Studies of new pipeline drugs

Mike Youle,

The Retroviruses Conference this year appeared to have a greater than usual emphasis on basic science and the clinicians were left feeling that a lot was in the pipeline but not much new around the corner.

This was certainly true of new antiretroviral agents where exciting data were shown on a range of novel agents especially targeting the various steps required for attachment of HIV to the cell, a potentially very attractive proposition since the likelihood of toxicity from these compounds is low.

Compounds covered in this report include:

  • Reverset (NRTI)
  • SPD-754 (NRTI)
  • GW678248 and GW695634 (NNRTIs)
  • TMC 114 (PI) and TMC 125 (NNRTI)
  • GW873140 (CCR5 receptor antagonist)
  • SCH-D (CCR5 receptor antagonist)
  • BMS-488043 (attachment inhibitor)

The main session on new drugs on Wednesday morning was opened by Dr Rob Murphy, from Northwest University in Chicago, who showed a study of Reverset, a novel nucleoside analogue (D-D4FC) with potent in vitro activity against many resistant strains of HIV, although it appears the drug is unlikely to act against the Q151M or 69 insertion mutants [1].

It has been difficult to select for resistance in vitro although after more than 20 passages several viruses with <15-fold resistance have been produced which include K65R and K70N along with 4-5 other RT mutations. Favourable single dose data was presented at the Paris IAS meeting last June and in this study, conducted at the Charité-University Hospital in Berlin, 30 subjects in three cohorts of eight treated and two placebo patients were given 50mg 100mg or 200mg of drug for 10 days. Subjects had >50 CD4 cells/mm3 (median 468 cells/mm3), >5,000 copies/mL HIV RNA (median 4.29 log10 copies/mL) and included six women. Study drug was given in blinded manner and after 10 days of dosing day 11 viral load was reduced by 1.32, 1.54 and 1.77 log10 copies/mL in each dose group respectively. With increasing dose the Cmax also rose from 2.3 to 5.4 to 9.8 ng/mL and the AUC increased from 11.9 to 31.7 to 74.6ng/mL.

Despite this, no serious adverse events were reported and there appeared to be no differences between drug and placebo in terms of minor adverse events, most of which consisted of flu-like symptoms, common at the time of the year the study was undertaken. During the treatment phase CD4 cell levels rose, but these declined after cessation of therapy and HIV RNA returned to baseline. No genotypic changes occurred during the study and specifically no new mutations appeared.

Further studies are now underway to evaluate the effects of this novel nucleoside analogue in 180 treatment experienced individuals. Questions to the speaker included whether the drug passed the blood brain barrier, for which no data exist, and whether in vitro mitochondrial toxicity has been seen of which none has been reported. Pigmentation of the nose, which appears in female dogs, has not yet been reported in human studies. Murphy said no mitochondrial toxicity has been observed yet, but no data to support this were shown and this remains to be seen.

A second nucleoside analogue, the deoxycytidine analogue SPD754 from Shire Pharmaceuticals, was presented next [2].

This drug also appears to have no laboratory induced mitochondrial toxicity and is additive or synergistic with most available nucleoside agents. The aim of this study was to evaluate the interaction due to phosphorylation between SPD754 600mg BID and lamivudine (3TC) 150 mg BID. In a study of 21 HIV-negative volunteers who were given each drug separately or in combination in a three-way study of four days treatment with seven days washout, no effects were seen on plasma concentrations. However, when the intracellular drug levels were examined there was six-fold reduction in SPD754 levels by the co-administration of 3TC, which did not occur, in the opposite direction. These data suggest that it is imperative to evaluate tri-phosphate concentrations of agents to assess drug-drug interactions prior to commencing clinical efficacy studies if the active moiety could potentially be affected by co-administration. The speaker pointed out, however, that since SPD754 is targeted at viruses that are already resistant to 3TC, this particular interaction should not, per se, affect the development of the compound.

A study of SPD75, at dose from 400mg to 1600mg daily, in 63 patients, some of whom had baseline thymidine analogue mutations, showed no evolution of new resistance mutation after 10 days monotherapy and substantial viral load reductions [3]. In addition, a 52 week safety study in cynomolgus monkeys demonstrated no significant toxicity, although some hyperpigmentation developed as well as mild gastrointestinal side effects [4]. This was in contrast to the racemate of the drug, BCH-10652, which was associated with significant degenerative skin disease.

Several other new compounds were presented as in vitro studies suggesting that the hunt for new drugs that target the reverse transcriptase enzyme has not yet reached saturation.

GlaxoSmithKline showed their new non-nucleoside agents, GW678248 and GW695634, both of which seemed to work well against panels of NNRTI resistant strains of virus [5]. In addition, the compounds were examined for evidence that they could reduce the primer unblocking reaction that has been proposed to contribute to AZT resistance and using a filter paper binding assay these agents seemed to reduce it significantly.

