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With Cancer Drug Nearing End of Phase Ib/IIa Trial, Senesco Exploring Partnership Opportunities

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As it continues a phase Ib/IIa study of its multiple myeloma therapy SNS01-T, Senesco Technologies is beginning to explore possible partnerships with bigger companies that could help take the drug into a bigger phase II trial alongside an existing therapy.

According to Senesco President and CEO Leslie Browne, once the ongoing trial is completed, the company anticipates testing the combination of SNS01-T and Celgene’s Revlimid against Revlimid therapy alone in patients with multiple myeloma.

“We have excellent superiority data [on the drug cocktail] in the animal model,” he told Gene Silencing News. Preclinical data also suggest that SNS01-T alone also performs better than Revlimid, but the combination of the two has proven “very potent.”

A clinical trial comparing the drugs would be an expensive one that would benefit from the resources of a bigger partner, he noted, adding that he’s “already started to test the water” regarding an alliance.

Meantime, Senesco is also considering following up the phase Ib/IIa trial with a pivotal phase II study in other B cell cancers including diffuse B cell lymphoma and mantle cell lymphoma. The company recently expanded the ongoing study to include patients with these cancers.

Given the unmet medical need, Browne added that it might be possible to pursue US Food and Drug Administration clearance for SNS01-T in either of these other indications based off of data from an uncontrolled phase II study, much as Onyx Pharmaceuticals did with its multiple myeloma drug Kyprolis.

Senesco, however, has yet to make a final decision on its next steps with drug, he said.

SNS01-T is an outgrowth of Senesco’s roots as a plant biology firm focused on applying its expertise around the a gene — eIF5A — to develop crops with improved traits such as drought resistance.

The company later out-licensed its eIF5A-related technology for agricultural applications to partners, and shifted its focus onto using the gene for human therapeutics.

According to Browne explained that, eIF5A codes for a protein called eukaryotic translation initiation factor 5A-1, as well as a companion protein generated by a post-translational modification of the amino acid lysine at position 50, which is converted into a new amino acid — hypusine.

The two proteins are “intimately involved in cell growth and cell death,” Browne said, but it is the hypusine form that protects against apoptosis.

SNS01-T comprises a polyethylenimine-based nanoparticle containing a DNA plasmid that expresses a stable form of eIF5A that has an arginine in position 50 instead of a lysine and maintains the protein’s pro-apoptotic characteristics. Also in the nanoparticle is an siRNA that down-regulates the wild-type lysine form of the protein, which reduces the level of pro-survival hypusinated eIF5A within a cell.

Importantly, the plasmid is under the control of the B29 promoter and enhancer, which has been shown to limit expression to B cells. Even though the nanoparticles are taken up in heart, kidney, and lung tissue, as well as cancer cells, “because of the B cell-specific promoter, it doesn’t do them any harm,” Browne explained.

“It doesn’t make the death signal, and a little down-regulation of the hypusine form doesn’t seem to have a deleterious effect,” he said.

In late 2011, Senesco moved SNS01-T into the phase Ib/IIa study in multiple myeloma patients. The trial is designed to test twice-weekly dosing of the drug for six weeks, followed by a four-week observation period after which new patients are treated at a higher dose level.

The first cohort of patients completed treatment at the 0.0125 mg/kg dose level last summer, and the company recently reported that two of the three patients in the second, 0.05 mg/kg dose cohort have been treated.

The trial is designed to also test 0.2 mg/kg and 0.375 mg/kg of SNS01-T, and Browne said it could be completed by the end of the year.

Late last year, Senesco reported preliminary data from the trial, noting that two of the three patients who finished the study at the lowest dose level achieved stable disease, with no signs of drug-related serious adverse events or dose-limiting toxicities observed in any patients.

In anticipation of additional promising results, Senesco is now in the process of exploring partnership opportunities for SNS01-T. Even if it should find a company interested in taking on the drug, Browne said that the technology underlying the drug would enable the creation of new drugs in other cancer indications.

“By removing the B cell-specific promoter from SNS01-T and putting in, say, a liver cancer-specific promoter, then we could target liver cancer specifically,” he said. “That is something we’re working on,” with “interesting” preclinical data also being generated in hepatocellular carcinoma.

So even if Senesco hands off the drug for B cell cancers to a partner, “we have multiple [versions] … that we could take on ourselves,” he said.

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