Antiretroviral activity of new and novel agents

Mike Youle MD Royal Free Hospital

This report focuses mainly on antiviral activity of compounds that are in development with a few reports on strategy for using existing drugs in difficult situation. A summary of pharmacokinetic and drug interaction studies presented on pipeline drugs are covered in a subsequent article.

This report looks at the following the following pipeline compounds:

Small molecule entry inhibitors:

  • Maraviroc (formerly UK 427,857)
  • Vicriviroc (Schering D 417690)
  • GW873140
  • Synergistic action of PRO140 with other drugs

New NRTIs, NNRTIs and PIs:

  • Reverset
  • TMC125
  • TMC120, as a potential microbicide
  • New NNRTI, BILR 355BS
  • New NNRTI, GW695634
  • Tipranavir (TPV)
  • TMC114
  • New tablet version of Kaletra called Meltrex

Other targets:

  • PA-457, the first maturation inhibitor
  • Reverset

Table 1: Selected abstracts on new drugs presented at IAS 2005

Compound Company Class Abstract number
Gp41 blockers NY Blood Bank Attachment TuOa201
Maraviroc (UK427857) Pfizer CCR5 TuOa204
Vicriviroc (SCH417690) Schering CCR5 TuOa205, TuPe3.1B03, TuPe3.1B05, TuPe3.1B06, TuPe3.1B07, TuPe3.1B08, TuPe3.1B09
GW 871340 GSK CCR5 TuPe6.1B13
PRO140 Progenics CCR5mAb TuOa0206
Thiovir Aventrix Foscarnet analogue TuPe6.1B16
Foscarnet AstraZeneca Foscarnet WePe12.9C16
Reverset Pharmasset NRTI WeOaB0103
TMC278 Tibotec NNRTI TuPe3.1B10, WePe3.3C15
TMC125 Tibotec NNRTI TuPe3.1B11, WePe3.3C16
TMC120 Tibotec NNRTI MoFo0105

Entry inhibitors

As has been noted before, CCR5 offers an ideal target against HIV, since it is well conserved, necessary for transmission with evidence that reduced activity is protective against HIV infection and progression (delta CCR5 homo- and heterozygotes respectively). The potential agents fall into three groups:

  1. Large molecules: e.g. PRO 140 (Progenics)
  2. Intermediate size molecules: such as modified native ligands (Met-RANTES, AOP-RANTES, NNY-RANTES, etc) which render CCR5 inaccessible
  3. Small molecules: against CXCR4 (AMD3100) or CCR5 (TAK-652, UK427, 857 (maraviroc), SCH D (vicriviroc), CMPD167, GW873140, UCB35625), etc., which interpolate into the membrane binding domain.

Maraviroc (formerly UK 427,857): An overview of the ongoing studies of maraviroc (formerly UK 427,857) were presented by Elna van der Ryst from Pfizer in the UK. [1]

There have been six studies with a total of 154 healthy volunteers and 66 HIV-positive patients, receiving maraviroc either once- or twice-daily, in doses from 3-1200mg. Dizziness nausea and tiredness occurred at the higher doses but postural hypotension was dose limiting above the 600mg dose with 3/355 subjects at that dose, but 6/9 at the 1200mg dose. This looks to be a very clean drug with no serious adverse events reported so far, and apart from two subjects with postural drop at the higher dose, no withdrawals from the studies due to drug related events. Also, no laboratory abnormalities were reported due to the drug, and specifically no QTC prolongation on the ECG which had plagued the Schering compounds.

61/63 (97%) of subjects with CCR5-tropic virus at baseline remained CCR5 at 10 days of monotherapy, two patients showed emergence of CXCR4-using variants under treatment at the 100mg dose. Dan Kuritzkes has previously noted that “the current sensitivity of tropism assays could be called into question…” and that the use or these agents could result in emergence of pre-existing minority variants due to selective pressure against R5 virus. In one patient, dual/mixed tropic virus emerged at day 11, but reverted at day 40 to CCR5 tropic; in the second, the mixed virus emerged at day 11 and remained mixed at one year with 80% CCR5-tropic virus. Phylogenetics suggests that the variants that emerged were due to pre-treatment R5/X4 virus, but that they could not be detected by the current assay sensitivity. Maraviroc is currently in Phase 2b/3 development in both naive and treatment-experienced patients using doses equivalent to 300 mg QD and 300 mg BID.

