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Carfilzomib (PR-171)   |   Oral Proteasome Inhibitor   |   Immunoproteasome   |   Alternative Targets

Carfilzomib (PR-171)

Carfilzomib is a structurally—and mechanistically—novel proteasome inhibitor that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. Carfilzomib is similar to Velcade® in that it is a potent inhibitor of the proteasome chymotrypsin-like activity, but unlike Velcade®, carfilzomib has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Preclinical studies indicate carfilzomib can be administered on consecutive days and is active against models of solid tumors, lymphomas and myeloma, and importantly, in in vitro studies, against myeloma cells from patients who are resistant to Velcade®. Phase 1 clinical studies demonstrated that multiple myeloma patients who have relapsed or progressed following multiple therapies (including Velcade®, immunomodulatory agents and stem cell transplant) can still achieve durable anti-tumor responses with carfilzomib. Carfilzomib is currently undergoing evaluation as a single agent in a pair of multi-center Phase 2 clinical trials in patients with relapsed or refractory multiple myeloma. In addition to the two Phase 2 trials in myeloma and an ongoing Phase 1 study in lymphoma, a clinical trial in solid tumors and a trial exploring carfilzomib in combination with Revlimid® will be initiated by the end of 2007.

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Oral Proteasome Inhibitor

Clinically, both Velcade® and carfilzomib (PR-171) are administered intravenously and although this route of delivery results in potent systemic proteasome inhibition, it may ultimately limit the clinical application of these inhibitors in part due to the necessity of frequent administrations.  Oral therapies utilizing the immunomodulatory drugs Revlimid® and Thalomid® are fast becoming the standard of care in both frontline and relapsed multiple myleoma.  An oral proteasome inhibitor would have the advantage of being more easily incorporated into multi-drug treatment regimens, could be administered easily on a daily schedule, and would have greater commercial acceptance in the market place.

Proteolix has developed a clinical candidate oral proteasome inhibitor, PR-047, which has demonstrated significant preclinical anti-tumor activity.  This compound also shows an improved therapeutic window over carfilzomib in experimental animal models.  Development activities, including manufacturing and Good Laboratory Practice (GLP) compliant toxicology studies are planned for early 2008 and an Investigational New Drug (IND) application for phase I clinical testing in hematologic and solid tumors is expected later that year.

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Immunoproteasome Selective Inhibitors

While the majority of cell types in the body express the standard form of the proteasome (constitutive proteasome), cells of the immune system and some types of hematological tumor cells express the immunoproteasome, a unique form of the proteasome in which the three catalytic subunits are different from those of the standard proteasome. Both Velcade® and carfilzomib (PR-171) inhibit both forms of the proteasome. An immunoproteasome-specific inhibitor would have the advantage of selectively targeting proteasome function in hematological tumor cells while sparing other tissues. This in turn may reduce toxicities and limit side effects that may be the result of constitutive proteasome inhibition in non-malignant cells.

Proteolix has undertaken a research program to identify hematologic malignancies that are most likely to be sensitive to selective inhibition of the immunoproteasome.  We have also generated potent inhibitors of the immunoproteasome that do not cross-react with the constitutive proteasome.  These inhibitors have cytotoxic activity against hematologic tumor cell lines and primary patient samples.  These compounds are also well tolerated in experimental animal models and maintain their selective inhibition of the immunoproteasome in vivo.  Currently, Proteolix is progressing this program towards the selection of a development candidate.

Proteolix has also determined that these immunoproteasome selective inhibitors have anti-inflammatory activities.  In cells, they block the production of key inflammatory mediators such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) and, more significantly, can ameliorate symptoms and block progression of disease in animal models of Rheumatoid Arthritis (RA).  Because of their broad anti-inflammatory properties, these molecules represent potential therapeutics in multiple autoimmune disorders, such as RA, psoriasis and Crohn’s disease.  Further preclinical studies are underway to determine a clinical development strategy of immunoproteasome inhibitors in the treatment of autoimmunity. 

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Alternative Targets

In addition to the core protease activities of the proteasome, which are targeted by proteasome inhibitors such as Velcade® and carfilzomib, there are multiple upstream proteasome activities that are required for efficient protein turnover. These include three coupled activities of the proteasome regulatory particle: 1) recognition of polyubiquitin chains on target proteins; 2) removal of polyubiquitin chains by the metalloprotease Rpn11; and 3) unfolding of the deubiquitinated proteins by a set of chaperone-like ATPases prior to delivery to the 20S core. Inhibitors of proteasome regulatory activities would suppress proteasome activity more completely than inhibitors of individual core proteases and may confer a therapeutic advantage in the treatment of disease. Proteolix has developed a unique 26S proteasome assay for the discovery of inhibitors of proteasome regulatory activities.

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