Cambridge Healthtech Associates this week launched the second phase of its project to evaluate Cellumen’s CellCiphr technology. The project’s second phase aims to improve the quality of the tool, which is used for preliminary safety assessment, by extending the number of its panels and the validation on its existing panels, according to a CHA official.
The start of phase 2, which is a collaboration between CHA, Cellumen, and the pharmaceutical industry, coincided with a web-based industry panel held this week entitled “Evaluating Cell-Based Safety Assessment Tools.”
Phase 2 is expected to last nine months, according to Lans Taylor, founder and CEO of Cellumen, who said that this timeline includes recruiting participating companies, submitting the blinded compounds to Cellumen, which will profile the compounds on its existing panels, plus adding a cytotoxicity panel of an additional cell type.
“When the members make themselves heard, my guess is that it will be a cardiomyocyte cell panel, but that will be determined by the members,” Taylor said.
The webinar panelists included Taylor; Ernie Bush, scientific director of cell-based safety tools at CHA; Thomas Baker, an associate senior toxicologist at Lilly Research Labs; and Thomas Steger-Hartmann, the head of laboratory diagnostics and genetic and ecotoxicology at Bayer Schering Pharma.
The goals of phase 2 are to further explore the application of the CellCiphr high-content screening tool in predictive toxicology, assess the CellCiphr’s ability to provide actionable early guidance regarding target organ specificity and the mechanism by which the compounds actually affect their target organs, recruit a panel of experts to guide the continued development of the CellCiphr for performing high-throughput safety assessment, and establish a paradigm for compound liability ranking or prioritization at a very early stage in the drug discovery process. Hopefully this can occur before resource-intensive in vivo safety testing has begin.
Ten companies participated in phase 1, which lasted for about eight months and ended in a roundtable discussion this past summer. It was not immediately known how many would take part in phase 2, Taylor said. However, he said the group expects between eight and 12 companies to sign on. He said anything above 12 would become too unwieldy.
According to Taylor, “a couple of participants [from] phase 1 have already decided that they want to do cytotoxicity testing with our panels on their own and they are starting to acquire the first panel reagents and are engaging us in collaborative work.” These companies will not be participating in phase 2.
In phase 1, Bayer provided compounds that either failed during development due to toxicity or are reference compounds where in vivo toxicological data is available, Steger-Hartmann told CBA News.
“Bayer Schering has yet to decide if it will participate in phase 2 because of budget questions and because it still needs to internally analyze the five compounds it contributed to phase 1 with its in vivo results,” Steger-Hartmann said.
The company will make the decision about whether or not to participate in about three months, he said.
The 10 pharmaceutical companies that participated in phase 1 each took 10 compounds of their choosing and submitted them to CHA, where they were blinded. They were also required to simultaneously submit in vivo safety data on those compounds, Taylor said.
“The concept here is to give both the discovery scientists and the preclinical safety people an indication of the probabilities of toxicity going forward.”
Cellumen provided an additional 57 reference compounds.
Cellumen profiled those compounds in its first two CellCiphr panels, HepG2 human cell line panels and rat primary hepatocytes, said Taylor. Using Cellumen’s cellular systems, the company took 11 biology profile, multiple-time point, multiple-parameter measurements.
The eleven parameters measured included mitochondrial redox state, cell-wall integrity, and other parameters that can be measured with fluorescent dyes and fluorescent microscope assays. The parameters were measured at 1 hour, 24 hours, and 72 hours, CHA’s Bush said.
CellCiphr profiles were used to identify compounds with similar activity profiles by clustering and correlating the CellCiphr data with the in vivo data provided by the participating pharmas, Taylor and Bush said.
These profiles were used to build an automated classification tool that provides toxicity rank ordering within each set of compounds found to have similar activity profiles. Compounds were ranked as highly toxic, moderately toxic, and essentially non-toxic, said Taylor.
A safety index was then developed as a single number to provide relative toxicity comparison between compounds. “The concept here is to give both the discovery scientists and the preclinical safety people an indication of the probabilities of toxicity going forward,” said Taylor.
The basic goal of phase 1 was to evaluate the CellCiphr primary rat hepatocyte and human Hep G2 cell line panels for predictive toxicology applications. The participants found that the rat hepatocyte panel added target organ specificity and improved overall reliability of the panels. They also found that correlation analysis and reduced the complex data set to more useful clusters and similarity scores.
The participants also reported that the automated classification tool was very reliable for identifying substantially toxic compounds, and that the safety index and rank ordering were very useful tools for prioritization.
The data generated during phase 1 was a more useful starting point for MOA studies than traditional single end-point assays, the participants found.
Phase 2 aims to extend this work with more panels and more cell types, said Taylor and Bush.Phase 2 will involve a blinded screen of between five and 20 compounds per participating company, and the panels will include human Hep G2, rat primary hepatocytes, rat primary hepatocytes in sandwich culture, and the yet to be developed cardiomyocyte panel.