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With Grant Funding, Empire Advancing Potential Companion Test for Proteasome Inhibitors

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Empire Genomics has discovered a genetic mutation that early studies suggest might be linked to increased response to a class of drugs called proteasome inhibitors.

If Empire can successfully develop a test that gauges this mutation and can predict which patients will respond to proteasome inhibitors, such as Velcade, such a diagnostic could help doctors personalize treatment for multiple myeloma patients.

Having recently garnered more than $140,000 from a Phase I SBIR grant from the National Cancer Institute, the Buffalo, NY-based firm will establish the sensitivity and specificity of a diagnostic that gauges the mutation. The company also plans to sequence the region where the translocation of interest is located to advance understanding of multiple myeloma. The SBIR grant, the first such award Empire Genomics has received, will fund the company's efforts to develop this test through 2013.

Empire CEO Anthony Johnson could not reveal the specific pharmacogenetic mutation the company has discovered, explaining to PGx Reporter that the firm is hoping to publish its findings in a peer-reviewed journal later this year. Additionally, due to discussions underway with drug developers, Empire also could not discuss the proteasome inhibitors that might be involved in clinical trials alongside its test.

"We have a translocation probe that when there is a particular break-apart in the gene, it actually conveys response to [the proteasome inhibitor]," Johnson said. "If you look at how these drugs work, at least in the case of multiple myeloma, they are used in conjunction with other treatments, such as dexamethasone and lenalidomide … [because] physicians are trying to be as aggressive as possible by using multiple cocktails. But, with this assay, we are hoping that we'll be able to home in on the population that might respond to single therapy with a proteasome inhibitor."

Proteasomes are protein complexes that remove damaged or unnecessary proteins. Inhibitors that block the activity of proteasomes allow these unwanted proteins to build up and cause cell death. Because cancer cells proliferate faster than normal cells, proteasome inhibitors have shown they can delay tumor growth by hindering cancer cells' ability to survive by removing damaged proteins.

The FDA approved Velcade (bortezomib), the first proteasome inhibitor, in 2003. The drug is indicated for the treatment of multiple myeloma and relapsed mantle cell lymphoma. Developed by Takeda subsidiary Millennium Pharmaceuticals, Velcade garnered more than 58 billion Yen ($568 million) in net sales last year.

In 2011, Millennium submitted to the FDA updated efficacy data for Velcade after a five-year follow up showing that in a randomized trial of nearly 700 patients, median overall survival for patients receiving a Velcade cocktail with prednisone and melaphalan was 56.4 months compared to 43.1 months for those in the comparator arm receiving melaphalan and prednisone. Some common adverse events associated with Velcade include thrombocytopenia, neutropenia, nausea, peripheral neuropathy, and diarrhea.

Other drugs in this class include Onyx Pharmaceuticals' Kyprolis (carfilzomib), which the FDA approved last year as a treatment for relapsed or refractory multiple myeloma. Nereus Pharmaceuticals is developing another proteasome inhibitor, marizomib, as a treatment for relapsed or refractory multiple myeloma. Millennium last year presented early data from human studies investigating MLN9708, potentially the first oral proteasome inhibitor against multiple myeloma.

With the help of the response-linked gene mutation, Empire is hoping to identify the subset of early-stage multiple myeloma patients who might respond exceptionally well to just Velcade or another proteasome inhibitor and avoid the adverse events associated with more toxic combination therapies.

In retrospective analyses conducted by Empire, patients harboring this particular gene mutation experienced greater reductions in residual disease after treatment with a proteasome inhibitor, according to the company. Patients on proteasome inhibitors "ultimately relapse," Johnson said. "The aim is to find ideal ways to treat patients early to reduce and remove the disease, but also to keep as many healthy cells as possible. So, if you can reduce the amount of [drug] you're using early on, because you know they won't be effective in treating the disease … then you will have longer periods before relapse comes, and when it does come, you might have a less aggressive form of the disease."

Early studies have shown that patients harboring the gene break of interest have a significantly higher response rate to proteasome inhibitors than do patients without the mutation, Johnson added. At the end of this year or early next year, Empire, in collaboration with Emory University and other partners, is planning to begin a Phase I clinical trial looking at how multiple myeloma patients with this mutation respond to a newer class of proteasome inhibitors.

There were more than 20,000 new cases of multiple myeloma in 2012 and more than 10,000 deaths from the disease.

Although there are companion genetic tests for personalizing a number of cancer therapies – HER2-targeted breast cancer drugs such as Herceptin (trastuzumab), the melanoma drug Zelboraf (vemurafenib), and the non-small cell lung cancer treatment Xalkori (crizotinib) – currently, there are no pharmacogenetically targeted treatments for multiple myeloma.

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