NATAP REPORT ON NEW HIV DRUGS & ENTRY INHIBITORS
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)
TMC125
PA-457: maturation inhibitor

NEW HIV DRUG CLASS: ENTRY INHIBITORS (CCR5, Attachment), How Do They Work-

NEW ERA OF HIV TREATMENT:
We are entering a new era of HIV treatment not unlike in 1995 when protease inhibitors were launched. Two years ago Fuzeon was the first entry inhibitor, a fusion inhibitor, to become available for treatment. Four orally administrated new entry inhibitors, CCR5 & attachment inhibitors, are now in studies in patients at various stages of clinical development. The furthest along in development is Pfizer's UK-427,857, which is entering large Phase III studies at the end of 2004. Hopefully these new drugs will be proven safe & effective. If so, a new era of therapy for HIV will be born. We will have to elucidate through studies & clinical use how to use each of these new drugs. Some key questions are: how will we use entry inhibitors within the context of currently available classes of drugs (NRTIs, NNRTIs, PIs); can we combine entry inhibitors; can we compose a regimen entirely of entry inhibitors; will safety & tolerability issues emerge.


THIS REPORT REVIEWS BELOW THE CURRENT STATUS OF 5 NEW ENTRY INHIBITOR DRUGS IN ACTIVE DEVELOPMENT & A DESCRIPTION OF HOW THIS BRAND NEW CLASS OF DRUGS WORK.

VIRUS ENTRY: ATTACHMENT, THEN FUSION

The events of virus entry into cells occur in several steps: the first step in the HIV-cell interaction that leads to virus entry is "attachment", followed by "fusion" that is necessary for entry into the cell: The virus' gp120 surface molecule fits into the CD4 receptor on the cell surface like a key in a lock and the virus becomes attached-but is left hanging loosely from the cell surface by this gp120-CD4 connection.

Once it is attached, gp120 is bound to another receptor (either one of the "co-receptors" for gp120, called CCR5 or CXCR4). Thus doubly bound, the gp120 molecule flips around to expose HIV's previously hidden "harpoon" molecule, gp41.

Once the free end of gp41 spears the cell membrane, solidifying HIV's attachment, gp41 doubles itself up into a tight coiled-coil structure. This brings the two ends of gp41 (one holding HIV, and one holding the cell membrane) very close together. The cell membrane and virus envelope come into contact and fuse. Fusion results in the virus' contents getting dumped into the interior of the cell. Virus 1, Cell 0.

A ROLE FOR EXTRACELLULAR AGENTS: ATTACHMENT AND ENTRY INHIBITORS

In the quest for agents that might have improved activity compared with older drugs, investigators have wondered if equally potent drugs targeting the parts of the virus life cycle that occur outside the cell might be better than drugs targeting events that take place inside infected cells. Why? Anti-HIV drugs that must be inside the cell to be active can be efficiently neutralized by some cells, using primitive, innate self-defense mechanisms such as "efflux pumps" which sense toxins and eject them outside of the cell. Many experts believe that this kind of "cellular resistance" could be an important reason for the viral persistence and evolution in patients on seemingly potent combination therapies. "Extracellular ART" would completely circumvent this problem. More immediately, any drug working on a separate part of the virus' life cycle would have little potential for "cross-resistance" with NRTI, NNRTI or PIs.

CURRENT THERAPY
The current range of approved HIV medications includes drugs that inhibit various steps in the virus' life cycle. Most classes of these drugs act inside HIV infected cells: many agents interfere in one way or another with reverse transcriptase (RT)-a viral enzyme which the virus uses to replicate itself within the cell. ("Nucleoside or nucleotide" and "non-nucleoside" RT inhibitors--NRTI and NNRTIs--are chemically very distinct and can work together with powerful synergy against this one target.) Other existing drugs interfere with the activity of HIV protease-which the virus uses to package itself for export out of an infected cell, to begin new rounds of destruction. The third major drug target that has been successfully exploited is HIV gp41-a molecule on the virus' surface that has to change its shape in a specific way in order for the virus to "fuse" with the cell it is attacking and empty its payload inside. By directly binding to gp41, the injectable peptides enfuvirtide (Fuzeon, formerly T-20). At the Bangkok Intl AIDS Conference in July 2004, researchers reported 3-year followup of Fuzeon phase III studies showing the drug to be durably potent for the 3 years.


NEW ENTRY INHIBITOR DRUGS MOVING QUICKLY IN HUMAN STUDIES
Reported by Jules Levin

There are several entry inhibitors moving along in clinical development-- in studies in HIV+ individuals. Pfizer's CCR5 antagonist 'inhibitor' UK-427,857 enters phase III studies soon & has shown antiviral effectiveness by significantly reducing HIV viral load in studies so far conducted. In a 10-day monotherapy study UK-427,857 was administered to patients at doses up to 300 mg bid & appeared safe & tolerable and reduced viral load by 1.3-1.6 log.

