Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Telen, Marilyn J.; Wun, Theodore; McCavit, Timothy L.; Castro, Laura M. De; Krishnamurti, Lakshmanan; Lanzkron, Sophie; Hsu, Lewis L.; Smith, Wally R.; Rhee, Sang Youl; Magnani, John L.; Thackray, Helen

doi:10.1182/blood-2014-06-583351

Cited by 188 publications

(171 citation statements)

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“…31,32 In particular, the randomized phase II study with GMI-1070 (Rivipansel), a pan selectin inhibitor, has shown that when given to SCD patients early in their hospitalization for treatment of vaso-occlusive events, it reduces the requirement for parenteral opioid analgesia and displays a trend toward decreased time to resolution as indicated by the patient's readiness for discharge from hospital. 28 Previous studies demonstrated that inhibition or deletion of AKT2 significantly decreases neutrophil and platelet activation, thereby reducing neutrophil-EC and platelet-neutrophil interactions and improving blood flow rates during vascular inflammation. 5,15 Furthermore, this study reveals that coadministration of HU and Akti XII has beneficial effects on acute vaso-occlusive events and survival in TNF-aor hypoxia/reoxygenation-challenged Berkeley mice.…”

Section: Discussionmentioning

confidence: 99%

“…Some novel agents that are currently in clinical trials induce HbF production (decitabine and HQK-1001), 26,27 inhibit the activation and adhesive function of neutrophils (GMI-1070) 28 and platelets (Prasugrel), 29 impair blood coagulation (Tinzaparin), 30 and decrease oxidative stress (omega-3 fatty acids and N-acetyl cysteine). 31,32 In particular, the randomized phase II study with GMI-1070 (Rivipansel), a pan selectin inhibitor, has shown that when given to SCD patients early in their hospitalization for treatment of vaso-occlusive events, it reduces the requirement for parenteral opioid analgesia and displays a trend toward decreased time to resolution as indicated by the patient's readiness for discharge from hospital.…”

Section: Discussionmentioning

confidence: 99%

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Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Barazia¹,

Li²,

Shabrani³

et al. 2015

Blood

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Key Points• Coadministration of HU and an AKT2 inhibitor has beneficial effects on acute vaso-occlusive events and survival in SCD mice.Heterotypic cell-cell adhesion and aggregation mediate vaso-occlusive events in patients with sickle cell disease (SCD). Although hydroxyurea (HU), an inducer of fetal hemoglobin, is the main therapy for treatment of SCD, it is unclear whether it has immediate benefits in acute vaso-occlusive events in SCD patients. Using real-time fluorescence intravital microscopy, we demonstrated that short-term coadministration of HU and Akti XII, an AKT2 inhibitor, efficiently reduced neutrophil adhesion and platelet-neutrophil aggregation in venules of Berkeley (SCD) mice challenged with tumor necrosis factor a (TNF-a) or hypoxia/reoxygenation. Importantly, compared with HU or Akti XII treatment alone, short-term treatment with both agents significantly improved survival in those mice. We found that the level of plasma nitric oxide species was elevated by HU but not Akti XII, AKT2 phosphorylation levels in activated neutrophils and platelets were reduced by Akti XII but not HU, and the expression of endothelial E-selectin and intercellular adhesion molecule 1 was decreased by either agent. Our results suggest that short-term coadministration of HU and Akti XII has immediate benefits for acute vaso-occlusive events and survival in SCD mice exceeding those seen for single therapy. (Blood. 2015;126(22):2511-2517 IntroductionSickle cell disease (SCD), an inherited blood disorder, results from a homozygous mutation at the 6th position (Glu6Val) of the b-globin chain (hemoglobin S [HbS]) or from compound heterozygous forms such as HbSC and HbS-b-thalassemia.1 HbS tends to polymerize in the deoxygenated state, and this leads to the sickling and hemolysis of red blood cells.2,3 Importantly, decreased nitric oxide (NO) bioavailability and increased oxidative stress contribute to the pathophysiology of SCD, including activation of endothelial cells (ECs), inflammation, and organ damage. 4 Recurrent vaso-occlusive events, the hallmark of SCD, are mediated by adhesion and aggregation of red blood cells, leukocytes, and platelets on activated ECs 5,6 and cause pain crises in SCD patients. 7 Hydroxyurea (HU), the only drug approved by the US Food and Drug Administration for treatment of SCD, stimulates HbF production,8 serves as an NO donor, 9,10 and inhibits tissue factor expression in leukocytes.11 Although the mechanism by which HU acts is still not fully understood, previous studies showed that treatment of SCD patients with HU is associated with the production of NO and increases HbF levels in an NO-dependent manner. 9,10 Studies that use a humanized SCD (Berkeley) mouse model have consistently shown that short-term treatment with HU can have immediate benefits in vaso-occlusive events, independently of HbF production. 12The authors further demonstrated that combination therapy of HU and a phosphodiesterase 9 inhibitor efficiently inhibits acute vasoocclusion in SCD mice. 12Intravital microscopic ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Barazia¹,

