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PRNewswire - December 18, 2001
"Despite the progress made in the development of anti-HIV drugs, the ability of HIV to mutate and become less sensitive to currently approved drugs necessitates the ongoing development of new compounds that may overcome or delay resistance," said Neil Graham MD, VP Medical Department, Tibotec-Virco, North Carolina. "Our Company is committed to developing new therapeutics that would provide more effective HIV therapy in the future while also continuing to expand the capabilities of HIV resistance monitoring systems to enable physicians to determine the most appropriate, individualized HIV therapy for people living with HIV/AIDS."
The ability of HIV to develop mutant strains that are resistant to HIV drugs is one of the main reasons why people living with HIV experience treatment failure. A survey previously conducted by Tibotec-Virco on almost 12,000 HIV patients in the U.S. found one in four HIV patients to be resistant to all three classes of HIV drug regimens.(1) In response to the emerging need for new therapeutics, Tibotec-Virco has developed and implemented a unique parallel drug profiling strategy to accelerate drug discovery and development by rapidly identifying new anti-HIV compounds, which in vitro are highly active against both wild type and resistant HIV and have favorable pharmacokinetic profiles.
New Anti-HIV Compounds Address Resistance, Demonstrate Strong Anti-Viral Effect
Data presented at ICAAC report on the strong antiviral effects and HIV-1 resistance profile of Tibotec-Virco's next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), TMC125. Additional studies reported on the safety, pharmacokinetics and tolerability of Tibotec-Virco's highly potent candidate protease inhibitor (PI), TMC114, against both wild-type and resistant HIV.
"These early data on Tibotec-Virco's candidate NNRTI, TMC 125, as well as our PI, TMC114, are leading to a better understanding of HIV mutant strains.
Our rapid progress is the result of the development and implementation of our unique drug profiling strategy," said Neil Graham MD, VP Medical Department, Tibotec-Virco, North Carolina. "We are delighted that our pipeline compounds may mean more effective HIV therapy in the future."
With Tibotec-Virco's unique drug profiling strategy, potential anti-HIV compounds are evaluated against a broad selection of HIV-mutant strains recognized to be important to the development of resistance and clinical isolates, the latter using the company's phenotypic test, the Antivirogram(R). Pharmaceutical characteristics of each compound are analyzed in parallel with the compound's anti-HIV activity in an early phase of development. Results from studies on Tibotec-Virco's novel compounds follow below.
Tibotec-Virco's Protease Inhibitor Shown To Be Safe and Active Against Resistant HIV Variants
Using Tibotec-Virco's unique drug profiling strategy, TMC114, one of 700 analogs of TMC126, was selected for clinical investigation for the treatment of HIV/AIDS patients on the basis of its potency against wild-type and resistant HIV.
In vitro data presented at ICAAC indicated that TMC114 is a highly potent protease inhibitor with an excellent profile against both wild-type (EC50=4.7nM, EC90=10.3nM, CC50>100uM) as well as HIV strains that are normally resistant to current protease inhibitors (no greater than a 5-fold increase in EC50 when tested against a panel of 20 PI-resistant HIV strains).
In a separate study, Tibotec-Virco's researchers examined the safety, tolerability and pharmacokinetics of single oral doses of TMC114 and found that single doses of this novel candidate protease inhibitor were safe and well-tolerated at all tested dosage levels.
The randomized, double-blind, placebo-controlled dose escalating trial involved two panels of 9 healthy volunteers (6 active, 3 placebo). The maximum tolerated dose of TMC114 was not reached. Further dose increases were limited because of diarrhea related to polyethylene glycol (PEG), a solvent used in dispersing TMC114.