Bristol-Myers Squibb has a program of a stable of 'attachment' inhibitor candidates. They are developing an attachment inhibitor '690', which is a novel, oral small-molecule attachment inhibitor of HIV-1 that blocks viral entry by preventing the binding of the viral envelope protein gp120 to cellular CD4 receptors. At the recent 2004 Retrovirus Conference, BMS researchers presented data on one of the candidates '034'. In an 8-day phase II monotherapy study of daily dosing of 800-1800 mg every 12 hours, HIV viral load was significantly reduced by 1-2 logs and the drug appeared safe & tolerable. BMS is refining this drug candidate for 'swift' development. Schering-Plough is developing it's 2nd generation CCR5 inhibitor, SCH-D. At the Retrovirus Conference, reported results from a 14-day monotherapy study in which patients received 10, 25 & 50 mg twice daily, and HIV viral load reductions were 1 to 1.6 log, and the drug appeared safe & tolerable. This drug is in further development, phase II studies are ongoing.

GlaxoSmithKline is also developing a new drug from this new class of HIV antivirals. GW873140 is a novel CCR5 receptor antagonist that binds specifically to human CCR5 and has demonstrated potent in vitro anti-HIV activity. At the 2004 Retrovirus Conference GSK researchers reported results from an early study looking at single & multiple doses to investigate safety, tolerability & drug levels (pharmacokinetics) in healthy volunteers. During single dose escalation, 3 groups of 10 subjects each (8 active / 2 placebo) received doses of 50, 200, 400, 800, 1200 mg, or 400 mg. During multiple dose escalation, 4 groups of subjects (8 active / 2 placebo) received doses of 200, 400, 600, or 800 mg as a single dose on day 1 and then twice daily for 7 days. The study investigators said the drug was safe & tolerable. Based on drug levels 'PK' in the study researchers said they would investigate once or twice daily dosing. GSK is developing this drug & results from ongoing studies will be presented soon.

Tanox is a small company that is developing TNX-355, an anti-CD4 domain 2 monoclonal antibody. TNX-355 is an attachment inhibitor that targets host CD4 cell receptors. It has showed potent anti-HIV-1 activity in vitro and in a phase 1a single-dose study in HAART-experienced subjects. Unfortunately this drug is administered by IV infusion once weekly and once every 2 weeks, which makes this drug less attractive but it may provide a useful treatment option. The company hopes to explore the potential for once monthly administration, but don't count on it.. Because the drug is a monoclonal antibody no toxicities and minimal side effects are expected. But the manufacturing process and ultimate cost of the drug is an unknown.

At CROI 2004 researchers said “Clearly, this drug is aimed for patients willing to receive intravenous administration once weekly or perhaps every two weeks and most likely for patients with extensive HIV drug resistance. Administration can be conducted in doctor's office or at infusion centers or by home attendants. If the drug completes development & is FDA approved it could be administered in the home by a visiting nurse weekly or every other week”.

Phase II study results were reported where patients received varying doses once or twice weekly for 9 weeks. Virtually all patients 21/22 had at least 0.5 log reduction in viral load. Many of patients had at least 1.0 log reduction. The study consisted of 21 treatment-experienced patients. There were several adverse events reported in this study report at Retrovirus, but company officials say they were not related to the study drug: serious adverse events (3)-- were recurrence of known depression (2) in same person with history of depression; suicidal ideation after 4th dose; 2nd episode after dose 8; new-onset grand mal seizure after vaso-vagal reaction during phlebotomy; transient acute renal failure with known renal insufficiency requiring dialysis: developed 38 days after final dose in subject with renal insufficiency with proteinuria and chronic hyponatremia; renal function returned to baseline after hydration and discontinuation of NSAID; there was 1 injection site reaction: infusion is into subcutaneous tissue. But company officials say these adverse events were not drug related.


New HIV Antiretroviral Drugs in Early Development: reported at 2004 Retrovirus Conference (CROI)


NEW DRUGS DISCUSSED BELOW
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)

TMC125
PA-457: maturation inhibitor

It appears that a lot of new drugs are in the pipeline but not much new around the corner. There appears to be much early exciting data 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.


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. 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. This has a better in vitro potency than SCH-C and improved bioavailability. A study evaluating SCH-D in subjects with CD4 >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 >1-log decline was 55%, 69%, and 81%, and for >1.5 log 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. 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 CD4 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 median CD4 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. CD4 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 >1-log decline 58% versus 67% and for >1.5-log 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.

