Studies of pipeline drugs: RDEA806, PRO140, bevirimat, elvucitabine

Simon Collins, HIV i-Base

Several posters provided information on interesting compounds in development.

RDEA806 – an NNRTI

Pharmacokinetic results from a Phase 2a study of a new NNRTI from Ardea, previously shown at Mexico, was presented by Graeme Moyle from the Chelsea and Westminster Hospital, London. [1]

Two cohorts of 12 treatment-naive HIV-positive participants were randomised (9 active: 3 placebo) to receive either RDEA806 400 mg twice daily (BID), or 600 mg once daily (QD), for 7 days and a single morning dose on day 8 for PK monitoring.

All participants achieved viral load reductions of 1.5 – 2.0 log with a trend between reductions and Ctrough (but not Cmax or AUC).

Mean Ctrough at steady state were 407 and 112 nM for the BID and QD groups, respectively, and were well above the EC50 for wild-type (3 nM) and resistant (K103N, 2.3 nM) HIV.

Studies with additional cohorts to evaluate higher once daily doses with an enteric coated tablet formulation are underway.

A second poster by Xu and colleagues from Ardea Bio presented results of in vitro resistance mutations selected in the presence of RDEA806. [2]

RDEA806 concentration was increased to 1500 nM in the virus culture over the course of 13 months. K104E was identified after > 300 days with no loss of susceptibility to RDEA806 or other NNRTIs. RDEA806 showed a minor loss of activity to the next virus selected, K104E-E138K-T240I, while efavirenz retained full activity. Virus with the final combination of 5 mutations in RT (K104E-E138K-T240I-V179D-F227L), which reduced phenotypic susceptibility to RDEA806 but only minor to moderate cross-resistance to other NNRTIs, had very low replication capacity.


1. Moyle G et al. RDEA806, a novel HIV NNTRI, shows positive outcome in treatment of naive HIV patients. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-893.

2. Xu W et al. Resistance to RDEA806 requires multiple mutations which have limited cross-resistance to other NNRTIs. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-1222.

PRO140 – a monoclonal antibody to CCR5

In a single dose (5mg/kg) study PRO 140 reduced viral load by –1.83 log in participants with early-stage HIV and R5 virus only. At ICAAC results were presented from a randomised placebo controlled study using 5 mg/kg and 10 mg/kg IV doses in participants with CD4 >300 cells/mm3 who had not used ARV treatment for the previous 12 weeks.

participants were followed for 58 days post-treatment and results presented from an interim analysis on data from the first 15 subjects.

Results: Interim enrollment was equally distributed across the treatment groups. Baseline HIV RNA and CD4 averaged 35,480 copies/mL and 403 cells/mm3, respectively.

At day 12, mean log10 changes in HIV RNA were +0.06, –1.88 (p<0.0001), and –2.01 (p<0.0001) for placebo, 5 mg/kg and 10 mg/kg, respectively.

Mean maximum viral load reductions in HIV RNA were 0.48 (range 0.15 to 0.73) for placebo, 1.90 (range 1.44 to 2.17, p<0.0001) for 5 mg/kg and 2.17 (range 2.09 to 2.26, p<0.0001) for 10mg/kg groups.

The authors concluded that these results indicated the potential for infrequent IV dosing and that sub-cutaneous dosing was also being evaluated.


The mechanism of action of this drug is different from the other CCR5 inhibitors and could potentially be synergistic with them, or work on viruses that have developed resistance to them.

The current intravenous administration of PRO 140 suggests dosing every 2 to 3 weeks, whereas modelling suggests that an increase in the dose might extend that to a month. The manufacturer is investigating other possible modes of administration, including a transdermal patch that might administer a more steady state of the drug.

There are patients who do not adhere to daily may be benefited from once every three weeks or longer gap regimen. Future studies might look at prophylactic use of the monoclonal antibody as a form of pre-exposure prophylaxis, at least in high-risk populations.

Ref: Jacobson JM et al. Antiviral activity and tolerability of 5 mg/kg and 10 mg/kg doses of PRO 140, a humanised monoclonal antibody to CCR5. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-1269a.

Bevirimat – maturation inhibitor

Lalezari and colleagues presented results from a phase 2 double-blind, randomised dose escalation study of bevirimat (PA-457), a maturation inhibitor that targets the Gag capsid SP-1 cleavage site. [1]

A poster at the international drug resistance workshop this year reported the impact of baseline polymorphisms in Gag on viral load response.

Changes at positions 369, 370 or 371 lead to reductions –0.16 (n=9), –0.24 (n=22) and –0.32 logs (n=11) respectively, compared to –1.08 logs in patients with no changes at 369-371. [2]

59 treatment-experienced participants received 2 weeks of bevirimat or placebo as functional monotherapy on top of a failing (VL >2000 copies/mL) background regimen. Patients initially received a 400 mg bevirimat tablet dose, or placebo; in the modified study, patients received a 250, 300, 350 or 400mg bevirimat liquid dose, or placebo.

Of 44 participants given the assigned bevirimat dose, the mean VL change was –0.6 log copies/mL vs +0.05 log for placebo (n=13). 12/13 (92%) participants with bevirimat trough levels >20 ug/mL and without the key Gag polymorphisms had reductions of >0.5 log; 10/13 (77%) had a VLR >1.0 log (group mean VLR: –1.26 log). 32/46 (70%) bevirimat treated patients and 10/13 (77%) placebo-treated participants had >1 adverse event (AE). For people treated with bevirimat and placebo respectively, the most common AEs were diarrhea (22%; 39%), nausea (20%; 31%) and headache (20%; 23%); all were Grade 1.

Phase 3 studies are planned to include Gag mutations screening criteria and pharmacokinetics to confirm the utility of bevirimat in people who are treatment-experienced.


1. Lalezari J et al. A Phase 2 safety and efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients identifies the target phase 3 study profile. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-891.

2. McCallister S et al. HIV-1 gag polymorphisms determine treatment response to bevirimat (PA-457). XVII IHDRW 2008, Sitges. 48th ICAAC, 25-28 October 2008. Washington. Abstract 8.


Elvucitabine (ELV) is a cytosine nucleoside analogue with a long half-life (90 hours), and has been shown in vitro to have potent activity against HIV-1. DeJesus and colleagues presented interim 48-week results from a Phase II study against 3TC in treatment-naive patients.

77 subjects were randomised to either ELV 10 mg versus 3TC 300 mg both administered daily in combination with efavirenz 600 mg and tenofovir DF 300 mg. Fifty-five subjects completed 48 weeks of treatment. The proportion of subjects at week 48 with viral load <50 copies/mL in the ITT patient population was marginally higher in the 3TC arm compared to ELV (78% vs. 65%, p=0.07). Adverse events were similar between treatment groups.


Elvucitabine’s efficacy in this study, in regard to intention-to-treat analysis, show that it is nonsignificantly inferior to 3TC. Earlier reports from 24 weeks study demonstrated more adverse side affects in the ELV arm which was not the case at 48 weeks. This drug will require further studies, for long-term antiviral activity and safety.


DeJesus E et al. Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. 48th ICAAC, 25-28 October 2008. Washington. Abstract: H-892.

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