Eli Lilly’s enzastaurin was an agent that showed promise in preclinical and early stages, and was subsequently trialed in a variety of solid and hematological cancers, in more than 3,000 patients.
However, it failed to reproduce its success in Phase II and III trials, either in combination or as a single agent, and is now seen as a lesson in how not to approach drug development. Denovo Biopharma acquired the candidate in 2014, and in March 2018 it initiated a new pivotal Phase III trial in diffuse large B-cell lymphoma (DLBCL), which is the most common subtype of non-Hodgkin’s lymphoma. Eli Lilly had previously conducted a Phase III trial in DLBCL, and enzastaurin had failed to meet its primary endpoint of overall disease-free survival. Denovo is hoping that one key differentiator from the previous trial will produce a more favorable outcome.
Denovo conducted an analysis of enzastaurin’s DLBCL clinical data and identified a subset of patients who showed improved survival. Using its proprietary biomarker discovery platform, the company identified a novel biomarker, which it has termed Denovo Genomic Marker 1 (DGM1). It claims that DGM1-positive patients exhibited significantly improved survival over DGM1-negative patients in DLBCL trials. Based on these findings, Denovo initiated a new biomarker-guided Phase III study, and in April 2018 it announced that the first patient had been dosed in this trial.
The ENGINE trial (NCT03263026) is assessing enzastaurin in combination with the R-CHOP regimen (which consists of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), against R-CHOP alone in first-line DLBCL patients, with or without the DGM1 biomarker. The primary endpoint of the trial is overall survival in patients who possess the biomarker, and it has a primary completion date of October 2020. However, Denovo has not released details regarding the DGM1 biomarker testing process.
Rituximab is the only targeted therapy approved for first-line DLBCL, and enzastaurin is being assessed in combination with a rituximab-containing regimen. Thus, an approval in this setting would mean that enzastaurin would be meeting an unmet need, and also would have no competition from other targeted agents. However, a lot hinges on whether Denovo’s new trial can produce data to back up the company’s claims, especially given the poor performance of enzastaurin in the past. Enzastaurin was granted orphan drug designation for DLBCL in 2009, and stratification on patients with the DGM1 biomarker may help the agent live up to this potential. In the event that it does, Denovo also needs to release further details about the biomarker, and the testing process. The need for biomarker testing will inherently reduce the available patient population for enzastaurin, and there is no information yet regarding what percentage of DLBCL patients possess this biomarker. The speed, ease, and cost of the testing process are all factors that would affect adoption. Nevertheless, Denovo’s approach marks an interesting innovation in a patient population with limited treatment options. Success in this trial would also demonstrate the efficacy of the company’s biomarker discovery platform, and would highlight its potential to be used to resurrect other forgotten but once-promising agents.
GlobalData (2018) B-Cell Non-Hodgkin’s Lymphoma (NHL): Opportunity Analysis and Forecasts to 2027, to be published
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