Boehringer Ingelheim (Canada) also presented new versions of nevirapine with quinolone moieties, which appeared to abrogate the effect of some of the mutations known to affect the efficacy of the parent compound [6]. No clinical data are yet available.

The team from Tibotec and Janssen Pharmaceuticals produced yet more potential agents with a study of diarylpyrimidines and diaryltriazines, which appeared more potent than available NNRTIs, and to have favourable pharmacokinetics [7]. Sadly Paul Janssen the doyen of Janssen Pharmaceuticals died recently and one hopes that his work will continue unabated since he was a great champion of HIV within the pharmaceutical industry and a formidable chemist, as well as a fascinating raconteur.

A clinical study of the new protease inhibitor TMC114 boosted with ritonavir was presented: TMC114-C207 [8].

This was a randomised three-arm study of 300mg, 600mg or 900mg twice daily with 100mg ritonavir as a pharmacokinetic booster in subjects failing on a PI-containing regimen. Thirty-five subjects were randomised to receive active drug or placebo and the median viral load decline was -1.2, -1.3 and -1.5log10 copies/mL in the three groups respectively although there was no statistical difference across the arms. The reduction in viral load was unaffected by phenotypic resistance to all licensed PI’s or baseline viral load. This drug seems promising although no tolerability data were presented. A further poster presentation on TMC114 examined the resistance profiling of the drug against 1600 PI clinical resistance isolates [9].

The isolates were grouped as >4-fold resistant to 1, 2, 4, 5, 6 or 7 currently available PIs and TMC114 performed well in vitro against all of these isolates, demonstrating at most a <4-fold change to isolates resistant to all seven drugs or with three major PI mutations. A similar study also examined the activity of TMC125, the Tibotec NNRTI that is now in Phase III studies. Four single mutants, one double and one triple mutant showed reduced susceptibility to TMC125 although these mutants were at low levels in the population. Mutations at positions 101, 179, 181 and possibly 227 and 230 may play a role in decreased susceptibility to the drug and the triple mutation K103N, L100I with either Y181C or T386A appears to produce >10-fold resistance to TMC125.

Moving from inside the cell to the surface, Steve Piscatelli from GlaxoSmithKline presented exciting data on GW873140, a CCR5 receptor antagonist which joins SCH-D from Schering and UK427,857 from Pfizer in the race to see who can first bring one of these receptor blocking agents to the clinic [10]. This drug has an IC50 of 1-5nM and a unique binding profile to the CCR5 receptor. A double blind randomised placebo controlled study was conducted in 70 fasted subjects (57 men and 13 women). Subjects received single doses of 50, 200, 400, 800 or 1200mg fasted or 400mg with a standard breakfast in cohorts of 10 subjects (eight treated and two placebos). Thereafter a multiple dose phase was conducted with a seven-day dosing of 200, 400, 600 and 800mg twice daily. Initial data suggested the drug was well tolerated with some mild to moderate side effects of abdominal cramping, diarrhoea and nausea. No changes occurred in ECG measures, specifically not QT prolongation, which has been a potential side effect (in other drug development programmes) and no serious or grade three or four adverse events were seen. The AUC increased from 130 to 479 ng/ml from the 200 to 800mg dose level and food increased the AUC by 1.7-fold and the Cmax by 2.2-fold. In the single dose arms the viral load had returned to baseline in 50% of the subjects by 24 hours with 66-84% occupancy of the receptor whereas in the multiple dose arms occupancy at two and 12 hours post dose was 93-99%. This agent unfortunately appears to have minimal CNS penetration, but looks set to advance through the development process apace with such favourable safety and viral load decline data. As with the other CCR5 inhibitors under evaluation, the question of whether the drug can be given once daily needs clarification in further clinical trials.

Mark Laughlin from Schering-Plough then showed their latest information on the second CCR5 receptor antagonist inhibitor the company has developed, SCH-D [11].

This has a better in vitro potency than SCH-C and improved bioavailability. A study evaluating SCH-D in subjects with CD4 >250 cells/mm3 and HIV RNA 5,000-200,000 copies/mL evaluated three dosage levels (10mg, 25mg and 50mg BID) in cohorts of 16 subjects (14 treated and two placebo). The viral load decline at 14 days was 1.0, 1.2 and 1.5 log10 copies/mL respectively for the three doses. One subject who was of mixed CCR5 and X4-virus showed a 0.5 log10 copies/mL drop in viral load with no change in susceptibility over the treatment phase. A further individual with >1.5 log10 copies/mL showed a transient detection of X4 virus following cessation of the drug. The percentage rates at each dose level (20, 50, 100mg/day) for >1log decline was 55%, 69%, and 81%, and for >1.5log decrease in HIV RNA 27%, 46% and 45% respectively. To date, 275 individuals have received this agent and no significant toxicity has been seen. There appears to be a good correlation between in vitro activity and in vivo efficacy, which will allow correlation of potency to be evaluated. It would appear also that this drug is extremely difficult to select resistant viruses for, which bodes well for the durability of efficacy. However, this will only be clear when prolonged dosing has been undertaken.

