Sickle Cell Disease. New Drug Therapies Anti-Adhesion Agents

Transcription

1 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 10 th Academy for Sickle Cell and Thalassaemia London, U.K. 5 October, October, 2016

2 Faculty Disclosure Matthew M. Heeney, MD Personal financial interests in commercial entities that are relevant to my presentation: Eli Lilly Pfizer Astra Zeneca Sancilio & Co Clinical Trial Funding Clinical Trial Funding Clinical Trial Funding Consultant I am Canadian! 2

3 Search Volume for Move to Canada The Economist (Economist.com) 3

4 Hurricane Matthew 4

5 Objectives Discuss new pathophysiologically-based sickle cell disease therapies that target: oplatelet activation oanti-adhesion o Specific o Non-specific 5

6 Intra-cellular dehydration Vaso-occlusion Reperfusion Injury Inflammation Endothelial Activation Hemolysis Nitric Oxide consumption 6

7 Sickle Cell Pathophysiology HbS deoxygenation / polymerization Hemolysis / NO consumption Inflammation / reperfusion injury Endothelial dysfunction / adhesion - Erythrocytes / Reticulocytes - Leukocyte - Platelets 7

8 Intravital Microscopy Cremaster Muscle Venule + TNF Frenette P et al. Microcirculation

9 Changing Landscape in U.S. 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. 9

10 Platelet inhibition 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 P2Y 12 ADP receptor. Platelet P2Y 12 ADP receptor antagonists exist. 10

11 Molecular targets of antiplatelet agents Michelson AD. Nat Rev Drug Discov Feb;9(2):

12 Eli Lilly (Prasugrel) Platelet inhibition - Phase 3 DOVE trial (NCT ) completed. Astra Zeneca (Ticagrelor) - Phase 2 HESTIA 2 trial (NCT ) completed results pending. - Phase 2 HESTIA 1 trial (NCT ) enrolling. 12

13 Eli Lilly (Prasugrel) Multinational Phase III, Double-Blind, Randomized, Efficacy and Safety Comparison of Prasugrel and Placebo in Pediatric Patients with Sickle Cell Disease. HbSS and HbSβ 0 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 13

14 Novel Features 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). 14

15 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 * Objectives intensity of VOC * hospitalization rate for VOC rate of acute chest syndrome rate of red blood cell (RBC) transfusion use of analgesics * school absence * * Using epro 15

16 CONSORT FLOW DIAGRAM Total Randomized N=341 Prasugrel N=171 Placebo N=170 Discontinued study prior to 9-month visit N=14 (8.2%) No N=36 (21.1%) 9-Month Visit completed No N=30 (17.6%) Discontinued study prior to 9-month visit N=10 (5.9%) 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 1 (0.06) 2 (1.2) 1 (0.06) 2 (1.2) 6 (3.5) 0 (0.0) 5 (2.9) Discontinued study after 9-month visit N=3 (1.8%) Yes N=135 (78.9%) Yes N=140 (82.4%) Discontinued study after 9-month visit N=6 (3.5%) 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 1 (0.06) 1 (0.06) 0 (0.0) 0 (0.0) 11 (6.5) 0 (0.0) 3 (1.8) Completed 24 months of double-blind period N=0 Completed 24 months of double-blind period N=2 Continuing Double-Blind Period N=22 (12.9%) N=132 (77.2%) N=132* (77.6%) N=20 (11.8%) Heeney MM et al, NEJM

17 Rate of VOC Treatment prasugrel (N=171) placebo (N=170) No Patients w/events (%) Total no events Length of follow-up Event rate Crude rate ratio Rate Ratio 95% CI (lower, upper) 115 (67.3) (0.66, 1.05) 123 (72.4) p-value.117 Heeney MM et al. N Engl J Med 2016; 374:

18 Mean number of VOC Heeney MM et al. N Engl J Med 2016; 374:

19 Rate of VOC by age Age Prasugrel Placebo Rate Events Years Rate Events Years Rate Rate ratio 95% CI p-value >=2 to < 6 >=6 to < 12 >=12 to < (0.49, 1.73) (0.68, 1.39) (0.51, 1.02) Heeney MM et al. N Engl J Med 2016; 374:

