD, CPNP, CDE

Arlene Smaldone, PhD, CPNP, CDE

Professor of Nursing, New York Academy of Medicine: Section on Evidence Based Health Care Columbia University School of Nursing
Dr. Smaldone is a Professor of Nursing and Dental Behavioral Sciences at Columbia University Medical Center. Dr. Smaldone is a behavioral researcher whose research focuses on self-management for youth with chronic health conditions. Dr. Smaldone's research in youth with sickle cell... Read More →

Friday October 12, 2018 4:00pm - 4:15pm EDT
Constellation C

4:15pm EDT

Sickle Cell Patients with Leg Ulcers have a Pro-Thrombotic Profile

Dr. Ugochi Ogu, Montefiore Medical Center, Ms. Ashley Buscetta, National Human Genome Research Institute/National Institutes of Health, Ms. Elena Crouch, Montefiore Medical Center, Dr. Shuo You, Montefiore Medical Center, Prof. Moonseong Heo, Montefiore Medical Center, Ms. Khadijah Abdallah, National Human Genome Research Institute/National Institutes of Health, Dr. Giacomo Vinces, ontefiore Medical Center,Mr. Vence Bonham, National Human Genome Research Institute/National Institutes of Health, Prof. Caterina Minniti, Montefiore Medical Center

- To review coagulation profile in sickle cell disease (SCD). 
- To describe coagulation profile in SCD patients with leg ulcers. 
Leg ulcers are a serious complication of Sickle Cell Disease, often linked to a hemolytic phenotype that includes, priapism, pulmonary hypertension and renal disease. In the SCD pathogenesis, hemolysis and ischemia-reperfusion injuries lead to WBC, platelet and endothelial cell activation, pro inflammatory cytokine production and subsequent activation of coagulation that tips the balance towards a prothrombotic state. Decreased levels of the naturally occurring anticoagulants (protein C, protein S, antithrombin III), have been observed in patients with SCD in steady state, with some reports stating no differences between steady state and crisis. These decreases occur due to decreased production, increased consumption, or a combination of both. However, the definite mechanisms have not yet been elucidated. Factor V Leiden and prothrombin G20210A mutations are rare in African Americans and in patients with SCD. We speculated that patients with leg ulcers would have a more pronounced pro-thrombotic phenotype than patients who never developed them. 
127 adults with and without SCD leg ulcers were evaluated at steady state in the prospective cross-sectional INSIGHTS study - Insights into Microbiome and Environmental Contributions to Sickle Cell Disease and Leg Ulcers (ClinicalTrials.gov Identifier NCT02156102). At the time of enrollment, a clinical examination and a complete past medical history were completed. Routine blood work including a full coagulation profile and analysis of blood clotting genetic mutations (thrombophilia genetic tests) were obtained. Laboratory results were compared between groups with and without leg ulcers using Chi-square or Fisher exact tests.
The study cohort consisted of 109 adults with Hb SS, 10 with Hb SC, 5 with Hb S beta thalassemia zero, and 3 with Hb S beta thalassemia plus. Of these, there were 35 subjects with leg ulcers (33 with Hb SS, 1 with Hb S beta thalassemia zero, 1 with Hb SC disease). Naturally occurring anticoagulants were found to be decreased in the sub-group of subjects with leg ulcers. In SCD patients with leg ulcers, 49% had functional protein C levels that were below the lower limit of normal, compared to 27% in SCD patients without leg ulcers (*p=0.0220); 74% had functional protein S levels that were below the lower limit of normal, compared to 51% in SCD patients without leg ulcers (*p=0.0181); 23% had antithrombin III (AT III) levels that were below the lower limit of normal, compared to 17% in SCD patients without leg ulcers (p=0.4820); and 29% tested positive for lupus anticoagulant, compared to 25% in SCD patients without leg ulcers (p=0.6818). In SCD patients with leg ulcers, none of the subjects had the prothrombin gene mutation, while 3 subjects without leg ulcers were heterozygous for the prothrombin mutation. None of the subjects in our cohort had factor V Leiden mutation.
In SCD patients with leg ulcers, protein C and protein S levels are significantly lower than in SCD patients without leg ulcers. Additionally, in SCD patients with leg ulcers, there is a trend towards decreased levels of AT III, and higher percentage of patients that are positive for lupus anticoagulant. Factor V Leiden and prothrombin gene mutations were rare in our cohort, consistent with the general population. 
Our results of decreased naturally anticoagulants confirm previous reports from our group that demonstrated similar findings. Of greater significance, however, is our finding that sickle cell patients with leg ulcers have further decreased levels of the naturally occurring anticoagulants, compared to their counterparts without leg ulcers. This finding lends credence to the hypothesis that sickle cell patients with leg ulcers have a procoagulant phenotype.1,2 In such patients, the clinical index of suspicion for thromboembolic events should be high. It is important to consider and evaluate for venous clots in such patients. A deep venous thrombus (DVT) found in a sickle cell patient with leg ulcer, could be the primary inciting factor for the ulcer or deterrent for wound healing.  
Future directions of our study involve correlating these laboratory values with clinical history and findings in these patients. History of thromboembolic events such as DVT and pulmonary embolism (PE) will be evaluated to detect if the laboratory findings clinically correlate to a procoagulant phenotype. 
1-Am J Hematol. 2011 Aug; 86(8): 705–708. 
2-Am J Hematol. 2014 Jan; 89(1): 1–6

