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New antiretroviral agents at 2004 Retrovirus Conference
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Reported for NATAP by Mike Youle, MD
Royal Free Hospital, London, UK
TOPICS
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 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.
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 [Abstract 137]. 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, thirty subjects in 3 cohorts of 8 treated and 2 placebo patients were given 50mg 100mg or 200mg of drug for 10 days. Subjects had >50 T4 cells (median was 468), >5,000 copies/mL HIV RNA (median 4.29 log10 copies/mL) and included 6 women. Study drug was given in blinded manner and after 10 days of dosing day 11 VL 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 T4 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 if the drug passed the blood brain barrier, for which no data exist and what 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. Ed note: Murphy said no mitochondrial toxicity has been observed yet but no data to support this was shown & this remains to be seen.
A second nucleoside analogue, the deoxycytidine analogue SPD754 from Shire Pharmaceuticals was next presented [Abstract 138]. 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. Ina study of 21 healthy volunteers who were given each drug separately or in combination in a 3 way study of 4 days treatment with 7 days washout, no effects were seen on plasma concentrations. However, when the intracellular drug levels were examined there was 6-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. He pointed out, however, that since SPD754 is targeted at viruses which are already resistant to 3TC, and 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 [Abstract 526]. In addition a 52 week safety study in cynomolgus monkeys demonstrated no significant toxicity, although some hyperpigmentation developed as well s mild gastrointestinal side effects [Abstract 527]. 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 which 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 [Abstract 529]. 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 some new versions of nevirapine with quinolone moieties which appeared to abrogate the effect of some of the mutations known affect the efficacy of the parent compound [Abstract 530]. No clinical data is 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 NNRTI’s and also to have favourable pharmacokinetics [Abstract 528]. 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 [Abstract 533]. This was a randomized 3 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 -1.5log10copies/mL in the 3 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 was presented. A further poster presentation on TMC114 examined the resistance profiling of the drug against 1600 PI clinical resistance isolates [Abstract 620]. The isolates were grouped as >4-fold resistant to 1, 2, 4, 5, 6 or 7 currently available PI’s and TMC114 performed well in vitro against all of these isolates demonstrating at most a <4-fold change to isolates resistant to all 7 drug or with 3 major PI mutations. A similar study also examined the activity of TMC125 the Tibotec NNRTI which is now in phase 3 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 Y181C or T386A appears to produce >10 fold resistance to the drug.
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 and UK427,857 from Pfizer in the race to see who can first bring one of these receptor blocking agents to the clinic [Abstract 139]. 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 (8 treated and 2 placebos). Thereafter a multiple dose phase was conducted with a 7 day dosing of 200, 400, 600 and 800mg twice daily. Initial data suggested the drug was well tolerated with some mile 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 programs) and no serious or grade 3 or 4 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 2 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 a pace 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 [Abstract 140]. This has a better in vitro potency than SCH-C and improved bioavailability. A study evaluating SCH-D in subjects with T4 >250 and HIV RNA 5-200,000 copies/mL evaluated 3 dosage levels (10mg, 25mg and 50mg BID) in cohorts of 16 subjects (14 treated and 2 placebo). The viral load decline at 14 days was 1, 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 two hundred and seventy five 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 has a stable of potential agents which they are developing to block this interaction. Last year they showed data on BMS-378806 a fore-runner for the new molecule, BMS-488043 they presented at this conference [Abstract 141]. Both of these are small molecules which have activity against viruses using all co-receptors, and in in vitro and 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 5 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 2 women in the lower dose cohort and 1 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 8 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 4 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.
All in all 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 which could dramatically alter the way HIV is treated.
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