Sickle Cell Disease New Drug Therapies –
Anti-Adhesion Agents
Matthew M. Heeney, MD Associate Chief, Hematology Director, Sickle Cell Program Children’s Hospital Boston
ASCAT 10th Academy for Sickle Cell and Thalassaemia
London, U.K. 5 October, 2016 - 7 October, 2016
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Faculty Disclosure
Matthew M. Heeney, MD
Personal financial interests in commercial entities that are relevant to my presentation:
Eli Lilly Clinical Trial Funding Pfizer Clinical Trial Funding Astra Zeneca Clinical Trial Funding Sancilio & Co Consultant
I am Canadian!
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The Economist (Economist.com)
Search Volume for “Move to Canada”
Hurricane Matthew
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• Discuss new pathophysiologically-based sickle cell disease therapies that target:
oPlatelet activation
oAnti-adhesion o Specific
oNon-specific
Objectives
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Intra-cellular
dehydration
Reperfusion Injury
Inflammation
Endothelial Activation
Vaso-occlusion
Nitric Oxide
consumption
Hemolysis
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Sickle Cell Pathophysiology • HbS deoxygenation / polymerization
• Hemolysis / NO consumption
• Inflammation / reperfusion injury
• Endothelial dysfunction / adhesion
- Erythrocytes / Reticulocytes - Leukocyte - Platelets
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Intravital Microscopy
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Cremaster Muscle Venule + TNF
Frenette P et al. Microcirculation 2004
• Orphan Drug Act (ODA 1983) – Tax incentives. – Enhanced patent protection and marketing rights.
• Rare Diseases Act (RDA 2002) – Establish Office of Rare Diseases at NIH.
• Pediatric Research Equity Act (PREA 2003) • Best Pharmaceuticals for Children Act (BPCA 2002)
– Increase pediatric trials to ensure adequate testing, safety, and efficacy of new therapies for children.
– Simple goal - develop new and innovative evidence-based therapies to extend/enhance lives of children.
Changing Landscape in U.S.
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• Biomarkers of platelet activation are elevated in SCD at baseline; further elevate during VOC.
• Rationale for antiplatelet therapy to reduce platelet activation, frequency and severity of VOC.
• ADP released from hemolyzing sickle cells induces platelet activation/aggregation through the platelet P2Y12 ADP receptor.
• Platelet P2Y12 ADP receptor antagonists exist.
Platelet inhibition
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Molecular targets of antiplatelet agents
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Michelson AD. Nat Rev Drug Discov. 2010 Feb;9(2):154-69.
• Eli Lilly (Prasugrel)
- Phase 3 DOVE trial
(NCT01794000) completed.
• Astra Zeneca (Ticagrelor)
- Phase 2 HESTIA 2 trial
(NCT02482298) completed – results pending.
- Phase 2 HESTIA 1 trial
(NCT02214121) enrolling.
Platelet inhibition
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• Multinational Phase III, Double-Blind, Randomized, Efficacy and Safety Comparison of Prasugrel and Placebo in Pediatric Patients with Sickle Cell Disease.
• HbSS and HbSβ0 thalassemia.
• Age ≥2 and ≤16 years. N=341
• 9 months of treatment with an OLE.
• 51 study sites in 14 countries. – USA, Canada, Brazil, Lebanon, Egypt, Turkey, Italy, Belgium, France, UK,
Netherlands, Ghana, Kenya, Oman, Saudi Arabia, UAE
Eli Lilly (Prasugrel)
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1. Inclusion of children from low-resource countries with a high disease burden.
2. Individualized treatment using a dose-titration strategy that balances potential clinical efficacy and safety.
3. Assessment of vaso-occlusive pain outcomes using a daily electronic diary (ePRO).
Novel Features
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• Primary objective:
– efficacy of Prasugrel compared to placebo as measured by reduction in the rate of VOC, a composite endpoint of painful crisis or acute chest syndrome.