TMC-125: new protease inhibitor; early studies show effectiveness for patients with PI resistance

Both TMC drugs have been moving along slowly, but are in phase II now in patients. This is a new next generation NNRTI in early stages of development and from Tibotec-Virco and Johnson & Johnson, and has shown in early studies to have antiviral activity against HIV with or without NNRTI resistance. This drug is expected to be effective for patients with drug resistance to the currently available NNRTIs, nevirapine (Viramune) and efavirenz (Sustiva). Currently, phase II dose finding studies are in progress and large phase III studies are planned for 2005. Patients with extensive resistance are being recruited for ongoing studies. For information on study sites for TMC125 & TMC114, go to www.clinicaltrials.gov and enter either TMC114 or TMC125 for the query. A list of all sites can be found with contact information.

Test tube studies show that when the K103N mutation was present alone, this is the signature mutation for efavirenz, there was little or no resistance to TMC125. Viruses with the double mutant K103N + Y181C, developed resistance to TMC125 comparable to that seen with currently available NNRTIs.
At CROI there was a poster on resistance. 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. Results from studies in patients will reveal the drug's antiviral effectiveness.

A small study in HIV-infected patients with NNRTI-resistance (efavirenz, nevirapine, delavirdine) has been conducted. Tibotec-Virco investigators reported that mutations found in the 16 study patients were K103N, Y181C, Y188L, G109A/S, L100I (all NNRTTI mutations) and combinations of these; so the patients had double NNRTI mutation combinations. This was an early open-label phase IIA study in 16 HIV-infected men who were failing NNRTI therapy and had efavirenz resistance. 80% of patients were taking nevirapine and 20% efavirenz. The patients received 900 mg TMC125 twice daily instead of the failing NNRTI but continued to take the same NRTIs for 7 days. After 7 days patients changed their NRTIs. Average patient CD4 count before switching to TMC125 was 389, viral load 10,000 copies. Before starting TMC125 the average resistance to efavirenz (change in IC50) was 111-fold while resistance to TMC125 ranged between 0.5 to 8 fold.

On day 8 the average viral load reduction was -0.86 log (range: -1.95 to +0.09). The response may be muted because patients were ART experienced and had drug resistance. In addition they did not change underlying drugs for which they probably had some resistance. 12 patients (75%) had a decrease in viral load of at least 0.5 log and 44% (7) of patients had a decrease of at least 1 log. Investigators reported 11 patients reported adverse events and TMC125 was well tolerated and safe in this early study. The most commonly reported side effects were diarrhea (5) and headache (4) and were reported to be mild in severity. This study is small and preliminary, so further studies are needed to characterize the effectiveness and side effect profile of this drug in patients with NNRTI resistance.

TMC-114, new protease inhibitor for PI-resistant HIV

At CROI, researchers presented results from a study in patients and TMC114 showed impressive short term virologic response in patients on failing PI regimens who had their PI switch to one of 3 different doses of TMC114, boosted with RTV (300mg/100mg BID, 600mg/100mg BID or 900mg/100mg q day) compared to a control group who remained on their failing PI. In this randomized phase 2a controlled study, 38 patients were enrolled and viral load response was monitored over 14 days. At day 14, viral load declines averaged 1.2 to 1.5 logs in the 3 TMC114 groups with maximal declines of up to 2.5 log seen. The reduction in viral load was unaffected by phenotypic resistance to all licensed PI's or baseline viral load. No tolerability data was presented. We look forward to the further development of this drug, particularly in patients with PI-resistance.

A further poster presentation on TMC114 examined the resistance profiling of the drug against 1600 PI clinical resistance isolates. 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.


Reverset: new nuke in early study for nuke resistant HIV reduced viral load by 1-1.7 log

Reverset is a novel nucleoside (NRTI, nuke) analogue (D-D4FC) with in vitro activity against HIV-1 strains that are resistant to AZT, 3TC, TDF and others. However, the multi-nucleoside resistance patterns (69insert and Q151M complex) appear in vitro to cause resistance to reverset. 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. In vitro there is no mitochondrial toxicity noted and the compound has a long intracellular half life. Rob Murphy reported a phase I, monotherapy study in antiviral naïve subjects.

Rob Murphy reported favorable data at CROI from a dose ranging study in which 30 subjects were randomized equally to one of three doses of RVT (50mg, 100mg or 200mg) versus placebo. Subjects were dosed for 10 days with 4 weeks of follow up, they 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 a blinded manner and viral loads declined in all treatment groups, with average declines of 1.2 to 1.7 logs by day 10. The plasma half life was measured at 5.2 hours and no nRTI-associated resistance emerged during the course of the study. 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. 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.  We anticipate clinical trials in patients with various patterns of nRTI-associated resistance.

HIV Maturation Inhibitor PA-457: new oral drug, early study results presented at Bangkok IAC

PA-457 is the first in a new class of antiretrovirals called Maturation Inhibitors directed against a novel viral target recently discovered by Panacos scientists. Because PA-457 has a different target than approved HIV drugs, it retains activity against virus isolates resistant to currently available treatments including reverse transcriptase inhibitors and protease inhibitors.