avatar for Ugochi Ogu, M.D.

Ugochi Ogu, M.D.

Assistant Professor/ Asssitant Director, Montefiore Medical Center Division of Hematology, Department of Oncology
Dr. Ogu is an Assistant Professor of Clinical Medicine and Pediatrics at the Albert Einstein College of Medicine. She obtained her medical degree at Windsor University School of Medicine in the West Indies, completed residency in Pediatrics at the University of Iowa, and fellowship... Read More →

Friday October 12, 2018 4:15pm - 4:30pm EDT
Constellation C

4:30pm EDT

Crizanlizumab Treatment is Not Asoociated with the Development of Proteinuria and Hematuria in Patients with Sickle Cell Disease: Sustain Study Safety Analysis

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.

avatar for Julie Kanter, MD

Julie Kanter, MD

Lifespan Hematologist, Medical University of South Carolina
Dr. Julie Kanter is a lifespan hematologist specializing in sickle cell disease.  She is an associate professor of Pediatrics at the Medical University of South Carolina and runs the first all-ages, Lifespan Comprehensive Sickle Cell Center.  Dr. Kanter works closely with national... Read More →

Friday October 12, 2018 4:30pm - 4:45pm EDT
Constellation C

4:45pm EDT

Genome Editing to Fix the Sickle Cell Disease Causing Variant in Sickle Cell Patient Hematopoietic Stem Cells

Dr. Matthew Porteus- StandFord University, Dr. Daniel Dever- StandFord University, Dr. Annalisa Lattanzi- StandFord University, Mr. Joab Camarena- StandFord University,Mr. Carsten Charlesworth- StandFord University, Dr. Helen Segal- StandFord University, Dr. Neehar Bhatia- StandFord University, Dr. David Digiusto- StandFord University

Objective: The objective our research program is to complete the pre-clinical work demonstrating the safety and efficacy of genome editing of somatic hematopoietic stem cells to correct the sickle cell disease causing variant in order to develop a strategy to potentially cure sickle cell disease.
Methods: We have developed a genome editing approach that utilizes the CRISPR/As9 nuclease system that directly corrects the sickle cell disease causing mutation in hematopoietic stem cells using homologous recombination. We isolate both healthy donor and patient derived CD34+ hematopoietic stem and progenitor cells (HSPCs). We then genetically modify these cells ex vivo using a combination of CRISPR/Cas9 nuclease and AAV6 transduction. We evaluate the efficacy of the approach by measuring the percent hemoglobin A in red blood cells derived from genome edited sickle cell patient HSPCs. We evaluate the safety and efficacy by measuring the how well the edited HSPCs engraft and generate blood cells following transplantation of the human cells into immunodeficient (NSG) mice. We measure safety by determining the location of potential off-target INDELs created by the CRISPR/Cas9 nuclease the frequency that INDELs are created at these sites in CD34+ HSPCs.
Results: In CD34+ HSPCs from sickle cell patients, we are able to achieve 60-80% allele correction of the sickle cell mutation. These edited cells give rise to red blood cells that express ~92% Hgb A and 8% Hgb S. When transplanted into mice, the percent allele correction remains above 50% in the human cells thus demonstrating that the modified cells retain their key stem cell properties--the ability to give rise to long-term hematopoiesis in an animal model. After transplantation there is no evidence of abnormal hematopoiesis from the human cells thus providing evidence of safety. When we use a high-fidelity version of Cas9, we detect off-target mutations at only a single site and this site is 95 kb away from the nearest protein coding gene and of no known functional significance. We have submitted a pre-IND application to the FDA and based on FDA feedback are performing the key experiments to file a successful IND to initiate a phase I/II clinical trial testing the strategy in patients. These experiments including scaling up the process to a clinical scale and performing more complete testing of safety in an animal model. These studies are ongoing and we will present ongoing results at the meeting.
Conclusions: Genome editing provides a potentially precise mechanism to genetically correct the disease causing variant that causes sickle cell disease. Our preclinical results are very promising and if we are able to complete our IND enabling experiments we hope to launch a phase I/II clinical trial testing the strategy in 2019.