Vicriviroc (Schering-D, SCH 417690) has a molecular weight of 650, making it relatively small, and therefore hopefully an easy and inexpensive compound to manufacture. It has a long half-life, is boosted by ritonavir, and exhibits synergy with existing compounds. After a slow start, due to toxicity concerns with the former compound Schering-C, this agent seems to be much improved. Francois Raffi presented the data on a phase I/II study where 49 subjects were dosed at 10mg, 20mg or 50mg for 14 days and had intensive PK assessment and then follow-up for 28 days. [2]

There were three non-drug related serious adverse events but as with maraviroc this seems a very safe drug. The half-life is long, which could lead to intermittent dosing, and viral load drops were good at 10 days and showed a dose response.

As with any new agent there is a flurry of pharmacokinetic and drug interaction studies and these are reported in the overview of pharmacokinetic studies later in the issue of HTB.

GW873140 (a spirodiketopiperazine), the third CCR-blocker reported on, was assessed against a panel of clinical isolates that were resistant to a range of antiretrovirals and to 64 mixed tropic viruses with varying degrees of resistance to HAART. [3]

All isolates were susceptible to the GW873140 (excluding the X4 component of the mixed tropic samples and treatment experienced patient samples appeared more susceptible to the drug (median IC50 of 5.83nM compared to 6.71nM for the antiretroviral naive samples). 95% of samples had an IC50 <16.5nM which reflects the concentration achievable with the current doses under study.

PRO140: In an oral presentation, Daniel Pevear discussed the synergistic action of PRO140 with other drugs that act to block CCR5. [4]

PRO140 is a humanised IgG4 monoclonal antibody that binds to a multi-domain epitope on CCR5 and blocks HIV, but not chemokine, binding to CCR5, and has shown prolonged control of HIV in the SCID mouse model. It acts independently of viral clade and target cell, showing a broad spectrum of inhibition. A combination index (CI) <1 represents synergy and all the current CCR5 inhibitors in development showed a favourable interaction when given with PRO140: TAK 779 (0.36, 0.10); SCH-D (0.51, (0.05); maraviroc (0.59, 0.04); and RANTES (0.59, 0.08, mean and SD for each respectively. This opens the door to combination CCR5 blockade. Interestingly this benefit is not seen with the fusion inhibitor enfuvirtide.

In a phase 1 study in healthy volunteers no serious toxicity arose and the drug was generally well tolerated. [5] Trials in HIV-positive patients should begin in the fourth quarter of 2005.

Finally, Jiang and co-workers from the New York Blood Bank presented data on a  screening exercise to identify small molecule entry inhibitors against HIV-1. [6] These were mainly N-substituted pyrrole derivatives and may offer new agents to act in this area should they be commercialised.

New NRTIs, NNRTIs and PIs

Reverset: The only novel nucleoside analogue to be showcased was Reverset. Cal Cohen headed a group, which examined the drug in 199 patients with detectable viraemia on HAART. Preclinical studies have shown Reverset to have activity against virus resistant to 3TC, AZT, tenofovir and other NRTIs. It has a long half-life of 17 hours and has not shown mitochondrial toxicity in vitro. [7]

The study was placebo controlled dose comparison of 50mg, 100mg or 200mg once-daily as a two week add on to the failing regimen, followed by a 14-week period with an optimised background, and then an 8-week cross over. It was conducted in 25 centres in USA, Germany and France.

After two weeks there was variable drop in viral load of around –1 log. The greatest reduction was seen in those patients who did not take 3TC/FTC. This change was continued out through the optimised background phase and resulted in a statistically significant difference in those who did not have 3TC or FTC in the background regimen.

When the drug was co-dosed with ddI 50% of subjects developed hyperamylasaemia compared to 5% when no ddI was used; 3 subjects developed pancreatitis and use in patients at risk of pancreatitis is not advised.

The new non-nucleoside reverse transcriptase inhibitors (NNRTIs) also had some new data on show at the meeting.

TMC278, a diarylpyrimidine or DAPY compound had a food effect study in 12 healthy volunteers which showed that food increased the levels of TMC278 by 45% compared to fasted with dose proportional pharmacokinetics from 25-100mg and steady state being reached within one week of dosing [8] a dose ranging study is on-going. A second PK study looked at the interaction with tenofovir and found that although TMC278 levels are unaffected the levels of tenofovir rise by approximately 24% in combination. [9] This is not thought to be clinically significant but the clinical studies will need to examine potential increase in kidney toxicity which theoretically could occur.

TMC125, the other Tibotec NNRTI, is further along in development but had the initial disadvantage of a high pill burden. TMC125 C170 was a randomised single dose crossover study in 45 HIV uninfected individuals to assess the standard granulolayered tablet compared to several novel formulations which reduce the pill load. [10] All the new formulations were better than the standard one and Tibotec are now deciding which one to move forward with.

