Cross-resistance Profile of Experimental PI Brecanavir

Brecanavir (BCV), a PI with high-affinity binding, shows >100-fold improved binding over currently approved PIs and 10-fold over TMC-114. BCV exhibits picomolar antiviral activity and a resilient resistance profile due to an adaptive thiazolylmethyl moiety.

In the present study, the cross-resistance profile of BCV, in Phase II development, was evaluated.

94 HIV-1 clinical isolates selected according to the presence of known PI RAS (defined by IAS USA, Fall, 2005) were analyzed for IC50 and fold change (FC) versus all approved PI except NFV using PhenoSense.

Results

The mean number of major PI RAS per isolate was 2.6 (range: 0 - 6; median 3).

The median IC50s for the other PI were significantly above that for BCV (geometric mean IC50 nM: BCV:0.4; APV:97, IDV:99, LPV:56, ATV:20, TPV:110).

The median fold change (FC) for BCV was lower than for all PIs apart from TPV (median FC: BCV:2.1, APV:8.6, IDV:15, LPV:19, ATV:15, TPV:1.3).

At the clinically derived cut-offs for IDV/r and LPV/r (10-FC), ATV/r (5.2-FC) and TPV/r (4-FC), 59%, 57%, 70% and 15% of isolates were resistant to these PI respectively.

For BCV, the 'resistant' proportions were 10% at 10-FC, 20% at 5.2-FC and 28% at 4-FC.

The mean number of major PI RAS for isolates with FCs ³ and < cut off were, 3.24/1.82, 3.17/1.95, 3.03/1.75 and 3.71/2.46 for IDV, LPV, ATV and TPV respectively; and 4.33/2.47, 3.53/2.42 and 3.27/2.41 for BCV at the same FCs (10, 5.2 and 4 respectively).
The TPV/r mean major PI RAS ratio at 4-FC was reproduced by BCV at FC 6.5-7.0.

Based on these findings, the authors conclude, "BCV shows greater potency than APV, IDV, LPV, ATV and TPV and lower FC than all PIs except TPV/r, which shows relatively low intrinsic potency and low clinical cut-off."

"The BCV virologic profile along with early signs of good tolerability and efficacy in subjects with PI-resistant isolates further supports its on-going development."

08/25/06

Reference
C Craig and others. Survey of brecanavir (BCV) and other protease inhibitor (PI) susceptibility to HIV-1 variants containing PI resistance-associated amino acid substitutions (RAS). 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract THPE0023.

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