20 Mean Number of Vaso-Occlusive Crises years of age Heeney MM et al. N Engl J Med 2016; 374:

21 PRU Distribution at Baseline and at Fully Titrated Dose ISTH Montpellier, France; May 25 28, 2016

22 Astra Zeneca (Ticagrelor) 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. (NCT ) HbSS and HbSβ 0 thalassemia. Age years. N= 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. 23

23 Astra Zeneca (Ticagrelor) 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 (NCT ) HbSS and HbSβ 0 thalassemia. Age 2-18 years. N= study sites in 10 countries. USA, Canada, Egypt, Ghana, Italy, Kenya, Lebanon, South Africa, Turkey, and United Kingdom. 24

24 Leukocyte contribution to VOC Manwani D and Frenette PS Blood. 2013:122(24):

25 Selectin Biology / Inhibition 27

26 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 (NCT ) - complete. Phase 3 Rivipansel: Evaluating Safety, Efficacy and Time to Discharge RESET (NCT ) - enrolling. 28

27 Rivipansel (GMI-1070) Phase II multi-center, prospective, randomized, double blind study in hospitalized sickle cell anemia patients experiencing VOC. (NCT ) N = 76 patients 22 N.A. sites Ages 12 to 60 years HbSS or HbSβ 0 thalassemia with VOC. Loading dose IV, followed by q 12 h doses. Telen M. Blood Apr 23;125(17):

28 Rivipansel (GMI-1070) Time to resolution of VOC was reduced by GMI-1070 (28% and 48% reduction in mean and median time to resolution). Telen M. Blood Apr 23;125(17):

29 Rivipansel (GMI-1070) Time to readiness for discharge and time to discharge were shortened with GMI Telen M. Blood Apr 23;125(17):

30 Rivipansel (GMI-1070) 83% reduction in cumulative IV opioid use (p=0.010). The effect on opioid use was seen within 24 h. Telen M. Blood Apr 23;125(17):

31 RESET (NCT ) Rivipansel Phase III multi-center, prospective, randomized, double blind study in hospitalized sickle cell disease patients experiencing VOC. N = 350 patients Ages >6 years 83 sites HbSS, HbSβ thalassemia, HbSC or HbS-Variant Loading dose IV, followed by 8 X q 12 h doses. 33

32 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. Selexys (SelG1) 34

33 P-selectin 35

34 Selexys SUSTAIN (NCT ) Phase II, multicenter, randomized, placebocontrolled, 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 years 2-10 VOC within the last 12 months. HbSS, HbSC, HbSβ 0 - and HbSβ + -thalassemia. N =

35 Selexys SUSTAIN (NCT ) 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). 37

36 Selexys SUSTAIN (NCT ) 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. 38

37 Endothelial Dysfunction Mast Therapeutics (MST-188 Velpoloxamer) EPIC trial (NCT ) Completed. 39

38 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. 40

39 A Phase III Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Vepoloxamer in Sickle Cell Disease with Vaso Occlusive Crisis. HbSS, HbSC, HbSβ 0 thal, or HbSβ + thal. Age 4-65 years. N=388 EPIC (NCT ) 77 study sites in 14 countries. USA, Canada, Belgium, Brazil, Dominican Republic, Jamaica, Jordan, Lebanon, Oman, Panama, Spain, Turkey... 41

40 September 2016 Velpoloxamer - Results 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 rehospitalization for VOC or the occurrence of acute chest syndrome. 42

41 Velpoloxamer Ramifications? 43

42 To Do Continue to urge development of pathophysiologically directed research and clinical trials. Need indefatigable investigators Need courageous patients/families. 44

43 CME Question Which of these is not like the others? Hint: There may be more than one Diva 45

44 Acknowledgements Russell E. Ware MD, PhD Ellis J. Neufeld MD, PhD 46