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TMC114 & TMC125 at 13th CROI, TMC114 Expanded Access Program
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PRESS RELEASE issued today by Tibotec.
New Data on Tibotec HIV/AIDS Investigational Product Portfolio
CORK, Ireland, Thursday 16th February 2006 - Data presented by Tibotec Pharmaceuticals Ltd. at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, CO last week reinforced the breadth of its research and development portfolio in HIV/AIDS. Since CROI last year, further progress has been made in the development of its investigational antiretrovirals, TMC114, a protease inhibitor (PI) and TMC125 a non-nucleoside reverse transcriptase inhibitor (NNRTI). Both TMC114 and TMC125 are currently in phase 3 clinical trials. The TMC114 file was recently submitted to both the FDA and EMEA. Both submissions are based on the efficacy and safety results of the 24-week dose-finding phase of two randomized controlled studies, known as POWER 1 and POWER 2, and supportive data from a non-randomized open label trial, POWER 3.
Tibotec research is focused on the identification and development of innovative compounds which may help reduce viral loads to undetectable levels.
First results of TMC114 and TMC125 in Combination
The first clinical results of virologic response to TMC114 and TMC125 investigational compounds in combination were shown in a late-breaker poster at CROI (Boffito et al). In this pharmacokinetic (PK) study in HIV-1 infected patients (N=10) with substantial PI and NNRTI resistance, it was observed that eight out of the ten patients achieved an undetectable viral load (<40 copies per ml HIV-RNA) by week twelve and all patient attained at least 2 log10 decrease in HIV-RNA at 12 weeks. In addition to TMC125 and TMC114 boosted with low-dose ritonavir, patients received two or more NRTIs; two patients used enfuvirtide for the first time. No significant PK interaction was observed. “These preliminary results are encouraging and suggest that the combination of these two investigational antiretrovirals may provide a new treatment option in heavily treatment-experienced patients such as these," said Marta Boffito MD, PhD, Chelsea and Westminster Hospital, London.
TMC125 is being studied in combination with TMC114 in the placebo-controlled phase 3 studies, DUET 1 and 2, which are currently enrolling in the US, Europe and other countries.
Understanding the factors predicting virologic response with TMC114
Following on from the primary results presented at IAS in July 2005 and ICAAC in December 2005, the results of resistance analyses of POWER 1, 2 and 3 showed that the TMC114 baseline fold change in EC50 (FC) was the strongest predictor of antiviral activity with TMC114 (De Meyer et al). A diminished TMC114 response was observed in the presence of multiple baseline PI-resistance-associated mutations (e10) together with one or more specific mutations; nonetheless this response was still greater than that observed in the control groups in POWER 1 and 2. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to additional data from long-term studies. Additionally the 24-week pharmacokinetic/pharmacodynamic analyses of the POWER 1 and 2 studies confirmed that baseline TMC114 FC rather than exposure influenced the virologic response to TMC114 (Sekar et al).
TMC125 showed activity against NNRTI-resistant virus
Tibotec presented the impact of baseline resistance on the virologic response to TMC125 from study TMC125-C223 (Vingerhoets et al). In the presence of one or two NNRTI mutations, viral load reductions of 1.65 log10 and 1.00 log10 respectively were observed at 24 weeks with TMC125 800mg twice daily treatment in combination with an optimized background regimen compared with a 0.19 log10 drop for the control group on best available regimen from licensed agents. This presentation follows the one made at ICAAC in Washington, DC, in December, looking at the 24-week primary efficacy and safety results. The most common adverse events (AEs) were diarrhoea and rash which were each 20% for the TMC125 groups compared with 15% and 8% for the active control group. Overall, 23% of TMC125 and 18% of control patients reported at least one SAE. Further analyses of the TMC125-C223 results, including resistance profile of TMC125, are ongoing. Additionally, a study investigating the interactions between TMC125 and tipranavir showed a significant decrease of TMC 125 exposure. (Scholler et al).
