Roneparstat, a Novel Heparanase Inhibitor for Multiple Myeloma Therapy

Heparanase cleaves heparan sulfate (HS) chains and thereby regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor host crosstalk, priming the tumor microenvironment to better support tumor growth. Heparanase represents a druggable target because there is only a single active heparanase in humans, heparanase null mice exhibit no obvious deficits, and the enzyme is poorly expressed in normal tissues but elevated in human cancer where it is associated with poor prognosis and short postoperative survival.

Development of heparanase inhibitors focused on carbohydrate-based compounds with heparin-like properties. Among these is SST0001 (Proposed INN Roneparstat), a reduced oxidized N-acetylated heparin, a potent inhibitor devoid of significant anticoagulant effect. In preclinical testing, SST0001 profoundly inhibits multiple myeloma (MM) tumor growth, angiogenesis and bone metastasis. Moreover in a model of dexamethasone resistant MM, the combination of SST0001 with dexamethasone inhibited tumor growth. This prompted a First in Man, multicenter phase I clinical study, currently ongoing in advanced heavily pre-treated refractory MM patients who have exhausted the available anti-MM therapies.

Heparanase in MM has been extensively studied, suggesting that it may play a role in affecting the tumor microenvironment as well as in determining resistance following chemotherapy. Thus, the ability of SST0001 to affect tumor burden in MM was further explored showing that SST0001 in preclinical models when combined with either bortezomib or melphalan significantly improved the effect of either of these drugs alone.

The outcome of the phase I clinical study together with these strong preclinical data will provide the rationale for further SST0001 development as combination therapy in MM.