Using a set of gene expression markers discovered as part of a phase III clinical trial, AB Science is working with diagnostic company Skuldtech to develop a companion diagnostic to predict which pancreatic cancer patients are likely to respond to treatment with AB Science's masitinib in combination with gemcitabine (Eli Lilly's Gemzar).
The test development will parallel AB Science’s progress as it seeks approval for the tyrosine kinase inhibitor in Europe and potentially the US for the genetic subset of pancreatic cancer patients who show improved survival with masitinib plus gemcitabine versus gemcitabine alone.
Masitinib has received orphan drug designation for the treatment of gastrointestinal stromal tumors, or GIST, from both the US Food and Drug Administration and the European Medicines Agency, according to the company.
Laurent Guy, AB Science’s chief financial officer, told PGx Reporter in an email that during the Phase III trial to evaluate the therapeutic efficacy of masitinib and gemcitabine compared with the current standard pancreatic cancer treatment of gemcitabine only, researchers also conducted gene expression profiling, identifying an expression signature in blood that can identify a subset of patients who are more likely to benefit from the combined treatment.
Guy declined to provide details on the number of genes in the signature or their identities, but said in his email that “the combination of the gene expression levels of these biomarkers enables [us] to stratify patients and to identify the ones who are the most likely to benefit from the masitinib in combination with gemcitabine for the first-line treatment of unresectable, locally advanced or metastatic pancreatic cancer.”
According to Guy, Paris-based AB Science and Montpellier, France-based Skuldtech began their partnership after completing a previous phase II clinical trial of masitinib. He said the collaboration is supported by a grant from France's Oseo, a public-sector institution that finances small and medium-sized companies.
“The goal of this grant was to support a way for filing a market authorization [for masitinib] through association of biomarkers able to stratify patient populations,” Guy wrote.
AB Science announced at the end of October results from its 348-patient, phase III trial, in which patients received either masitinib in combination with gemcitabine or placebo and gemcitabine. The company said that it had also conducted a pharmacogenomic analysis on patients' pretreatment blood samples to identify genetic expression patterns predictive of overall survival or treatment benefit.
According to the company, while results in the overall study population did not show a significant advantage for masitinib in combination with gemcitabine, the researchers did find that combined treatment significantly extended median overall survival — from five months with placebo plus gemcitabine to 11 months with masitinib — in a subset of about 65 percent of patients with gene expression levels associated with more aggressive disease progression.
For this molecularly-defined subset, overall survival rates at 12 and 18 months were about 41 percent and 18 percent, respectively, in the masitinib treatment arm versus 11 percent and four percent, respectively, in the placebo arm, AB science reported. In another subset of patients stratified according to their reported pain, the combined treatment also improved OS by two months, according to the company.
AB Science said the results were used to support a Marketing Authorization Application to the European Medicines Agency for conditional approval of masitinib in combination with gemcitabine for the treatment of pancreatic cancer.
Guy said that AB Science and Skuldtech began their biomarker discovery process using next-generation sequencing to quantify the full content of RNA in patients' blood. The researchers then moved on to validate promising expression markers using PCR.
According to Guy, the two companies intend to create a commercial companion diagnostic based on the signature of predictive markers identified in the trial. He said this test will be PCR-based, and will operate on an FDA- and EMA-approved RT-PCR platform.
Guy said the company's plan is to launch the diagnostic, hopefully, after AB Science gains approval for masitinib to treat the subset of pancreatic cancer patients with the gene expression signature indicative of more aggressive disease.
At the point of approval, he said the final diagnostic design would be "ready to produce within a couple of months."
According to the company, AB Science is also pursuing phase III studies evaluating masitinib in metastatic melanoma, multiple myeloma, mastocytosis, severe persistent asthma, rheumatoid arthritis, and progressive multiple sclerosis.