INTELENCE is the first NNRTI to show antiviral activity in patients with NNRTI-resistant virus

Cork, Ireland -- August 29, 2008 -- The European Medicines Agency (EMEA) has granted marketing authorisation for the anti-HIV medication Intelence (etravirine). Intelence is a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI) and the first to show efficacy in patients with NNRTI-resistant HIV. Intelence is the first new NNRTI to be introduced in approximately 10 years. Also known as TMC125, Intelence was developed by Tibotec Pharmaceuticals, Ltd., and will be marketed in Europe by Tibotec, a division of Janssen-Cilag. Janssen-Cilag International NV will hold the marketing authorisation.

"NNRTIs have been trusted by physicians and used in antiretroviral therapy for more than a decade, but NNRTI resistance has limited the use of this important class of HIV medication," said Professor Christine Katlama, Head of the AIDS Clinical Research Unit in the Department of Infectious Diseases at Pitié-Salpêtrière Hospital in Paris, France. "Intelence extends the NNRTI class to thousands of treatment-experienced patients in Europe who have NNRTI-resistant virus, providing them with the potential to suppress their virus to undetectable levels -- the ultimate treatment goal."

Intelence, in combination with a boosted protease inhibitor and other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients.

This indication is based on week 24 analyses from two randomised, double-blind, placebo-controlled phase III trials in highly treatment-experienced patients with viral strains harbouring mutations of resistance to non-nucleoside reverse transcriptase inhibitors and protease inhibitors, where Intelence was investigated in combination with an optimised background regimen (OBR) which included darunavir/ritonavir [boosted Prezista].

The data showed that significantly more patients in the Intelence arm achieved undetectable viral load (less than 50 copies/mL) compared to placebo (58.9 percent vs. 41.1 percent [p < 0.0001]). Intelence was generally safe and well tolerated. Rash, generally mild to moderate, was the most common adverse event of moderate intensity or greater (? grade 2) associated with Intelence compared to placebo (9 percent vs. 3.2 percent).

The recommended oral dose of Intelence tablets is 200 mg (two 100 mg tablets) twice daily following a meal. Patients may also disperse the tablets in a glass of water.

"The approval of Intelence demonstrates our ongoing commitment to providing innovative therapies for treatment-experienced HIV patients," said Roger Pomerantz, President, Tibotec Research & Development. "We are committed to working with national health authorities to quickly make this drug available to people living with HIV in Europe who need new treatment options."

The EMEA decision follows similar approvals earlier in the year in Switzerland, Russia, Argentina, Canada, South Korea and the U.S. Commercial launches will vary from country to country, based on local price and reimbursement discussions with national authorities.

The NNRTI Class

NNRTIs block reverse transcriptase, a key enzyme the HIV virus uses to replicate. NNRTI drug resistance occurs when HIV develops mutations that partially or completely stop the NNRTI from binding to the reverse transcriptase enzyme, causing the drug to lose effectiveness. Generally, when patients develop resistance to one NNRTI, they are resistant to all first-generation drugs in the class. Intelence is the first NNRTI to show efficacy in patients with NNRTI-resistant virus.

DUET-1 and -2 Study Design

The DUET-1 and -2 studies, identical in design but conducted in different regions, assessed the efficacy and safety of Intelence in combination with an OBR in treatment-experienced adult HIV-1 patients with documented evidence of NNRTI and protease inhibitor (PI) resistance. They were large, randomised, controlled studies with a primary endpoint of less than 50 copies/mL (known as undetectable viral load) at week 24. European AIDS Clinical Society treatment guidelines define less than 50 copies/mL as the goal of therapy for treatment-experienced patients.

Patients with HIV-1 who were eligible for the DUET studies had a viral load of greater than 5,000 copies/mL, while on a stable antiretroviral therapy regimen for at least eight weeks and had evidence of at least one NNRTI-resistance-associated mutation, either at screening or from prior resistance tests, as well as evidence of three or more primary PI mutations (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M) at screening.

DUET-1 and -2 Results

Participants in the DUET studies were randomised to receive Intelence 200 mg twice daily (599 patients) or placebo (604 patients), each given in addition to an OBR. For all patients, the OBR included darunavir/ritonavir, plus at least two investigator-selected antiretroviral drugs (N(t)RTIs with or without enfuvirtide).

The 24-week pooled analysis of the DUET studies showed the following results for Intelence plus OBR vs. placebo plus OBR:

• Approximately 3 out of 5 patients in the Intelence arm achieved undetectable [viral load].

• 58.9 vs. 41.1 percent achieved < 50 copies/mL (p < 0.0001).

• Significantly greater mean increase in CD4 cell count from baseline; mean increase of 86 vs. 67 cells/mm3 (p < 0.006).

The resistance profile of Intelence was also studied. Intelence retained activity in the presence of multiple NNRTI mutations, including K103N, which was the most prevalent NNRTI substitution in DUET-1 and -2 studies at baseline. Other NNRTIs are not expected to be active in patients with this mutation.

The results of DUET-1 and DUET-2 were published separately in two articles in the 7 July, 2007 issue of The Lancet. The pooled analysis from the DUET studies was presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2007 as well as at the International AIDS Conference (IAC) in August of this year.

Important Safety Information

Etravirine does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

• Severe skin rash has been reported with etravirine; Stevens-Johnson Syndrome has been rarely (< 0.1 percent) reported. Treatment with etravirine should be discontinued if severe rash develops. In general, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. Discontinuation rate due to rash was 2 percent.

• No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of etravirine have not been studied in patients with severe hepatic [liver] impairment (Child-Pugh Class C). Therefore, INTELENCE should be used with caution in patients with severe hepatic impairment.

• Based upon the safety profile, no dose adjustment is necessary in patients coinfected with hepatitis B and/or C virus [HBV, HCV].

• Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

• Immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, including etravirine.

• The most frequently reported adverse events (>10 percent) of any intensity that occurred at a higher rate than placebo were rash (17 percent), diarrhea (15 percent) and nausea (13.9 percent).

Please see full prescribing information for more details.

About 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, USA. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need. Tibotec is a member of the Johnson & Johnson family of companies.