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Denovo Taking on Failed Phase III Lilly Drug to Pursue for Genomic Responder Subset


NEW YORK (GenomeWeb) — Biomarker development firm Denovo Biopharma has acquired the late-stage oncology drug enzastaurin from Eli Lilly and Company, and plans to use its genotyping platform to uncover a genomic marker or markers that can support new clinical trials advancing the drug for a genomic subset of best-responders.

Lilly was originally developing enzastaurin in a variety of indications, including through Phase II and Phase III clinical trials for diffuse large B-cell lymphoma, but the drug did not meet the primary endpoint in the DLBCL maintenance setting in Phase III. Based on the results, Lilly announced last year that it would stop developing the enzastaurin. The decision came during a period when the drugmaker was experiencing patent expirations for several key products, including its top selling antipsychotic Zyprexa and the antidepressant Cymbalta.

However, a meaningful subset of patients in that failed trial showed significantly improved progression-free survival, and Denovo Biopharma took note. Michael Haller, the company's COO, told PGx Reporter this week that following the Lilly deal, its first acquisition from a major pharmaceutical company, Denovo Biopharma plans to scoop up other failed late-stage compounds from drug companies. Denovo Biopharma was previously named Denovo Biomarkers.

"One or two drugs fail Phase III every week," Haller said. "In focusing on rescuing failed drugs from Phase III, we know that our sample size is going to be large enough — 500-to-1,000-plus patients — that we can be hopeful to be able to identify a molecular subset of responders."

Industry and regulatory leaders haves begun to call for pharmaceutical companies to incorporate biomarker analyses earlier in the drug development process. Interest in genomically analyzing patients well before the drug reaches Phase III trials in order to identify best-responders is growing, but still nascent.

Meanwhile, many diagnostics companies are churning out biomarker-based assays that they hope to be able to use to ink companion diagnostic partnerships with pharma. But given the frequency of late-stage failures, Denovo sees itself charting a middle path — acquiring drugs after they fail Phase III for unselected populations and rescuing them in smaller molecularly-defined indications.

With enzastaurin, the company is planning to reanalyze retrospective samples from the drug's previous Phase III trial using its SNP-based genotyping platform.

Haller did not explain the company's biomarker discovery technology in detail, but the firm's website describes the platform generally as "scanning the entire human genome and conducting a proprietary data analysis" on plasma samples. According to Denovo, the process can be completed in as little as 90 days at an "affordable cost."

According to Haller, while enzastaurin failed to meet the primary endpoint in Phase III, Denovo and Lilly have calculated that a substantial subset of patients — about 20 percent — showed significant progression-free survival.

"We've not done any analysis yet. We can't until we get samples and data from Lilly, but we have identified a subset of around 20 percent of patients, in cooperation with Lilly, that had a response with a p-value below 0.01," Haller said. "Our hypothesis is that that 20 percent has a genetic basis for their response."

Denovo is now hoping that its platform will be able to uncover a biomarker, or markers, that distinguish this responsive subset from the rest of the study cohort. If this is successful, the company will then develop a diagnostic assay for that particular marker, and use it to recruit patients for a genomically guided Phase II or pivotal trial of the drug. This would hopefully support approval of enzastaurin for a molecularly defined subset of DLBCL patients.

Of course, Denovo's genotyping could fail to uncover a biomarker that discriminates responders from non-responders in the trial. Haller said that while the team is hopeful, they aren't naive about that possibility.

Keeping this possibility in mind, Denovo's plan is to mitigate risk by diversifying, Haller said, hoping to acquire three to five drugs like enzastaurin in the next two years.

Meanwhile, he said the company expects to complete the transfer of data and samples from Lilly and its own biomarker discovery work on the enzastaurin cohort, hopefully moving into the clinical trial phase of its plans by this time next year.