A monoclonal antibody targeting the adhesion protein P-selectin halved the annual rate of painful blood vessel blockages in patients with sickle cell disease in a phase 2 trial. The positive data prompted Basel-based Novartis to exercise an option to buy Selexys Pharmaceuticals, in a deal announced in November 2016 that could be worth as much as $665 million for the Oklahoma City–based biotech developing the therapy. This is the second clinical validation for selectins' role in the painful and organ-damaging complications from sickle cell disease. In June 2015, New York–based Pfizer started a phase 3 trial of rivipansel, a small-molecule pan-selectin inhibitor in patients hospitalized with pain caused by the disease.
Selexys, founded in 2002, was initially backed by venture capital; then, in 2012, it granted Novartis the option to acquire the company pending phase 2 trial results for its lead compound crizanlizumab. The data that prompted the acquisition were presented in December 2016 at the American Society of Hematology meeting in San Diego, California, and simultaneously published in the New England Journal of Medicine.
The humanized monoclonal antibody cut the number of painful crises by 45.3% compared with that experienced by patients receiving placebo (N. Engl. J. Med. doi:10.1056/NEJMoa1611770, 2016). The phase 2 study tested the highest dose of intravenous crizanlizumab—5 mg/kg administered 14 times over 52 weeks—and enrolled nearly 200 patients, including those already being treated with hydroxyurea, the only approved therapy for sickle cell disease. Hydroxyurea, originally approved to treat blood cancers and available as a generic, is only modestly effective in preventing vaso-occlusive crises, and is burdened by serious side effects.
According to the US Centers for Disease Control and Prevention in Atlanta, roughly 100,000 people in the US alone have a form of sickle cell disease. This genetic blood disorder, caused by mutations in the hemoglobin subunit beta (HBB) gene, is marked by a defective hemoglobin protein that has a lower-than-normal capacity to carry oxygen, and contorts red blood cells to the disease's eponymous shape. The constant hypoxia in individuals with sickle cell disease creates a chronic inflammatory condition that results in increased levels of cell adhesion molecules, including selectins, expressed on blood vessel walls, explains John Magnani, CSO and senior vice president of research at Rockville, Maryland–based Glycomimetics, which licensed global rights to rivipansel to Pfizer in 2011. “And when selectins are expressed, leukocytes will roll and bind to these selectins,” says Magnani. Once attached, the immobilized leukocytes express additional adhesion molecules, he says, binding platelets and red blood cells, and potentially setting off vaso-occlusive crises when the cells pile up and block vessels.
By inhibiting selectin binding, “we're also inhibiting expression of ICAM-1, MAC-1 and LFA1,” he says, referring to an alphabet soup of integrin adhesion molecules. Preventing or alleviating these blockages could reduce or eliminate the pain and downstream organ and tissue damage that are hallmarks of sickle cell disease. Pfizer's rivipansel inhibits P-selectin, E-selectin and L-selectin, of which Magnani says E-selectin is the dominant actor in the occlusion cascade.
“Selexys has proven their compound can be given as a prophylactic” thanks to the long half-life of the antibody, says Stockholm-based Modus Therapeutics CEO Christina Herder. But although halving the number of vaso-occlusive crises is a substantial advance, it doesn't completely eliminate the problem, she says. Modus is developing sevuparin, a P-selectin and L-selectin inhibitor that also blocks other adhesion molecules (Blood 122, 182, 2013), to treat patients hospitalized with vaso-occlusive crises. The phase 2 compound is a modified form of heparin in which the original compound's anti-coagulation properties have been significantly weakened by removing anti-thrombin binding sites. Like crizanlizumab and rivipansel, sevuparin has been granted orphan drug designation by the US Food and Drug Administration.
Novartis has yet to disclose plans for crizanlizumab's phase 3 program and declined an interview request for this article. Pfizer is studying rivipansel in patients with vaso-occlusive crises who are admitted to the hospital and treated with opiates for pain. “From a commercial positioning standpoint, this is a setting where patients are receiving the drug in a controlled setting and being managed by hospital staff,” says Glycomimetics CEO Rachel King. “If we can get patients out of the hospital faster and reduce the use of medical care, there are potential pharmaco-economic benefits” as well, she says. Treatment with high-dose crizanlizumab in Selexys' phase 2 study reduced the length of hospital stays by nearly 42% compared with placebo, but unlike the reduction in vaso-occlusive crises themselves, that difference was not statistically significant. Pfizer declined to comment about whether it would develop rivipansel to prevent sickle cell pain crises or for use in any setting prior to hospital admission, such as the emergency room or an out-patient clinic.
“This is a monogenic disease and you'd think it'd be quite simple, with one target,” says Herder. Indeed, tackling sickle cell drew the interest of gene therapy pioneers (Nat. Biotechnol. 34, 791–793, 2016). “But the vaso-occlusive crisis is much more complicated” owing to the cascade of cell–cell interactions, and the sickle cell field has been a difficult one for drug developers, she says.
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Morrison, C. Novartis snaps up Selexys for sickle cell. Nat Biotechnol 35, 106 (2017). https://doi.org/10.1038/nbt0217-106