Trofile Assay Accurately Determines HIV Co-receptor Tropism and Identifies Patients
Who Can Use CCR5 Antagonist Maraviroc Monogram launched the Trofile co-receptor tropism assay this past August, coinciding with the Food and Drug Administration's approval of maraviroc. Studies presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Chicago looked at the performance of the Trofile test. Below is Monogram's press release highlighting these presentations. Monogram Biosciences. Studies Highlight Superior Performance of Trofile Assay. Press release. September 19, 2007. Studies Highlight Superior Performance of Trofile Assay: Data based on the Trofile assay presented at 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy SOUTH SAN FRANCISCO, Calif., Sept. 19 -- PRNewswire-FirstCall -- Monogram Biosciences, Inc. today announced multiple presentations demonstrating the strength of its Trofile Assay at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Among the presentations is one that details the superior ability of Monogram's Trofile assay to identify HIV patients that are most likely to respond to co-receptor inhibitors, a new class of drugs, compared to less sophisticated genotypic approaches. Another presentation reports on technical advances that will allow improvements to be made to the assay resulting in a tenfold increase in Trofile's ability to identify patients with virus populations that harbor rare variants that are unlikely to be inhibited by specific drugs in this new class, and consequently are prone to treatment failure. Trofile is a cell-based infectivity assay that directly and accurately determines whether HIV is able to gain entry into cells via the CCR5 or CXCR4 co-receptor, or both CCR5 and CXCR4. Last month, Pfizer Inc. received FDA approval for Selzentry (maraviroc), a CCR5 antagonist and the first orally available HIV treatment in this new class of medications. In a first for an HIV drug approval, the FDA approved label states that tropism testing should be used to guide the use of Selzentry, i.e. identify patients most likely to respond to treatment. "As the only clinically proven assay for assessing tropism, our Trofile Assay has played a critical role in guiding the selection of appropriate patients for Selzentry in Pfizer's clinical trials and expanded access program, and that role is expanding now that drug is approved," said Monogram CEO Bill Young. "The studies presented this week enhance that position by providing further evidence of the superiority of our current Trofile Assay over potential genotypic approaches. Our presentations also detail technological advances that will improve the ability of the assay by tenfold to detect whether individuals are infected with CXCR4-tropic viruses, and therefore unlikely to respond to treatment with CCR5-inhibitors. In a world where patients and physicians are increasingly concerned about delivering the right drug to the right patient at the right time, we are pleased that Monogram continues to set the highest scientific standards in patient selection." Trofile More Accurate than V3 Sequencing In the first study (Abstract H-1028), Monogram scientists compared the abilities of nucleic acid sequencing to Monogram's Trofile co-receptor tropism assay in accurately determining the tropism profile of HIV in treatment- experienced patients. Conventional nucleic acid sequencing approaches examine the genetic sequence of a relatively small region (V3) of the HIV envelope gene and use various algorithms to derive predictions of coreceptor tropism. Trofile's phenotypic approach provides a direct determination of co-receptor tropism by assessing the ability of viruses containing the entire envelope protein of a patient's virus to infect cells expressing either the CXCR4 or CCR5 co-receptor. The researchers found that determining the V3 sequences of envelope genes derived from patient viruses is technically hampered by the sequence diversity and heterogeneous length of the V3 region. The study also demonstrated that when V3 sequences can be unambiguously determined, state of the art interpretation algorithms significantly under-report the presence of viruses that use CXCR4 and are therefore highly unlikely to respond to Selzentry. Advancements in Trofile Assay Increase Sensitivity A second study (Abstract H-1026) demonstrated that technical enhancements made to the Trofile assay allow it to identify patients that are infected with viruses that contain minor subpopulations of CXCR4-using HIV. These advances should make the Trofile assay an even more powerful tool for the selection of patients that can be successfully treated with CCR5 inhibitors. The detection of minor variants that use CXCR4 was enhanced tenfold without sacrificing the ability to reliably detect CCR5 variants. Tropism and Disease Progression In a third study (Abstract H-1027), Monogram scientists evaluated the correlation between disease progression and HIV co-receptor tropism in untreated patients with chronic HIV infection. The study revealed that among these patients, individuals with viruses that can use the CXCR4 coreceptor have a faster rate of HIV disease progression compared to individuals with viruses that use only the CCR5 coreceptor. About Trofile Trofile is a patient selection co-receptor tropism assay that determines whether a patient is infected with a strain of HIV that uses either the CCR5 coreceptor, the CXCR4 coreceptor, or a combination of CCR5 and CXCR4 to enter cells. The use of CCR5, CXCR4 or both coreceptors defines the "tropism" of the virus strain. Trofile amplifies the envelope gene from a patient's HIV genome (from their blood sample) and then uses it to make HIV particles containing the patient's virus envelope protein. The resultant HIV particles are then used to infect cells that contain the CCR5 co-receptor or the CXCR4 co-receptor on the cell surface. Once the virus infects the cell and it undergoes a single round of replication. Virus replication results in the production of luciferase from a luciferase gene that is carried into the cell by the virus. The production of luciferase in either CCR5 cells, CXCR4 cells or both cell types defines the co-receptor tropism of the patient virus. About Monogram Biosciences, Inc. Monogram is advancing individualized medicine by discovering, developing and marketing innovative products to guide and improve treatment of serious infectious diseases and cancer. The company's products are designed to help doctors optimize treatment regimens for their patients that lead to better outcomes and reduced costs. The company's technology is also being used by numerous biopharmaceutical companies to develop new and improved antiviral therapeutics and vaccines as well as targeted cancer therapeutics. More information about the company and its technology can be found on its web site at www.monogrambio.com. 09/21/07 Source Monogram Biosciences. Studies Highlight Superior Performance of Trofile Assay. Press release. September 19, 2007. References E Stawiski, J Whitcomb, E Coakley, and others. Co-Receptor Tropism Predictions Based on V3 Loop Sequence in Antiretroviral-Experienced Patients are Specific but Insensitive for the Detection of CXCR4-Using Variants. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (47th ICAAC). Chicago, September 17-20, 2007. Abstract H-1028. JD Reeves, D Han, Y Liu, and others. Enhancements to the Trofile HIV Coreceptor Tropism Assay Enable Reliable Detection of CXCR4-Using Subpopulations at Less Than 1%. 47th ICAAC. Abstract H-1026. MB Goetz, R Leduc, JR Kostman, and others. Prediction of Disease Progression by HIV Co-Receptor Tropism (CRT) in persons (P) with Untreated Chronic HIV Infection. 47th ICAAC. Abstract H-1027.
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