avatar for Matthew Porteus, MD

Matthew Porteus, MD

Clinical Trial Specialist, Stanford University
Dr. Porteus is physician-scientist trained in Pediatric Hematology/Oncology who is an Associate Professor at Stanford University. His research program has focused on genome editing of hematopoietic stem and progenitor cells to develop cell based autologous cures for patients with... Read More →

Friday October 12, 2018 4:45pm - 5:00pm EDT
Constellation C

5:00pm EDT

Correction of the Sickle Mutation in Hematopoietic Stem/Progenitor Cells with CRISPR/Cas9: The Berkeley/UCSF/UCLA Sickle Cell Clinical Translation Project

Dr. Mark Dewitt-UC Berkeley, Mrs. Wendy Magis-CHORI, Dr. Stacia Wyman-UC Berkeley, Dr. Zulema Romero-UCLA, Mr. Jonathan Vu- UC Berkeley, Prof. Dario Boffelli- CHORI, Dr. Mark Walters- USCF Benioff Children’s Hospital Oakland, Dpt. Of Hematology/Oncology: Center for Inherited Blood Disorders, Dr. Donald Kohn-UCLA, Prof. Jacob Corn –UC Berkeley, Prof. David Martin- CHORI

Sickle Cell Disease (SCD) is a recessive genetic disorder caused by a single nucleotide polymorphism (SNP) in the ß-globin gene (HBB). CRISPR/Cas9 is a gene editing technology that can be used to correct the sickle mutation directly. Here we report progress towards clinical translation of a CRISPR/Cas9 gene editing approach to treat SCD. Our focus is on direct correction of the disease mutation itself. Our approach is based on electroporation of a Cas9 ribnucleoprotein (purified Cas9 protein and a synthetic protected sgRNA) with an optimized single-stranded DNA donor which programs correction of the sickle mutation by homology-directed repair (HDR) in hematopoietic stem/progenitor cells (HSPCs) from sickle cell disease donors. Our approach relies on animal-free synthetic reagents, avoiding use of viral vectors. By avoiding viral HDR donors, our approach promises to reduce manufacturing costs, and ultimately improve accessibility. We obtained surplus HSPC from participants in a sickle cell disease gene therapy trial after mobilization with plerixafor, the same source of cells in our planned clinical protocol. Using an optimized gene correction protocol, we routinely achieved >30% correction of the mutation in these cells. When differentiated into erythroblasts, 70% of hemoglobin is non-sickle, of which 40% is corrected adult hemoglobin. When transplanted into immune-deficient mice, corrected cells maintain engraftment ~10-fold better than cells edited with a AAV6 viral HDR donor. Most importantly, the corrected allele is maintained in 22% of alleles in bone marrow, a substantial improvement over previous studies in SCD. In glycophorin-expressing erythroblasts in circulating blood, the corrected allele is further enriched to 30%, evidence for ineffective erythropoiesis in sickle- or indel-containing cells.
To define the off-target genotoxicity of our sickle correction protocol, we identified off-target sites using a combination of GUIDE-seq and bioinformatics. Using a pooled primer PCR approach, we find that the vast majority of these off-targets have no detectable mutagenesis. We found that a commercially-available high-fidelity Cas9 variant can reduce off-target activity 20-fold or more in HSPCs, with no loss in on-target activity. Only one single off-target site is targeted in >0.2% of the cells. Together, these studies suggest a manufacturing protocol to correct CD34+ HSPC from SCD patients that is both safe and effective in delivering a long-term clinical benefit. We have started IND-enabling studies, and anticipate filing an IND to commence a Phase I clinical trial in 2019.

avatar for Mark Dewitt

Mark Dewitt

Project Scientist, Berkeley University
"Mark DeWitt is project manager for a late-stage preclinical development project in sickle cell disease, funded through a grant from the California Institute for Regenerative Medicine (CIRM). The project is a collaboration between UCLA, UC Berkeley, and UC San Francisco. Our approach... Read More →

Friday October 12, 2018 5:00pm - 5:15pm EDT
Constellation C

5:15pm EDT

The Clinical-Stage SGC Stimulator Olinciguat Prevents Increase Of Plasma Biomarkers Of Intravascular Inflammation And Suppresses Leukocyte-Endothelial Interactions In Tnfa-Treated Mice

Authors:Dr. Regina Graul- IronWood Pharmaceuticals, Dr. Boris Tchernychev- IronWood Pharmaceuticals, Ms. Susan Feil- University of Tubingen, Prof. Robert Feil- University of Tubingen, Ms. Elisabeth Lonie –IronWood Pharmaceuticals, Dr. Peter Germano- IronWood Pharmaceuticals, Dr. G. Todd Milne- IronWood Pharmaceuticals, Mr. John Hadcock- IronWood Pharmaceuticals, Dr. Yueh-Tyng Chen- IronWood Pharmaceuticals, Dr. Mark Currie- IronWood Pharmaceuticals    