Research Insights at CROI
Tibotec and its collaborators presented new data on the resistance profiles and proposed a mechanism of action of the nucleotide-competing reverse transcriptase inhibitors (NcRTIs), a potential new class of antiretrovirals currently under investigation. (Gotte et al; Jochmans et al).
A new approach to analyzing complex patterns of protease resistance, known as bioinformatics resistance determination (BIRD), was also described for the first time (Van Marck et al).
TMC114 Expanded Access Program
In some countries outside Ireland, TMC114 is available through an expanded access program for HIV-1 infected adults who have limited or no treatment options due to virologic failure or intolerance to multiple ARV regimens. Patients must be three-class experienced, including at least two PI-based regimens, and have a CD4 cell count of equal to or less than 200 cells/mm3 and be ineligible for other Tibotec clinical trials. For more about the program, healthcare professionals and people living with HIV/AIDS may obtain information by visiting www.tibotec.com or www.clinicaltrials.gov.
Pending regulatory approval, Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., will commercialize TMC114 in the U.S. and Tibotec, a division of Janssen-Cilag, will commercialize the product in Europe and other countries. The trade name for the marketed product has not yet been determined.
Tibotec Pharmaceuticals Ltd.
Tibotec Pharmaceuticals Ltd., based in Cork, Ireland, is a pharmaceutical research and development company. The Company's main research and development facilities are in Mechelen, Belgium with offices in Yardley, PA. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need.
Tibotec Therapeutics: US Sales & Marketing
Tibotec Therapeutics, a division of Ortho Biotech Products, L. P., is headquartered in Bridgewater, N.J., and is dedicated to delivering innovative oncology, virology and other specialty therapeutics that help healthcare professionals improve patients' survival and quality of life, and address serious unmet needs in the health care community.
Tibotec, a division of Janssen-Cilag: European Sales & Marketing
Tibotec, a division of Janssen-Cilag, will bring innovative products for HIV/AIDS to patients in Europe, the Middle East and Africa. This new division was created within the Janssen-Cilag companies in October 2005 to focus on patient's and health care provider's specific needs in this disease domain. The company will also commercialise medicine against other viral diseases in the future. Janssen-Cilag is a leader in traditional and biological medicines for disorders such as in gastroenterology, women's health, mental health and neurology as well as for pain, oncology, haematology and nephrology.
CROI Presentations
Marta Boffito: Pharmacokinetics (PK) and antiretroviral (ARV) response to TMC114/r and TMC125 combination in patients with high level viral resistance.
Sandra De Meyer: Effect of Baseline Susceptibility and On-treatment Mutations on TMC114 and Control PI Efficacy: Preliminary Analysis of Data from PI-experienced Patients from POWER 1 and POWER 2.
Vanitha Sekar: Pharmacokinetic/pharmacodynamic (PK/PD) analyses of TMC114 in the POWER 1 and POWER 2 trials in treatment-experienced HIV-infected patients.
Johan Vingerhoets: Impact of Baseline Resistance on the Virologic Response to a Novel NNRTI, TMC125, in Patients with Extensive NNRTI and PI Resistance: Analysis of Study TMC125-C223.
Marianne Harris: Pharmacokinetics (PK) and Safety of Adding TMC125 to Stable Regimens of Saquinavir (SQV), Lopinavir (LPV), Ritonavir (RTV) and NRTIs in HIV+ Adults (TMC125-C145).
Monika Scholler: Significant decrease in TMC125 exposures when co-administered with tipranavir (boosted with ritonavir) in healthy subjects (TMC125-C161).
Matthias Gotte: Nucleotide-Competing Reverse Transcriptase Inhibitors Form a Stable Dead-End-Complex with the HIV-1 Enzyme.
Dirk Jochmans: Mutational Patterns Associated with Reduced and Increased Susceptibility to NcRTI in >6000 Clinical HIV-1 Isolates.
Herwig Van Marck: Analyzing complex resistance patterns of protease inhibitors with bio-informatics resistance determination (BIRD) - A novel approach employing synthetic viral genes carrying clinically relevant patterns of PI-resistance mutations.
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