• Secondary objectives
– efficacy of Prasugrel • rate of VOC *
• intensity of VOC *
• hospitalization rate for VOC
• rate of acute chest syndrome
• rate of red blood cell (RBC) transfusion
• use of analgesics *
• school absence *
Objectives
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* Using ePRO
Total Randomized
N=341
Prasugrel
N=171
9-Month Visit completed
No
N=36
(21.1%)
No
N=30
(17.6%)
Discontinued study
prior to 9-month visit
N=14 (8.2%)
Completed 24 months
of double-blind period
N=0
Completed 24 months
of double-blind period
N=2
N=132*
(77.6%)
Discontinued study
after 9-month visit
N=6 (3.5%)
Discontinued study
prior to 9-month visit
N=10 (5.9%)
CONSORT FLOW DIAGRAM
Continuing Double-Blind Period
Discontinued study
after 9-month visit
N=3 (1.8%)
N=20
(11.8%)
N=132
(77.2%)
N=22
(12.9%)
Placebo
N=170
Yes
N=135
(78.9%)
Yes
N=140
(82.4%)
1 (0.06)
1 (0.06)
0 (0.0)
0 (0.0)
11 (6.5)
0 (0.0)
3 (1.8)
1 (0.06)
2 (1.2)
1 (0.06)
2 (1.2)
6 (3.5)
0 (0.0)
5 (2.9)
Discontinuation during
double blind period
N=16 (9.4%)
Death
Adverse event
Sponsor decision
Physician decision
Subject decision
(Consent withdrawn)
(Consent revoked)
Parent/caregiver decision
Discontinuation during
double blind period
N=17 (9.9%)
Death
Adverse event
Sponsor decision
Physician decision
Subject decision
(Consent withdrawn)
(Consent revoked)
Parent/caregiver decision
Heeney MM et al, NEJM 2016
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Rate of VOC
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Treatment No Patients
w/events (%)
Total no events
Length of follow-up
Event rate
Crude rate ratio
Rate Ratio 95% CI (lower, upper)
p-value
prasugrel (N=171)
115 (67.3) 328 142.89 2.295 0.830 0.83 (0.66, 1.05)
.117
placebo (N=170)
123 (72.4) 408 147.44 2.767
Heeney MM et al. N Engl J Med 2016; 374:625-635
Mean number of VOC
Heeney MM et al. N Engl J Med 2016; 374:625-635
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Rate of VOC by age
Age
Prasugrel Placebo
Rate Rate ratio 95% CI
p-value
Events Years Rate Events Years Rate
>=2 to < 6
35 16.6 2.1 34 14.8 2.3 0.92 (0.49, 1.73) 0.804
>=6 to < 12
140 60.9 2.3 150 63.0 2.4 0.97 (0.68, 1.39) 0.856
>=12 to < 18
153 65.4 2.3 224 69.7 3.2 0.72 (0.51, 1.02) 0.063
Heeney MM et al. N Engl J Med 2016; 374:625-635
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Mean Number of Vaso-Occlusive Crises 12 -17 years of age
Heeney MM et al. N Engl J Med 2016; 374:625-635
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PRU Distribution at Baseline and at Fully Titrated Dose
ISTH Montpellier, France; May 25 – 28, 2016
• Randomized, Double-Blind, Placebo controlled, Multicenter, Phase II Evaluation of Ticagrelor in Reducing the Number of Days With Pain in Young Adults With Sickle Cell Disease HESTIA 2. (NCT02482298)
• HbSS and HbSβ0 thalassemia. • Age 18 - 30 years. N= 90 • 12 weeks of treatment. • Number of days/intensity of SCD pain (ePRO) • 21 study sites in 8 countries.
– USA, Egypt, France, Italy, Kenya, Lebanon, Turkey, & UK.
Astra Zeneca (Ticagrelor)
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• Multicenter, open-label, randomized, PK/PD dose-ranging Phase II study of ticagrelor followed by a double-blind, randomized, placebo-controlled 4 weeks extension in pediatric patients with SCA HESTIA 1 (NCT02214121)
• HbSS and HbSβ0 thalassemia. • Age 2 - 18 years. N= 40 • 35 study sites in 10 countries.
– USA, Canada, Egypt, Ghana, Italy, Kenya, Lebanon, South Africa, Turkey, and United Kingdom.
Astra Zeneca (Ticagrelor)
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Leukocyte contribution to VOC
Manwani D and Frenette PS Blood. 2013:122(24):3892-3898
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Selectin Biology / Inhibition
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Glycomimetics / Pfizer (Rivipansel)
– Synthetic glycomimetic molecule
– Rationally designed to inhibit all 3 selectin types (E-selectin, L-selectin and P-selectin)
– “Pan-selectin”
– Episodic acute VOC treatment approach.
– Phase 2 (NCT01119833) - complete.
– Phase 3 Rivipansel: Evaluating Safety, Efficacy and Time to Discharge RESET (NCT02187003) - enrolling.
