New antiretroviral compounds at ICAAC: new PI brecanavir from GSK; maturation inhibitor PA-457; antiviral activity of monoclonal antibody; TNX-355 in treatment experienced patients

Simon Collins, HIV i-Base

There was only one oral slide session at ICAAC for HIV studies. Luckily this included results on several new drugs that were all worth reporting and are included below.

New PI from GSK: brecanavir

Optimistic results were presented from a proof-of-concept study of a protease inhibitor in development by GSK. In vitro, bracanavir (GSK 640385) has antiviral activity against multi-PI resistant HIV and is up to 100-fold more potent than currently marketed PIs. It needs to be taken with food, and also requires ritonavir boosting.

Although the 8-week results are in the printed abstract submitted to the original ICAAC meeting, the intervening period until the rescheduled conference enabled 24-week results to be analysed and presented.

This was an open label, non-randomised, 48-week study in 25 patients with wild-type virus and six patients with drug resistance. Dual nucleoside backbone was decided by treatment history and resistance profile, with 27/31 using AZT/3TC (Combivir). Tenofovir was not allowed as interaction data at the time of the study were not yet available. The dose studied was brecanavir 300mg with ritonavir 100mg, both twice-daily (Q12H).

The six patients with resistant virus had a median of two primary PI and five NRTI mutations. Median (IQR) CD4 and viral load at baseline was 311 cells/mm3 (203 to 405) and 4.71 logs (4.3 to 5.1). Median baseline viral load for the six patients with resistant-HIV was approximately 1 log lower than that of naive patients (4.2 vs 5.0 logs).

At week 24, 77% patients had viral load <50 copies/mL and 81% had <400 copies/mL by intent-to-treat analysis (ITT, missing data = failure). Median reductions of –2.2 and –3.3 log in the experienced and naive patients respectively, was related to different baseline levels and censuring by the lower limit of the test.

There were four discontinuations of the study drug; one due to nausea and vomiting, and a second due to a grade 3 increase in AST, and two due to withdrawal of consent. There were no clinical reports of toxicity greater than Grade 2. Grade 3-4 laboratory abnormalities were CPK (n=3) raised lipids (n-2), AST, GGT, hypoglycemia, total bilirubin and neutropenia (all n=1). Lipid changes included median increases in total cholesterol, HDL and triglycerides of 30.9, 3.9 and 62.3 mg/dL respectively, with no effect on LDL.

The resistance profile of one of the 5/6 treatment experienced patients who achieved <50 copies/mL included broad resistance with mutations associated with protease resistance at positions 10, 24, 33, 46, 48, 53, 54, 62 and 82; associated with RTI resistance at 41, 44, 67, 210, 215 and the K103N conferring resistance to NNRTIs.


Unusually, a single-arm, single-dose study was run in treatment naive and experienced patients looking at tolerance and efficacy, prior to controlled dose-finding study. Results from such a study have therefore created a higher profile for this compound prior even to Phase 2 dose-finding results.

Given the competitive difficulties sometimes experienced in recruiting treatment-naive patients, this should help recruitment into future studies. The Phase IIb brecanavir study (HPR20001, STRIVE) will enrol 130 multi-PI experienced patients in the US and Europe and includes sites in the UK.


Ward D, Lalezari J, Johnson M et al. Preliminary antiviral activity and safety of 640385/ritonavir in HIV-infected patients (Study HPR10006): an 8-week interim analysis. Abstract H-412.

Maturation inhibitor PA-457: safety and efficacy during 10-day monotherapy study

Svilen Konov, HIV i-Base

Beatty and colleagues from Panacos Pharmaceuticals reported results from a double-blind, placebo-controlled, 10 day monotherapy study that looked at the safety and efficacy of PA-457. This is the first in a new class antiretrovirals, called maturation inhibitors. Maturation inhibitors prevent HIV core proteins from maturing, thus making the new viral particles non-infectious.

The study randomised 33 patients (CD4 >200 cells/mm3 and viral load 5000-250,000 copies/mL) who were either treatment-naive or who were more than 12 months without therapy, to an oral dose of once-daily placebo or 25, 50 100 or 200mg PA-457. The 100 mg and 200 mg doses produced statistically significant median reductions in viral load of –0.48 and –1.03 logs respectively, compared to placebo. At day 11 the participants from the 200mg dose group with baseline viral load <100,000 copies/mL had median viral load reduction of –1.52 log10 copies/mL. The genotypic data obtained at the end of the study (in 21 out of 33 people) demonstrated no evidence of resistance development to PA-457. No grade 3/4 lab abnormalities were seen at any dose, and any adverse events categorised as mild to moderate.

One person had a grade 2 increase in triglycerides that returned to normal by the end of the study. Another participant suffered a lacunar CVA (cerebrovascular accident, minor stroke) but the researchers suggest that this is probably a result of previous poorly-controlled hypertension. The researchers reported that the half-life of PA-457 is close to 60 hours, which is promising for current ARV research focused on once-daily dosing.

Ref: Beatty G, Lalezari J, Eron J, et al. Safety and antiviral activity of PA-457, the first-in-class maturation inhibitor, in a 10-day monotherapy study in HIV-1 infected patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-416d.

Antiviral activity of monoclonal antibody TNX-355 in treatment experienced patients

Svilen Konov, HIV i-Base

TNX-355 is a humanised monoclonal antibody (an antibody that is produced artificially from a single cell clone and, therefore, consists of a single type of immunoglobulin) that binds to CD4 receptors, disrupting viral replication. The compound is aimed at treatment-experienced patients. At ICAAC the 24-week interim assessment of the ongoing 48-week double-blind, placebo-controlled, randomised phase II study showed that TNX-355 in combination with optimised background regimen (OBR) exhibited greater antiviral activity than OBR alone in treatment-experienced HIV-1-infected individuals.

The study randomised 82 three-class experienced patients to either15 mg/kg every 2 weeks or 10 mg/kg every week for 8 weeks followed by 10 mg/kg every two weeks; or to placebo; with OBR for all groups. The mean RNA log drop was –1.2 (p<0.001), –0.97 (p<0.001), and –0.41 in the 15 mg, 10 mg and placebo groups respectively. The compound, however, needs to be infused intravenously, which might turn it into a last resort choice. The researchers did not present information on the relative ARV experience of the participants in the study or impact on treatment history on the results.

Another study [2] showed that TNX-355 is active against CCR5-, CXCR4-, and dual/mixed-tropic HIV-1 in vitro. In addition, strong synergistic antiretroviral activity was demonstrated between TNX-355 and T-20 (enfuvirtide) in vitro (CIs of 0.27±0.13 and 0.12±0.11 for single and continuous exposure, respectively). These results suggest that combining two entry inhibitors might have a potential of becoming a treatment approach in the future.


  1. Norris D, Morales J, Gathe J et al. TNX-355 in combination with Optimized Background Regimen (OBR) Exhibits Greater Antiviral Activity than OBR Alone in HIV-Treatment Experienced Patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract LB2-26.
  2. Godofsky E, Zhang X, Sorenson M, et al. In vitro antiretroviral activity of the humanized anti-CD4 monoclonal antibody, TNX-355, against CCR5, CXCR4, and dual-tropic isolates and synergy with enfuvirtide. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract LB-26.

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