Pfizer deal for selectin inhibitor highlights potential of glycomimetic drugs

You have full access to this article via your institution. Download PDF GlycoMimetics has granted Pfizer exclusive worldwide rights to develop and commercialize GMI-1070, a rationally

designed glycomimetic inhibitor of E-, L- and P-selectin, for vaso-occlusive crisis associated with sickle cell disease (SCD). Under the terms of the agreement, which could be worth up to

US$340 million to GlycoMimetics, the company will remain responsible for the completion of an ongoing Phase II trial of GMI-1070, and Pfizer will then assume all further development and

commercialization responsibilities. SCD is a rare genetic disorder for which there are limited available treatments. The main clinical feature of the disease is the recurrent, painful and

life-threatening vaso-occlusive crisis that occurs when the flow of blood is blocked, as sickle cells become stuck within a blood vessel. At present, treatment primarily relies on supportive

therapy consisting of hydration and pain relief. By inhibiting selectin interactions, GMI-1070 may be able to decrease leukocyte adhesion and recruitment to inflamed tissues in various

disorders, such as the inflamed venules in SCD. “An adhesive interaction between the sickle red cell and the endothelium is an essential event initiating vaso-occlusion. Some evidence

suggests that the sickle cell–endothelium interaction is initiated by selectins, particularly P-selectin,” explains Martin H. Steinberg (Professor of Medicine, Pediatrics, Department of

Pathology and Laboratory Medicine, Boston University School of Medicine, Massachusetts, USA). There is also evidence that E-selectin, expressed by inflamed vascular endothelial cells,

activates neutrophils that capture sickle cells, promoting vaso-occlusion. “Therefore, the pan-selectin antagonist GMI-1070 represents a valuable and novel therapeutic compound for acute

sickle cell crisis,” comments Beat Ernst (Professor of Molecular Pharmacy, University of Basel, Switzerland). GMI-1070, which has been granted orphan drug and fast track status by the US

Food and Drug Administration, successfully completed Phase I trials in 2009 (ClinicalTrials.gov identifier: NCT00911495) for the treatment of vaso-occlusive crisis associated with SCD. Data

from a double-blind, placebo-controlled Phase II trial in 78 patients receiving standard therapy are expected next year (ClinicalTrials.gov identifier: NCT01119833). GMI-1070 has to be given

intravenously, which is not ideal when attempting to prevent vaso-occlusive events. “The best treatment approach to inhibit these cellular interactions would be to use an oral selectin

inhibitor as a prophylactic,” says Steinberg. However, “developing a carbohydrate lead into an orally available mimetic that is not rapidly excreted remains a challenge”, says Ernst, and

although monoclonal antibodies could also be used to target specific selectins, he adds that “one of the advantages of using a glycomimetic, such as GMI-1070, is that all three selectins can

be antagonized with one compound”. GMI-1070 is also being evaluated in preclinical studies for the treatment of other diseases in which adhesive interactions have a key role in the disease

process. Recent data (abstract number 453) presented at the 2010 Annual Meeting of the American Society of Hematology demonstrated that GMI-1070 inhibits the homing of multiple myeloma cells

to the bone marrow and improves the efficacy of bortezomib (Velcade; Millennium Pharmaceuticals) in animal models. In summary, although GMI-1070 is not an oral drug and its long-term use

might interfere with intercellular interactions that are vital for homeostasis, such as neutrophil migration to infected tissues, its plasma half-life and safety profile support the

viability of glycomimetic drugs. As Ernst concludes: “GMI-1070 could be a door opener for other glycomimetic drugs — for example, in the field of infectious diseases or cancer.” RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Pfizer deal for selectin inhibitor highlights potential of glycomimetic drugs. _Nat Rev Drug Discov_ 10, 890 (2011).

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