TMC120, the final NNRTI from the same group, is no longer being developed for oral use but is under assessment as a potential microbicide. In a study by the International Partnership for Microbicides, the compound was examined for activity in both cell based assays and cervical explant, including migratory cells from the explants. [11]

It was effective both alone and as a gel formulation in semen and cervical fluid did not reduce the effect, biocompatibility with the cervical tissue was excellent. In addition the drug appeared to produce anti-HIV memory effects with activity lasting up to 6 days post treatment and thus seems to be a promising candidate for a microbicide. It would also be important to asses the agent in rectal models since anal intercourse is common and clearly a risk in both men and women.

An interesting study from the HIV Center for Clinical and Behavioural Studies in New York assessed acceptability of different volumes of microbicidal gel in 20 HIV uninfected men who were having unprotected anal intercourse. [12]

It was a dose escalation study and the maximal acceptable dose was 50mL in 9 subjects, 35mL in 6 and 20mL for 3, with two lost to follow-up. It appeared that 35mL was the most suitable level to use and that this could be an important prevention tool for men who do not use condoms consistently.

BILR 355BS, an NNRTI in development at Boehringer-Ingelheim, is an 8-substituted dipyridodiazepinone. A crystallographic model of the interaction with the drug with wild-type virus and with various mutants showed BILR 355BS to be better at binding to the mutants through specific modifications to the core substitution patterns. The drug is now in clinical trials. [13]

GW695634 from GSK is the last drug in this class to have data presented. A group headed by Steve Becker from San Francisco performed a double blind, placebo controlled study of four doses (100mg, 200mg, 300mg, 400mg BID) for 7 days versus placebo in 46 subjects who had NNRTI resistance. The drug was generally well tolerated although rash occurred in 17%, nausea in 15% and diarrhoea in 11% of subjects. At day 8 median viral load reductions were -1.2, -1.1, -1.6 and -1.3 logs for the groups on active drug at the doses above and were significant compared to placebo (p<0.001). [14]


A number of new presentations on data on tipranavir (TPV) were presented (Abstract numbers WeOa0205, WePp0103, TuPe7.8C01, WePe4.4C19, WePe6.2C05, WePe6.3C07, and WePe16.7B07). Valdez and co-workers presented week 24 data from the resist studies by co-use of enfuvirtide (T20) and tipranavir inhibitory quotient (IQ). [15]

Most of the 450 subjects who received TPV/r at a dose of 500 mg/200 mg BID achieve TPV trough concentrations >60-fold in excess of the TPV IC50 of their isolates:

  • TPV IQ of 30 or more produces large (>1 log10) early (4 weeks) VL reductions, but these are sometimes not sustained because of lack of background regimens
  • This TPV IQ, when used with another active drug (T-20), is able to achieve VL below the limit of detection (BLD, <400 copies/mL) in the majority of these hard-to-treat patients at week 24
  • A third of these hard-to-treat patients with TPV IQs >60 achieve a VL below 50 copies/mL at week 24
  • The TPV concentrations achieved in most patients are not associated with increased levels of hepatotoxicity
  • TDM does not appear necessary when the TPV/r dose of 500mg/200mg BID is used among highly treatment experienced patients


Christine Katlama presented the efficacy data on the Power 1 study, 24 week primary analysis, a randomised 4 dose arm versus best option PI, with all arms receiving optimised background therapy. [16]

Two hundred and twenty-five patients were dosed with TMC114/r and 63 were randomised to the control arm. All had a median of three primary PI mutations and eight PI resistance mutations (mainly L90M V82A, M46I/L and L33F/I).

Approximately 44% of patients received T20 in the optimised backbone. Results showed the 600mg plus 100mg ritonavir to be the best dose with a median reduction in viral load of -2.03 logs and a CD4 rise of +124 cells/mm3 at 24 weeks.

There no adverse events seen more commonly in the TMC114/r arms and liver and lipid events were reported in <10% of patients. Sub-group analysis suggested that the concurrent use of enfuvirtide (T20) was beneficial as was having <3 primary mutations to PIs.

In a further late-breaker poster the safety data for this study was presented and essentially showed that there was no difference in adverse events between the arms compared to control. [17]

The rates of nausea, diarrhoea and headache however were reduced in the TMC arms. This is a difficult population to assess for safety and the studies in earlier stage patients will likely reveal the true toxicity rates of the agent at the chosen dose of 600mg BID. Ongoing studies will address the pharmacokinetics and utility of combining TMC114/r with TMC125, a combination which may prove highly beneficial to patients with late stage HIV disease.