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Rivipansel (GMI-1070) • Phase II multi-center, prospective,
randomized, double blind study in hospitalized sickle cell anemia patients experiencing VOC. (NCT01119833)
• N = 76 patients 22 N.A. sites
• Ages 12 to 60 years
• HbSS or HbSβ0 thalassemia with VOC.
• Loading dose IV, followed by q 12 h doses.
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Telen M. Blood. 2015 Apr 23;125(17):2656-64
Rivipansel (GMI-1070)
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Telen M. Blood. 2015 Apr 23;125(17):2656-64
• Time to resolution of VOC was reduced by GMI-1070 (28% and 48% reduction in mean and median time to resolution).
Rivipansel (GMI-1070)
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Telen M. Blood. 2015 Apr 23;125(17):2656-64
• Time to readiness for discharge and time to discharge were shortened with GMI-1070.
Rivipansel (GMI-1070) • 83% reduction in cumulative IV opioid use (p=0.010). • The effect on opioid use was seen within 24 h.
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Telen M. Blood. 2015 Apr 23;125(17):2656-64
Rivipansel • RESET (NCT02187003)
• Phase III multi-center, prospective, randomized, double blind study in hospitalized sickle cell disease patients experiencing VOC.
• N = 350 patients 83 sites
• Ages >6 years
• HbSS, HbSβ thalassemia, HbSC or HbS-Variant
• Loading dose IV, followed by 8 X q 12 h doses.
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Selexys (SelG1) • SelG1 is a humanized
monoclonal antibody that binds to human P-selectin and blocks the interactions with its ligand PSGL-1.
• Human IgG2 heavy chain constant region.
• Human kappa light chain constant region.
• Murine derived complementarity zones of the variable regions.
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P-selectin
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http://www.selexys.com/
Selexys – SUSTAIN (NCT01895361)
• Phase II, multicenter, randomized, placebo-controlled, double-blind, Study to Assess Safety and Efficacy of SelG1 With or Without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises.
• Chronic preventive approach.
• Age 16 - 65 years
• 2 - 10 VOC within the last 12 months.
• HbSS, HbSC, HbSβ0- and HbSβ+-thalassemia.
• N = 174
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Selexys – SUSTAIN (NCT01895361)
• Primary endpoints
– Rate of SCPC per year in each dose level as compared to placebo (efficacy).
– Frequency and severity of adverse events and other safety data in each arm as considered appropriate (safety).
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Selexys – SUSTAIN (NCT01895361)
• Administered IV over 30 minutes.
• Loading Dose: Day 1 and Day 15 ± 3 days
• Maintenance Dose: beginning at Week 6 and continuing every 4 weeks through Week 50 (Final Dose).
• Study completed – Results pending.
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• Mast Therapeutics (MST-188 Velpoloxamer)
– EPIC trial (NCT01737814) Completed.
Endothelial Dysfunction
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Velpoloxamer - Background & Rationale
• Vepoloxamer is a nonionic material that reduces erythrocyte aggregation and cellular adhesion to the vascular endothelium in a non-specific manner.
• Vepoloxamer adheres to damaged cell membranes, restoring the cell’s natural, hydrated, non-adhesive surface and decreases whole blood viscosity.
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• A Phase III Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Vepoloxamer in Sickle Cell Disease with Vaso Occlusive Crisis.
• HbSS, HbSC, HbSβ0 thal, or HbSβ+ thal.
• Age 4 - 65 years.
• N=388
• 77 study sites in 14 countries. • USA, Canada, Belgium, Brazil, Dominican Republic, Jamaica, Jordan,
Lebanon, Oman, Panama, Spain, Turkey...
EPIC (NCT01737814)
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Velpoloxamer - Results
September 2016
• Velpoloxamer did not significantly reduce in the mean duration of VOC compared to placebo (82 hours vs 78 hours (p=0.09)).
• No statistically significant differences between Velpoloxamer and placebo for the rate of re-hospitalization for VOC or the occurrence of acute chest syndrome.
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Velpoloxamer – Ramifications?
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To Do • Continue to urge development of
pathophysiologically directed research and clinical trials.
• Need indefatigable investigators
• Need courageous patients/families.
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CME Question
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Which of these is not like the others?
Hint: There may be more than one Diva
Acknowledgements
Russell E. Ware MD, PhD
Ellis J. Neufeld MD, PhD
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