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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