First Clinical Results of TMC125 Demonstrates Strong Antiviral Effect in HIV Patients after 7 days
Data from a randomized, double-blind, placebo-controlled Phase IIA study using Tibotec-Virco's novel NNRTI, TMC125, as monotherapy in 18 previously untreated HIV-positive patients, produced significant reductions in viral load. The reductions ranged from a 1.1 log drop to a 3.4 log drop (mean -2.0 log10 copies per ml) after 7 days. Eight of the 12 subjects who received TMC125 had their viral loads reduced to less than 400 copies of HIV/ml, with two subjects below the 50-copy limit of a more sensitive test. TMC125 was well tolerated during the study period with no differences in side effects apparent between TMC125 and placebo.
Additional clinical trials are ongoing to study TMC125 in NNRTI-experienced patients. Previous laboratory research has demonstrated that TMC125 and other NNRTIs under development at Tibotec-Virco are highly active against strains of HIV that are resistant to current NNRTIs.
Reduced Resistance to Tibotec-Virco's NNRTIs Shown In Experimental Setting
In another study being presented at ICAAC, Tibotec-Virco scientists set out to compare the rates of resistance development between the Company's non-nucleoside reverse transcriptase inhibitors (NNRTIs), TMC125 and TMC 120, and first generation NNRTIs, efavirenz and nevirapine. The study was performed using cultures of MT4 cells infected with wild-type HIV-1 (with a high rate of infection to maximize the genetic diversity of the virus population) at various concentrations of inhibitors. In this setting, researchers found that resistance to first generation NNRTIs occurred rapidly (on average within 3-7 days) with resistant viruses harboring only one mutation, while resistance to TMC125 or TMC120 was significantly delayed or did not occur after thirty days at higher doses of the drugs. Furthermore in these experiments the development of resistance to TMC125 required the presence of at least two mutations.
HIV Resistance Testing Integral to the Prediction of Treatment Response
HIV resistance testing has increasingly become an essential tool in routine HIV management. There are approximately 250 different mutations that can occur in HIV's genetic code which are known to confer HIV drug resistance.
By understanding the susceptibility of the virus to antiretroviral drugs, resistance tests enable clinicians to select the most effective combination of drugs for the individual patient and improve their response to treatment. In addition to the data being presented at ICAAC, Tibotec-Virco has recently further developed its resistance tests, which are summarized below.
Newly-Approved Viread(TM) Added to Testing Panels for both the VirtualPhenotype(TM) and Antivirogram(R)
Following FDA approval of Viread(TM) (tenofovir disoproxil fumarate) on 26th October 2001, Tibotec-Virco added this new antiretroviral drug to both the VirtualPhenotype and Antivirogram reports on 5th November 2001. In response to the FDA's classification of this antiretroviral as a new class of inhibitor (nucleotide reverse transcriptase inhibitor, NtRTI), Tibotec-Virco created a new NtRTI category for both resistance test reports. Tibotec-Virco worked closely with Gilead and the Viread development program and as a result over 6,000 matched genotype and phenotype pairs already reside in Tibotec-Virco's growing proprietary database used for the VirtualPhenotype. A biological cut-off value of 3.0 was established for both the Antivirogram and VirtualPhenotype using methods previously described for all other antiretrovirals.(2) According to studies cited in the FDA label for Viread, treatment-experienced patients with a fold-change in resistance of > 4 exhibited a diminished response to Viread. This 4-fold value may represent a clinical cut-off value for Viread and this information is also described on both resistance reports.
The studies presented at ICAAC by Tibotec-Virco highlight advanced strategies to further elucidate the genetic determinants of resistance to antiretrovirals such as didanosine, lopinavir, and the NNRTI class.
Selected findings from some of the Tibotec-Virco studies are highlighted below. All studies used Tibotec-Virco resistance testing technology (Antivirogram(R) and/or VirtualPhenotype*):
* Important work presented at this meeting on further understanding tenofovir resistance using Tibotec-Virco's Antivirogram(R) showed that phenotypic susceptibility to tenofovir remained most frequently within the normal range when analyzed in combination with other RT inhibitors including 3TC, AZT, d4t, ddI, and ABC. Tenofovir, both as a single agent and when used in combination with other RT inhibitors, was examined to determine the existence and extent of susceptibility. Nearly 5,000 clinical HIV-1 samples, predominantly from treatment-experienced patients, were examined and results suggest that the majority of these patients (88% within 3-fold normal range for tenofovir) have HIV that could be susceptible to tenofovir DF therapy.