Meltrex formulation of Kaletra

The new tablet version of Kaletra called Meltrex (melt-extrusion) which reduces the pill burden from 6 to 4 pills daily, does not require refrigeration), and hopefully the gastro-intestinal side effects, had an oral presentation from George Hanna, Abbott Laboratories. [18]

In 141 healthy volunteers in 3 studies the drug was evaluated in various food states and with single and multiple doses. The tablet formulation met bioequivalence criteria compared to the soft gel capsule (Kaletra) and there was less food effect than with the old formulation.

Undoubtedly this agent will be now the gold standard against which other PIs will be compared and this means that several of the ongoing studies comparing the new saquinavir 500mg tablet formulation (Gemini study) and the naive study compared to atazanavir (in development) must consider their comparator formulation carefully if they are to get the best information from the studies.


PA-457 is the first molecule of a new and exciting class of compounds, called maturation inhibitors, which interfere with the creation of new virions prior to them budding from the surface of the infected cell. It prevents the conversion of the HIV-1 capsid precursor, CA-SP1 (p25) to mature capsid proteins (p24) resulting in defective core condensation and release of non-infectious viral particles. Further PK modelling was presented from the double blind, placebo controlled single dose study, which evaluated doses of 75mg, 150mg and 250mg and placebo in 4 groups of 6 patients who were antiretroviral naive or off-therapy for at least four weeks, (first presented at CROI in Boston, 2005. Abstract 159). [19] The half-life was 60.3 hours with linear pharmacokinetics suggesting a possibility of a less than daily dosing schedule.

This article has been edited from a report posted to the website that will also appear in the next edition of the Journal of Viral Entry.


All references are to the Abstracts from the 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janiero, July 2005.

  1. McHale M, Abel S, van der Ryst E et al. Overview of phase 1 and 2a safety and efficacy data of maraviroc (UK-427,857). Abstract TuOa204.
  2. Schuermann D, Pechardscheck C, Rouzier R et al. SCH 417690: antiviral activity of a potent new CCR5 receptor antagonist. Abstract TuOa205.
  3. Demarest J, Bonny T, Vavro C et al. 873140 exhibits potent antiviral activity against a broad panel of HIV-1 envelopes from treatment naive and experienced subjects. Abstract TuPe6.1B13.
  4. Murga J, Olson W, Pevear D et al. Antiviral synergy between the CCR5 mAb PRO 140 and small-molecule CCR5 antagonists. Abstract TuOa0206.
  5. Olson W, Doshan H, Zhan C et al. First-in-humans trial of PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Abstract WePe6.2C04.
  6. Jiang S, Lu H, Liu S et al. Small molecule HIV entry inhibitors targeting gp41. Abstract TuOa0201.
  7. Choen C et al. WeOaLB0103.
  8. Hoetelmans R, Kestens D, Marien K et al. Effect of food and multiple dose pharmacokinetics of TMC278 as an oral tablet formulation. Abstract TuPe3.1B10.
  9. Hoetelmans R, Kestens D, Stevens M et al. Pharmacokinetic interaction between the novel non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate (TDF) in healthy volunteers. Abstract WePe3.3C15.
  10. Scholler M, Hoetelmans R, Beets G et al. Substantial improvement of oral bioavailability of TMC125 using new tablet formulations in healthy volunteers. Abstract TuPe3.1B11.
  11. Harman S, Perumal D, Fletcher P et al. TMC120 blocks HIV-1 infection in cellular and human cervical tissue models. Abstract MoPp0105.
  12. Carballo-Dieguez A, Mayer K, Dolezal C et al. Rectal microbicide acceptability: results of a volume escalation trial. Abstract MoPp0206.
  13. Coulombe R, Fink D, Landry S et al. Crystallographic study with BILR 355 BS, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a broad anti HIV-1 profile. Abstract WePp0105.
  14. Becker S, Lalezari J, Walworth al. Antiviral activity and safety of GW695634, a novel next generation NNRTI, in NNRTI-Resistant HIV-1 infected patients. Abstract WePe6.2C03.
  15. Valdez H, McCallister S, Kohlbrenner V et al. Tipranavir/ritonavir (TPV/r) 500 mg/200 mg BID drives week 24 viral load (VL) below 400 copies/mL when combined with a second active drug (T-20) in protease inhibitor experienced HIV+ patients. Abstract WeOa0205.
  16. Katlama C et al. TMC114/r
  17. TMC114 late breaker. WePeLB6.2C01.
  18. Awni W, Chiu Y-L, Zhu T et al. Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation. Abstract WeOa0206.
  19. Ogundele A, Smith P, Forrest A et al. Pharmacokinetic/Pharmacodynamic effects of a novel maturation inhibitor (PA-457) in HIV-infected patients following a single oral dose. Abstract TuPe3.1B01.

Links to other websites are current at date of posting but not maintained.