Li²,

Shabrani³

et al. 2015

Blood

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“…After a successful initial Phase I/II study in SCD, 126 a subsequent Phase II study of GMI-1070 was conducted in a prospective multicenter, randomized, placebo-controlled, double-blind, study of 76 SCD children and adults hospitalized for vaso-occlusive pain. 127 Comparing active treatment group to placebo, clinically meaningful reductions in mean and median times to crisis resolution of 41 and 63 hours were demonstrated. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P=0.010).…”

Section: Anti-adhesion Therapies/anti-hemostatic Agentsmentioning

confidence: 99%

Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

Dampier¹

2015

ODRR

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Abstract:While an orphan disease in the USA, sickle cell disease (SCD), a group of genetic disorders of hemoglobin structure and function, is a major public health problem in much of the rest of the world, particularly sub-Saharan Africa. The pathophysiology of SCD stems from the formation of sickle hemoglobin polymers that deform the erythrocyte into a characteristic sickle shape, the rapidity of which is regulated by its intracellular hemoglobin concentration. Subsequent vaso-occlusion is dependent on adhesion of sickled erythrocytes, and perhaps other cellular elements, including leucocytes and platelets, to abnormal vascular endothelium using a number of receptor-ligand pairs. This propensity for vaso-occlusion may be enhanced by altered vascular tone from excessive amounts of vaso-constrictive factors or diminished amounts of vasodilatory factors. Acute pain is the hallmark symptom caused by sickle polymer formation and subsequent vaso-occlusion, and is represented in the endpoints of most previous and current clinical trial designs. Numerous failures of prior investigational agents have frustrated clinicians and patients alike. Hydroxyurea is currently the only US Food and Drug Administration-approved drug for SCD and reduces the frequency of vaso-occlusive complications in many individuals. A considerable therapeutic need remains as hydroxyurea usage is currently not approved for all types of SCD, is not always clinically effective, and requires frequent monitoring. Recent improvements in our understanding of SCD pathophysiology have generated many new therapeutic targets and associated investigational agents. For example, a number of more specific fetal hemoglobin inducers and several therapies to reduce sickle polymer formation are being tested in preclinical and early phase clinical trials. Several agents that target receptor-ligand interactions which mediate cellular adhesion to vascular endothelium have shown considerable promise and are entering Phase III trials, but present some continuing challenges in clinical trial design and conduct. Gene therapy trials are poised to start and offer the potential for curative therapy.

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“…35,42 In particular, preclinical and clinical studies with rivipansel (GMI-1070, a pan-selectin inhibitor) revealed that inhibition of leukocyte-endothelial cell interactions attenuates vaso-occlusion and improves survival in SCD mice, 29 and reduces time to resolution of vaso-occlusive events and requirement for opioid analgesia in SCD patients. 43 Nevertheless, complete inhibition of leukocyte-endothelial cell interactions could cause side effects by disrupting immune responses. We found that oral administration of ARQ 092 significantly, but not completely, inhibited cell-cell interactions in microvessels of TNF-α-challenged SCD mice.…”

Section: P=0067 Student T-test)mentioning

confidence: 99%

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

Barazia

Tseng

et al. 2016

Haematologica

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Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Abstract: Key Points GMI-1070 led to statistically insignificant but large reductions in time to resolution of VOC and a significant reduction in opioid use. These results support a role for selectins in VOC and progression to a phase 3 study of GMI-1070 for SCD patients with vaso-occlusion.

Cited by 188 publications

References 33 publications

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

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