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Myriad Genetics, Pharma Mar Explore PGx Strategy for DNA-Damaging Synthetic Alkaloid PM1183

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Originally published July 30.

Myriad Genetics will use its BRACAnalysis test to pick out best responders to PM1183, a new type of DNA-damaging agent that drug developer Pharma Mar is studying as a potential treatment for advanced breast cancer.

Under this latest companion diagnostics agreement involving its flagship BRACAnalysis test, Myriad will assess the BRCA status of metastatic breast cancer patients enrolled in a Phase II study investigating Pharma Mar's PM1183.

"This agreement covers the Phase II trial," a Myriad spokesperson told PGx Reporter. "We are hopeful the data will demonstrate the importance of BRCA in predicting response. If this turns out to be the case we’ll work with Pharma Mar to make a companion diagnostic BRACAnalysis test available."

Pharma Mar, a company that specializes in marine-derived drugs, has conducted in vivo and in vitro studies with PM1183, in which the investigational agent has shown antitumor activity against a number of cancer cell lines, including breast cancer. PM1183, a new synthetic alkaloid, works by binding to the minor groove of DNA and causing double strand breaks. In this way, the drug interrupts cancer cells from replicating and causes them to die.

Results from preclinical studies indicate that PM1183's activity is "different from that of conventional alkylating agents," Pharma Mar has previously stated in public statements about the drug.

The Myriad spokesperson explained to PGx Reporter that Pharma Mar is interested in looking at whether PM1183 works especially well in breast cancer patients with germline BRCA mutations because BRCA 1 and BRCA 2 genes are involved in the double-stranded DNA repair pathway. As such, Pharma Mar is hypothesizing that patients with germline mutations in BRCA 1 and BRCA 2, who have reduced ability to repair double stranded DNA breaks, might be more sensitive to the DNA-damaging mechanism of PM1183.

According to a description of the Phase II study on Clinicaltrials.gov, researchers from Pharma Mar and Massachusetts General Hospital will also "evaluate the pharmacogenomic expression profile of selected putative markers potentially predictive of response to PM1183, in tissues from archived tumor samples."

In particular, study investigators will investigate whether PM1183 is safe and efficacious in breast cancer patients in a molecularly defined patient subset (such as harboring BRCA 1 or BRCA 2 gene mutations) and in a molecularly unselected population. Researchers will also explore drug response when patients are grouped by hormonal receptor status, HER2 overexpression, prior treatments, as well as other histological and molecular classifications.

The investigators plan to enroll around 117 breast cancer patients in the trial. The primary study endpoint is overall response rate for patients treated with PM1183 at 10 to 12 months if the results are negative, and 26 to 28 months if the study reaches its patient enrollment target. Other study endpoints include progression-free survival and overall survival at 36 months.

Myriad has companion diagnostic development agreements with several drug companies who are developing PARP inhibitors, including Abbott Pharmaceuticals, Astra Zeneca, and BioMarin Pharmaceuticals. The PARP1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer cells. In patients with BRCA mutations, however, PARP inhibitors can thwart repair of DNA lesions needed to drive the cancer (PGx Reporter 6/30/2010; 4/23/2011).

Myriad also has a deal with Teva subsidiary Cephalon to conduct BRCA1 and BRCA2 mutation testing on patients enrolled in a Phase I/II clinical study investigating an undisclosed compound.

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