The earliest step in the entry of the virus into the host cell is the attachment of gp120 on the virus coat to the CD4 receptor on the cell surface.

Bristol Myers Squibb have a stable of potential agents that they are developing to block this interaction. Last year they showed data on BMS-378806, a forerunner for the new molecule BMS-488043 they presented at this conference [12].

Both of these are small molecules that have activity against viruses using all co-receptors, and in vitro and in animal studies appear non-toxic with no cross-resistance to currently available agents. The EC50 for the new compound is 36.5 compared to 61.5 for BMS-378806 and it has a superior half-life.

The latest study, AI430-003, is a proof of concept trial involving subjects not receiving antiretroviral therapy and with a T4 count >250 and a viral load between five and 500,000 copies/mL. Subjects were randomised 4:1 to receive active drug or placebo and two cohorts of 15 subjects were given 800mg or 1800mg twice daily with a high fat meal. There were two women in the lower dose cohort and one in the 3600mg cohort. Baseline median viral load was 4.77 and 4.65 log10 copies/mL and medianT4 count 413 and 372 respectively. Viral load decline at day eight was 0.72 and 0.96 log10 copies/mL for the two dosage groups and maximal median decline was 1.01 and 1.23 log10 copies/mL. T4 cell rises were seen of 106 cells (range -214 to +272) for the 1600mg arm and 48 cells (range -177 to +191) for the 3600mg arm. The percentage rates at the two dose levels was for >1log decline 58 versus 67% and for >1.5log decrease 24 compared to 42%. No serious adverse events or discontinuations occurred and apart form mild fatigue in four subjects and headache in two, no side effects were reported. The optimisation of exposure-response relationship is ongoing for this drug and it appears a very promising new agent.

Overall, there is a rosy picture emerging of antiretroviral opportunities for the next couple of years with the drugs acting outside the cell holding promise for effective non-toxic drugs that could dramatically alter the way HIV is treated.



  1. Murphy RL, Schürmann D, Beard A et al. Tolerance and potent anti-HIV-1 activity of Reverset following 10 days of mono-therapy in treatment-naïve individuals. 11th CROI 2004, Abstract 137.
  2. Bethell R, Adams J, De Muys J et al. Pharmacological evaluation of a dual deoxycytidine analogue combination: 3TC and SPD754. 11th CROI 2004, Abstract 138.
  3. Collins P, Shiveley L, Anderson C et al. Analysis of the genotypes of viruses isolated from patients after 10 days monotherapy with SPD754. 11th CROI 2004, Abstract 526.
  4. Locas C, Ching S, and Damment S et al. Safety profile of SPD754 in cynomolgus monkeys treated for 52 weeks. 11th CROI 2004, Abstract 527.
  5. Roberts G, Porter D, Boone L et al. Kinetic and thermodynamic parameters for binding of the non-nucleoside inhibitors GW678248 and GW695634 to wild type and 12 mutants of HIV-1 reverse transcriptase. 11th CROI 2004, Abstract 529.
  6. Bonneau PR, Doyon L, Duan J et al. Characterisation of a novel series of nevirapine-like next-generation NNRTI with broad antiviral potency against NNRTI-resistant HIV. 11th CROI 2004, Abs 530.
  7. Van Herrewege Y, Michiels J, Kara Z et al. Diarylpyrimidines and diaryltriazines constitute a new class of highly active non-nucleoside reverse transcriptase inhibitors. 11th CROI 2004, Abstract 528.
  8. Peeters M, Van Baelen B, De Meyer S et al. TMC114/RTV activity in multiple PI-experienced patients: correlation of baseline genotype, phenotype, pharmacokinetics, and IQ with antiviral activity at day 14. 11th CROI 2004, Abstract 533.
  9. De Meyer S, Van Marck H, Van Den Bulcke T et al. Phenotypic and genotypic profiling of TMC114, a potent next-generation PI, against some 1600 recent PI-resistant clinical isolates. 11th CROI 2004, Abstract 620.
  10. Demarest J, Adkison K, Sparks S et al. Single and multiple dose escalation study to investigate the safety, pharmacokinetics, and receptor binding of GW873140, a novel CCR5 receptor antagonist, in healthy subjects. 11th CROI 2004, Abstract 139.
  11. Schurmann D, Rouzier R, Nougarede R et al. SCH D: Antiviral activity of a CCR5 receptor antagonist. 11th CROI 2004, Abs 140LB.
  12. Hanna G, Lalezari J, Hellinger J et al. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. 11th CROI 2004, Abs 141.

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