Four Studies Affirm Significance of Monogram's “Trofile” HIV Co-Receptor Tropism Assay

Monogram Biosciences, Inc. (Nasdaq: MGRM) reported on four studies demonstrating the utility and clinical significance of its Trofile co-receptor tropism assay at the 16th International AIDS conference in Toronto. The studies suggest the need for and value of phenotypic assays in evaluating co-receptor tropism.

Tropism refers to the specific cellular co-receptors (either CCR5 or CXCR4) that individual strains of HIV use to gain access to host cells. Analyzing tropism plays an essential role in determining whether the use of new drugs which target the CCR5 co-receptor (CCR5 antagonists) is likely to be effective in individual HIV-infected patients.

Bill Young, CEO of Monogram Biosciences, told HIV and Hepatitis.com in a telephone interview that his company developed the tropism assay, called “Trofile,” to enable researchers to identify which HIV patients are best able to use the CCR5 entry inhibitors successfully. “Some of the CCR5 entry inhibitors have the potential to be used to great advantage in combination with other classes of antiretrovirals in HIV patients. Preventing the virus from entering immune cells is an achievement that may be of great benefit to these patients,” said Young. “We at Monogram Biosciences are excited to have developed a diagnostic test that will help identify for whom these drugs hold the most promise.”

Monogram's Trofile assay is able to directly and accurately determine whether a patient's virus is able to gain entry into cells via the CCR5 or CXCR4 co-receptor, or a combination of the two. The Trofile assay has been used for patient selection in Pfizer's phase III trial of maraviroc, its investigational CCR5 antagonist, and Monogram is collaborating with Pfizer Inc. to make its co-receptor tropism assay available for patient use on a global basis in anticipation of FDA and EMEA approval.

The first study (Abstract # THPE0045), confirms that the Trofile assay can accurately characterize the tropism of a panel of diverse HIV strains. Researchers at Monogram used the assay to evaluate the co-receptor tropism of a panel of 46 well-characterized strains of HIV-1 that included multiple subtypes (CCR5, CXCR4, or dual/mixed tropism (DM)).

The assay accurately measured the tropism of all 46 strains. The assay also was accurate when tested against three clonal viruses (CCR5, CXCR4 and DM). When CCR5 and CXCR4 clones were mixed together, the assay was able to detect minor variants down to 10 percent in all samples tested, and to 5 percent in 83 percent of samples tested.

To date, 94 percent of more than 8,000 samples received for ongoing clinical trials of co-receptor antagonists in North America and Europe have been successfully tested. Together, the data show that Monogram's Trofile assay is an accurate, precise, sensitive, reproducible and robust assay for the measurement of tropism and support its use as the standard assay for patient screening and monitoring in the development of co-receptor antagonists.

The second study, also presented by Monogram scientists (Abstract # THPE0046), compared the abilities of V3 sequencing and Monogram's Trofile assay to accurately characterize tropism. V3 sequencing examines the genetic sequence of only the V3 region of the envelope gene of HIV taken from a patient and uses algorithms to predict co-receptor tropism. The Trofile assay uses the entire envelope gene taken from the patient's virus to measure viral tropism directly.

The study used patient-derived virus sequences representing multiple subtypes of HIV-1, and found that sensitivity for detection of viruses using the CXCR4 co-receptor varied widely depending on viral sub-type and on the interpretation system used. In comparison to phenotypic analysis with Trofile, which accurately and directly measures co-receptor usage, genotypic measures, on average, were only approximately 65% accurate, and in many cases were even less accurate. These results demonstrate that genotypic approaches are inferior for assessing tropism when compared with Trofile.

"These data confirm that the Trofile assay is more sensitive and precise in determining co-receptor tropism," said Chris Petropoulos, Chief Scientific Officer. "The region of the virus involved in cellular entry has a particularly heterogeneous genetic sequence, which renders genotypic methods significantly less effective."

In a study (Abstract # THLB0215) presented by scientists from Pfizer, Inc., the negative predictive value of Monogram's Trofile co-receptor tropism assay was assessed in an ongoing Phase III trial of Pfizer's investigational CCR5 antagonist, maraviroc (Study 1029). Results show that patients identified by the assay as having virus using both the CXCR4 and CCR5 receptors (dual/mixed tropic) did not respond to the investigational (CCR5) therapy. These data suggest that screening patients with the Trofile assay will allow physicians to avoid treating patients with expensive drug therapy who are unlikely to respond to that therapy.

A separate study (Abstract # THLB0217) presented by investigators from the AIDS Clinical Trial Group 5211 study team and Schering Plough demonstrated the positive predictive value of the assay in patients participating in a Phase IIb trial of Schering-Plough's investigational CCR5 antagonist vicriviroc. In this study, patients identified by the assay as having virus utilizing only the CCR5 co-receptor demonstrated clinical responses to the investigational therapy.

"These data suggest that the Trofile co-receptor tropism assay is an effective method of identifying appropriate patients for treatment with CCR5 antagonists," said Petropoulos. "By virtue of its high positive and negative predictive values, the Trofile assay is highly capable of insuring that individuals receive treatments that are most likely to provide them with clinical benefit."

8/15/06

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