The company summarized the results from the Bangkok studies and their conclusions about the future use of this drug. . The safety and pharmacokinetics of PA-457 were examined in uninfected, healthy male volunteers following a single oral dose of 25 mg, 50 mg, 100 mg or 250 mg in a dose escalation protocol. At each dose level, six subjects received PA- 457 and two additional individuals received placebo. PA-457 was well tolerated at all doses, with good oral bioavailability and favorable pharmacokinetics. All doses produced mean circulating plasma levels which exceeded the target therapeutic concentration, and at doses of 50 mg or greater PA-457 levels continued to exceed the target concentration 24 hours after administration. These results suggest that PA-457 will be suitable for once daily oral dosing.

Based on the promising results of the first clinical study, Panacos has now advanced PA-457 into a multiple dose Phase 1 study to examine the safety and pharmacokinetics of the compound administered once daily to uninfected, healthy volunteers for 10 days. We anticipate moving PA- 457 into Phase 2 testing in HIV-infected patients later this year." In the same presentation, Dr. Martin summarizes results of pre-clinical studies that suggest PA-457 is unlikely to exhibit drug-drug interactions when used in combination therapy with approved HIV drugs.

In cell culture studies, PA-457 shows activity against drug-resistant HIV strains that is comparable to that against wild type virus, strongly supporting the compound's potential value for treating strains of the virus that are resistant to approved drugs. Dr. Allaway also describes the results of a collaborative study with scientists from the Gladstone Institute (San Francisco, CA), demonstrating that PA-457 is a potent inhibitor of HIV replication following oral administration in the SCID-hu mouse model of HIV infection. In this study, PA-457 exhibited similar potency to the approved HIV drug EPIVIR(R) (lamivudine or 3TC).

SPD754: new NRTI in early development stages

New study data was presented at CROI on SPD754, a new NRTI in very early stages of development from Shire Pharmaceuticals. This drug appears to have no laboratory induced mitochondrial toxicity. 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. It was pointed out, however, that since SPD754 is targeted at viruses which 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. 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.

GW695634: NEW NNRTI for resistance in early development

At Bangok IAC, GlaxoSmithKline researchers reported early data on a new NNRTI GW695634, which is a prodrug of the active compound GW678248, a new NNRTI in development for treating HIV. GW678248 is active in vitro, in the test tube, (IC50≤2 nM) against NRTI-resistant mutants and NNRTI-resistant mutants (IC50≤7 nM). In a panel of patient isolates (blood samples) from NNRTI-experienced patients that showed efavirenz and/or nevirapine resistance, >80% of the viruses were susceptible to GW678248 with ≤10 fold change in IC50 value. The drug has the potential to be an effective therapeutic option for treatment-experienced patients.

Data was presented from an early study designed to establish initial safety, tolerability and pharmacokinetics of GW695634 and GW678248 in healthy subjects; also to study the effect of food on the relative bioavailability of 695634 and 678248, and to support the dose selection for future clinical studies. The study enrolled healthy male subjects in a double-blind, randomized, parallel, placebo-controlled, single-ascending dose study of 695634. Study doses were 10mg, 25mg, 75mg, 200mg, 400mg, 600mg, and 800mg. At each dose level, 10 subjects were enrolled with 8 receiving GW695634 and 2 receiving placebo. To study the effect of food on the relative bioavailability of 695634 and 678248, the 200mg dose was given on a second occasion with a standard high fat meal.

Study authors reported that GW695634 was generally well tolerated. No serious adverse events, deaths, or withdrawals due to AEs occurred during the study. The most commonly reported AEs were rash (14 subjects; 18%), headache (10 subjects; 13%), erythema (8 subjects; 11%), skin irritation (5 subjects; 7%), skin laceration (4 subjects; 5%), pharyngolaryngeal pain (4 subjects; 5%), and increased serum ALT values (4 subjects; 5%). Authors reported that the subjects who experienced rash (14 subjects), erythema (8 subjects), and skin irritation (5 subjects) had these due to ECG electrode site irritation and not due to the drug in the opinion of the investigator.

All AEs were reported mild to moderate in intensity; no severe AEs were reported; no notable trends in AEs were observed with increasing doses of 695634. No notable trends in laboratory values were observed.

Changes from placebo in QTc were generally small (-4.436 to +2.161 msec) for the overall population. There were no QTc, QTcF, QTcB, or QTcl abnormalities of >60 msec duration, missed heart beats.

Authors concluded 695634 can be administered with or without food. A study to further evaluate the clinical efficacy of 695634 for use in the treatment of HIV-infected patients has been initiated in NNRTI-experienced patients.