 Objective: Olinciguat is a soluble guanylate (sGC) stimulator in clinical development for the treatment of patients with sickle cell disease (SCD). sGC is a signaling enzyme that increases the production of cyclic guanosine 3’,5’-monophosphate (cGMP) from guanosine triphosphate in response to nitric oxide (NO) binding. The sGC stimulator olinciguat binds to sGC and enhances its NO-dependent activity. Conditions of low NO bioavailability, as seen in hemoglobinopathies such as sickle cell disease, are proposed to lead to increased vascular inflammation, cellular adhesion, and reduced blood flow due to vasoconstriction. By enhancing NO signaling through sGC, olinciguat is hypothesized to reduce vascular inflammation and restore blood flow and tissue oxygenation. Preclinically, modulation of the NO-sGC-cGMP pathway via treatment with NO or with inhibitors of the cGMP-selective phosphodiesterase 9 has been demonstrated to significantly attenuate TNFa-induced intravascular inflammation in C57BL/6 and sickle cell mice. We evaluated the effect of olinciguat alone and with hydroxyurea (HU, current SCD standard of care) on biomarkers of intravascular inflammation, leukocyte-endothelial cell interactions, and neutrophil trafficking in C57BL/6 mice.
Methods and Results: Treatment of C57BL/6 mice with TNFa (50 ng/mouse, ip) increased the plasma levels of biomarkers of endothelial cell activation (sP-selectin, sE-selectin, sICAM-1) and leukocyte activation (MIP-2, sL-selectin). Pretreatment of mice with olinciguat (10 mg/kg, po) attenuated the increase in plasma concentrations of MIP-2 and sL-selectin following TNFa challenge by 81% and 58%, respectively. The TNFa-induced increase in plasma levels of sP-selectin, sE-selectin, and sICAM-1 were attenuated by 31%, 37%, and 34%, respectively, in olinciguat-treated mice. Co-treatment with HU augmented the effect of olinciguat on plasma concentrations of sE-selectin and sICAM-1 in TNFa-treated mice.
The effects of olinciguat, HU, and the combination on leukocyte endothelial cell interactions were assessed using intravital microscopy of post-capillary venules of the mouse cremaster muscle. Compared to controls, TNFa-treated C57BL/6 mice had slower leukocyte velocity (5.5±0.7 vs 26.6±3.1 µm/sec in controls) and leukocyte rolling flux (16.1±2.7 vs 43.3±7.1 cells/min in controls). Pretreatment with olinciguat (10 mg/kg) alone resulted in faster leukocyte velocity and rolling flux (10.3±1.1 µm/sec and 24.1±2.3 cells/min, respectively) compared to TNFa-treated controls. Similarly, pretreatment with HU (100 mg/kg, po) alone led to faster leukocyte velocity and leukocyte rolling flux (5.5±1.7 µm/sec and 50.2±5.9 cells/min, respectively). Co-administration of olinciguat and HU led to even faster leukocyte velocity and leukocyte rolling flux (19.7±1.9 µm/sec and 64.5±5.5 cells/min, respectively). Treatment with either olinciguat, HU, or the combination did not change leukocyte adherence following TNFa stimulation. To further evaluate the effect of olinciguat on neutrophil extravasation and trafficking we used a peritoneal recruitment model. Intraperitoneal injection of TNFa induced accumulation of Gr.1 polymorphonuclear leukocytes (PMN) in the mouse peritoneal cavity (4±0.4×105 PMNs/peritoneal lavage). Trafficking of PMNs into mouse peritoneum was attenuated by pretreatment of mice with HU (2.7±0.5×105 PMNs/peritoneal lavage). Co-administration of olinciguat and HU further attenuated the number of neutrophils extravasated into the peritoneum of TNFa-challenged mice (1.4±0.3×105 PMNs/peritoneal lavage) relative to TNFa-treated controls.
 Conclusion: In summary, prophylactic treatment with olinciguat inhibited the TNFa-induced increase in plasma levels of biomarkers of intravascular inflammation and attenuated the effect of TNFa on transient adhesive interactions between leukocytes and endothelial cells in mice. Co-administration with HU led to significantly reduced neutrophil trafficking and augmented the effect of olinciguat on biomarkers of endothelial cell activation and transient adhesive interactions in the mouse cremaster muscle. This study supports evaluation of the sGC stimulator olinciguat in patients with SCD.


Boris Tchernychev


Friday October 12, 2018 5:15pm - 5:30pm EDT
Constellation C