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Eutropics Drug-Response Platform Being Used by Tolero Pharma in Phase II AML Rx Study

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NEW YORK – Eutropics Pharmaceuticals has been awarded a $500,000 Small Business Innovation Research grant from venture capital firm MassVentures to explore clinical applications for its PraediCare Dx cancer drug response companion diagnostic platform.  

The Cambridge, Massachusetts-based firm also plans to commercialize a new version of its in vitro diagnostic platform for drug treatment response in the near future, which the firm said will directly detect heterodimer protein complexes in a patient's cancer cells.

Among the studies using the first-generation PraediCare Dx platform is a Phase II trial of Tolero Pharmaceuticals' investigational acute myeloid leukemia (AML) drug alvocidib. Under a 2014 collaboration with Tolero, researchers from Eutropics began assessing the ability of PraediCare Dx to predict which AML patients would respond to alvocidib, and the partners have now entered the second stage of a Phase II study.

Eutropics CEO Michael Cardone explained that in the first stage of the Phase II trial, PraediCare Dx was able to identify malignant cells that were dependent on the anti-apoptotic protein MCL-1. 

In the second stage, 79 AML patients with demonstrated MCL-1 dependence of 40 percent or greater by mitochondrial profiling in bone marrow will be randomized to receive either alvocidib plus cytarabine and mitoxantrone or just the chemotherapies cytarabine and mitoxantrone.

The researchers primarily aim to compare the complete remission rate of the AML patient cohort between the two arms. In addition, the group will also track other elements including the patients' overall survival rate, combined complete remission rate, and combined respond rate over two years. The collaborators expect to complete the study by the end of 2020.

"With Tolero, our goal was to discover an assay, perfect it, and then transfer it to a company that's going to take it to the FDA," Cardone said. "We've sublicensed [PraediCare Dx] to a Tolero-selected third party, since the study is happening in multiple countries in Europe, Asia, as well as the US."

Eutropics launched in 2005 to focus on developing small molecule drugs, but pivoted in 2009 to focus on the diagnostic space with its cancer treatment-prediction platform. Cardone explained that the original screening platform and pharmacodynamic assays were developed while he was a researcher at the Massachusetts Institute of Technology and at Merrimack Pharmaceuticals, and that Eutropics initially sought to discover a theranostic application for BH3 mimetics.

In 2012, the firm landed a $1.7 million grant from the National Cancer Institute to develop two biomarker-based companion diagnostics for multiple myeloma and AML that employed BH3 profiling to determine if mitochondria in cancer cells are preset to trigger cell death and to identify whether cancer cells will respond to apoptosis signals. Two years later, Eutropics inked a $1.5 million NCI contract to develop the Praedicare Dx platform for guiding treatment in AML.

Later that same year in 2014, Eutropics' Cambridge-based laboratory received CLIA certification, which cleared the path to launch a PraediCare assay for research use. The firm has since been generating revenue via research collaborations with pharma partners, which are using its platform to inform drug development.

Cardone explained that PraediCare Dx applies a flow cytometry-based method to detect and isolate a patient's cancer cells. After collecting about 1 to 5 ml of a patient's blood or bone marrow, researchers extract cells and treat them with drugs that directly "perturb upstream signals or the cells themselves."

The firm's researchers immunophenotype the cells by labeling them with fluorescent antibodies directed against surface proteins on their membranes. By choosing appropriate antibodies, the researchers can accurately distinguish the malignant cells. Afterward, the researchers use either fluorescence readouts or a flow cytometer to analyze the cells.

According to Cardone, PraediCare Dx measures the kinetics of cell apoptosis with seven different molecules to derive tumor-protein interactions before and after drug treatment. Afterward, the researchers run a predictive clinical correlation algorithm that includes certain key variables, such as the patient's cytogenetics, mutational status, and cancer cell counts.

"This means that we can use drugs … or pieces of proteins themselves that are competing analytes for disrupting interactions, to indirectly measure the heterodimers of pro- and anti-peptide proteins," Cardone explained. "PraediCare measures the extent that the complexes exist in cancer cells, providing a biomarker for the response to drugs."

However, Cardone acknowledged that researchers need to establish a cutoff for each type of treatment option, since variables such as readouts, cutpoints, and detected analyte will differ for each method of treatment.

Eutropics currently offers three RUO assays on the PraediCare Dx platform, including a flow cytometry-based test for (AML) and two fluorescent plate-based versions of the assay for chronic lymphocytic leukemia and multiple myeloma. The firm believes researchers can apply the platform to a wide range of therapies, including MDM2 inhibitors, proteasome inhibitors, and hypomethylating agents. According to Cardone, the assay can process and produce predictive results for up to two samples per day per operator.

Since launching PraediCare Dx in 2014, Eutropics has begun developing a new version of the platform, which directly measures the amount of heterodimer complexes on cancer cell surfaces instead of indirectly measuring the presence of the biomarker. Cardone said the researchers will be able to use the tool in fixed embedded archival samples and freshly collected samples using either immunohistochemistry or by flow cytometry. In addition, he noted that the next generation will be able to use fluorescence, enzyme-activated chromogenic readouts, or amplified fluoresence readouts.

Cardone highlighted that Eutropics is initially applying the tool to detect drug response in breast cancer, followed by colon and prostate cancer. The firm anticipates using the initial components of the platform in RUO clinical studies in the fourth quarter of this year, with the results determining the timeline for companion and general diagnostic use.

Cardone acknowledged that Eutropics has dealt with both logistical and technical challenges while developing and improving the cancer drug response platform over the last decade. The team has struggled to find researchers who understand how to work with the technology to provide a consistent biomarker signal and "getting the reagent and execution" perfect. 

"The test itself takes a full day, even with a highly trained operator," Cardone said. "Getting the test to qualify for clinical use took us a lot of time, yet we've made several discoveries along the way that improved our reagents, methods, and more."

Cardone noted that the US Patent and Trademark Office has issued Eutropics several patents over the years, both related to the current PraediCare Dx and the next-generation platform. He noted that his team licensed the original experimental therapeutic molecules and additional diagnostic IP from Harvard Medical School. However, Cardone highlighted that all the in-licensed IP was returned in favor of IP developed and held by Eutropics.

"Each time we developed a test for a particular application, it becomes another patent that we file, so our portfolio is designed to cover a broad use, and most importantly, applications with particular therapeutics," Cardone said.

Additional collaborations

Cardone said that Eutropics is working with the University of Southern California and the City of Hope to use PraediCare Dx as an exploratory biomarker tool in a Phase Ib study investigating Amgen's MDM2 inhibitor AMG-232 in combination with decitabine in newly diagnosed or refractory AML patients.

"Eutropics is performing testing on all patients and will perform response correlation analysis," Cardone said. "If warranted, the platform test readouts could be used for patient selection in later-stage studies."

Eutropics' platform is also being in collaboration with the University of Texas MD Anderson Cancer Center in a multiple myeloma drug trial, as well as examining AML in standard of care amd BH3 mimetic drugs, as well as breast cancer with BH3 mimetics and kinase inhibitors.

The company also has similar partnerships with Washington University to use its test within a multiple myeloma treatment study, as well as within AML treatment trials with the Fred Hutchinson Cancer Research Center. 

Cardone believes that drugmakers are interested in using PraediCare Dx in their cancer therapeutic trials because it can potentially shorten drug development times and reduce costs. "For the last two years, we've been talking to these companies about providing novel predictive diagnostic tests that are accurate in guiding patient cancer treatments," Cardone said. "The PraediCare Dx platform speeds up drug development and improves the efficacy of use by identifying patients who are most likely to respond."