By Turna Ray
AstraZeneca is doing it, Abbott is doing it, and now Pfizer is also doing it … but a little differently than the rest.
In line with others in the pharmaceutical industry, Pfizer this week became the latest drug developer to announce plans to use biomarkers to personalize cancer treatment with an investigational PARP inhibitor. However, unlike its competitors, who have chosen to use Myriad Genetics' BRCA gene mutation test to help personalize their drugs, Pfizer is working with MDxHealth to identify methylation-specific markers.
PF-01367338 is a PARP inhibitor that Pfizer is developing as a potential treatment for breast and ovarian cancer in partnership with Newcastle University and Cancer Research Technology, the technology development and commercialization arm of Cancer Research UK. This week, MDxHealth signed a deal with the three partners under which it will use its methylation platform in clinical trials for the identification of drug response biomarkers and possibly develop a companion test to guide treatment with PF-01367338 to best responders.
This latest deal comes as drug developers are making a heavy investment in advancing PARP-inhibiting oncologics with companion tests to help discern which patients are most likely to benefit from these types of treatments.
Myriad has previously disclosed that it is working with AstraZeneca and Abbott to use its BRCA mutation test in their development programs for PARP inhibitors. Abbott is using Myriad's BRACAnalysis to stratify breast cancer patients for its investigational PARP inhibitor veliparib, in Phase III clinical trials. Myriad also has a similar deal with AstraZeneca to use BRCA mutation testing in clinical trials for the PARP inhibitor olaparib in ovarian cancer (PGx Reporter 06/30/10).
Departing from this trend is Sanofi-Aventis, which has not yet said whether it is using a biomarker to personalize its investigational PARP inhibitor for triple-negative breast cancer, iniparib. Myriad said it plans to reach out to Sanofi to see if it wants to do a retrospective biomarker study for the drug in light of disappointing Phase III results (see related story, this issue).
From a competitive standpoint, MDxHealth is open to collaborating with any firm that is interested in using its methylation platform in drug development, but did not say whether it had contacted Sanofi regarding a companion diagnostic effort for iniparib. "MDxHealth is permanently engaged in discussions with pharma and biotech companies on companion diagnostics partnerships. But while those discussions are ongoing they are not disclosed," a spokesperson for the company told PGx Reporter.
As part of its Rx/Dx collaboration for PF-01367338, "MDxHealth will profile the methylation patterns of DNA damage repair genes to seek to identify those involved in predicting tumor development and response to PARP inhibition," the company said in a statement. "MDxHealth's aim is to ultimately set up a high-throughput platform that is clinically validated to rapidly test for epigenetic defects in key DNA damage repair genes to support the design and implementation of clinical trials to enable development of optimized, targeted therapies."
The MDxHealth spokesperson specified to PGx Reporter that the company plans to validate methylation of BRCA1 and other DNA repair genes with pre-clinical samples.
The PARP1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. However, in patients with mutations in the BRCA gene, when PARP inhibitors destroy the PARP1 enzyme, tumors are unable to repair DNA damage and die. As such, tests that characterize the genetic underpinnings hindering the process of DNA damage repair may be able to predict which patients will respond to PARP inhibitors such as PF-01367338.
By testing for epigenetic defects in DNA damage repair genes, any commercial companion diagnostic that is developed using MDxHealth's proprietary methylation-specific-PCR technology will differ from Myriad's BRACAnalysis, which gauges mutations in the BRCA gene via sequencing. MDxHealth claims that methylation techniques to assess epigenetic changes in DNA repair genes will be a more accurate gauge of PARP inhibition.
According to the MDxHealth spokesperson, both methylation and mutation testing can gauge the absence of BRCA1 gene activity, and therefore can predict drug response. However, the BRCA1 gene is never simultaneously methylated and mutated, and methylation of the gene occurs more frequently than do mutations.
"BRCA methylation appears in … about 40 percent to 50 percent of triple-negative breast cancer patients, and about 10 percent and 30 percent in sporadic breast cancers," the spokesperson said. Comparatively, BRCA mutations appear in approximately 5 percent of breast cancers and 10 percent of ovarian cancers.
"The prevalence of methylation is much higher than mutation so in retrospect it might seem indeed strange that people only would consider looking at mutation rates," the spokesperson said. "What should happen in clinical practice is to look at both since both are predictive."
Another advantage, according to MDxHealth, is that gene methylation can be detected with low amounts of DNA in formalin-fixed paraffin-embedded tissues or even in small samples garnered through needle biopsies.
The collaborators did not disclose the financial terms of the deal. However, under the arrangement, MDxHealth will handle biomarker discovery, assay development, and clinical trial testing. The company will also retain rights to any methylation-based commercial companion diagnostic test resulting from the collaboration.
In turn, Newcastle University's Nicola Curtin and Richard Edmondson will lead biomarker discovery efforts. CRT will have rights to develop and commercialize new biomarkers "in other fields." Finally, Pfizer will fund the collaboration and provide input through its translational research team.
A search on clinicaltrials.gov shows that PF-01367338 is currently being studied as part of three trials.
First, a Phase II trial led by researchers from Cancer Research UK and Newcastle University is investigating the response rate and toxicity to PF-01367338 as experienced by patients with locally advanced or metastatic breast cancer or advanced ovarian cancer who have BRCA1 or BRCA2 mutations.
In this study, patients' samples will be analyzed for tumor markers CA 125 and CA 15.3; AG-014699 plasma levels with liquid chromatography or mass spectrometry; as well as PARP activity and PARP protein expression via western blotting immunoassays. Additionally, investigators will analyze paraffin-embedded tissue sections for PARP protein expression using immunohistochemical techniques.
"Pleural and ascitic fluid may be collected and analyzed for DNA DS break repair proficiency via immunohistochemical technique," the trial description notes. "Some patients [will] also undergo biopsy of tumors and samples [will be] analyzed for BRCA 2 mutation as well as PARP activity via validated PARP immunoblotting assay." This trial is currently recruiting participants.
MDxHealth's deal with Pfizer and its partners is for the validation of methylation-specific markers and potentially the development of a commercial test. Meanwhile, the study is looking at BRCA mutations. As such, it is currently unclear whether Pfizer and its academic collaborators are considering commercializing PF-01367338 with companion tests that look at both BRCA mutations and methylation markers.
In another Phase II study, Pfizer and the Hoosier Oncology Group are studying the PF-01367338/cisplatin combo in triple-negative breast cancer patients who are ER/PR-positive, HER2-negative, and have BRCA1 or BRCA2 mutations. The randomized safety and efficacy study is currently recruiting participants.
The drug is also being investigated in a Pfizer-sponsored Phase I safety trial. In this study, investigators are looking at the pharmacokinetic and pharmacodynamic parameters of PF-01367338 when given in combination with various chemotherapy treatments. This Phase I study, which is currently recruiting participants, does not describe the use of a biomarker to stratify patients to treatment arms.
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