* Phenotypic resistance to ddI was shown to be less frequent than with other therapeutics including AZT, 3TC or ABC (12.4% of samples examined were resistance to ddI compared to 32.9%, 50% and 27.5% for AZT, 3TC and ABC respectively). Tibotec-Virco researchers utilized a resistance database of more than 7,100 North American clinical samples with genotypes and phenotypes to distinguish the common genetic determinants and assess the frequency of ddI resistance. Phenotypic drug susceptibility was determined by using Tibotec-Virco's phenotypic test, Antivirogram*.
* Data presented by Tibotec-Virco scientists show that HIV variants with high-level phenotypic resistance to ritonavir and indinavir may, in fact, have decreased susceptibility to lopinavir. This study investigated the cross-resistance and genotype-phenotype relationships between lopinavir, the most recently introduced protease inhibitor (PI), and two other PIs, ritonavir and indinavir, to establish relationships and identify interactions. Using Tibotec-Virco's phenotypic test, Antivirogram*, researchers evaluated more than 2,300 samples, either clinically derived and/or from drug naive patients. In assessing the resistance profile of lopinavir, more than 30 mutations in the HIV protease were identified as being associated with resistance to lopinavir.
"These data further illustrate Tibotec-Virco's ongoing commitment to the resistance testing field. We continue to map out resistance to anti-HIV drugs by identifying and analyzing genetic mutations, which, in turn, depict common patterns or 'blueprints' of resistance to HIV therapeutics and are instrumental in establishing clinically relevant and drug-specific cut offs for our resistance tests," said Graham. "These findings are very encouraging and can be translated to clinical applications which ultimately contribute to more effective, individualized treatment options for people living with HIV/AIDS."
About Tibotec-Virco
Tibotec-Virco is a multinational biotechnology company with headquarters in Belgium and operating subsidiaries in the United States and Ireland.
Tibotec-Virco develops new drugs and individualized disease management products and services for HIV and other viral diseases with the ultimate aim of enhancing and extending peoples' lives.
The Company has two novel antiretroviral compounds in clinical development, TMC125, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and TMC114, a protease inhibitor (PI). Tibotec-Virco is focusing on the discovery and development of HIV/AIDS compounds that are active against both wild-type and strains of HIV that have developed drug resistance, a major cause of treatment failure.
Tibotec-Virco is widely regarded as a world leader in HIV resistance testing. The Company has built the world's largest relational database of more than 120,000 HIV genotypes and phenotypes. The VirtualPhenotype(TM) test combines the best features of both genotyping and phenotyping by using information from this immense database. It provides physicians with comprehensive, accurate and cost-effective resistance information for improved patient management.
The Company was formed from the merger of Virco Group NV and Tibotec Group NV on March 14, 2001 and brings together the complementary expertise of Tibotec in drug discovery and development and that of Virco in pharmacogenomics and molecular diagnostics.
For further information, please visit Tibotec-Virco's website: http://www.tibotec-virco.com
(1) Bloor S, Kemp SD, Hertogs K, Alcorn T, Larder BA. Patterns of HIV drug resistance in routine clinical practice: a survey of almost 120,000 samples from the USA in 1999. Antiviral Therapy 2000; 5 (Supplement 3): 132. Abstract 169.
(2) Harrigan RP, Montanner J et al. The Worldwide Variation in HIV-1 Phenotype Susceptibility in Untreated Individuals: Biologically Relevant Values for Resistance Testing. AIDS 2001, 15; 1671-1677.
SOURCE Tibotec-Virco Web Site: http://www.tibotec-virco.com
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