Antiviral Therapy 14:

Antiviral Therapy 14:111 115 Short communication A Phase I study to explore the activity and safety of SCH53276, a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients Sarah L Pett 1,2 *, Michael C McCarthy 3, David A Cooper 1,2, Karen MacRae 1, Amol Tendolkar 3, Richard Norris 1, Julie M Strizki 3, Kenneth M Williams 4,5 and Sean Emery 2 1 HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent s Hospital, Sydney, Australia 2 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, Sydney, Australia 3 Schering Plough Research Institute, Kenilworth, NJ, USA 4 Clinical Trials Centre, St Vincent s Hospital, Sydney, Australia 5 Clinical Pharmacology Department, St Vincent s Hospital and University of New South Wales, Darlinghurst, Sydney, Australia *Corresponding author: E-mail: spett@nchecr.unsw.edu.au Background: SCH53276 is a novel small molecule chemokine receptor-5 (CCR5) antagonist with high in vitro potency (mean 9% inhibitory concentration [IC 9 ].15 7. nm) against diverse HIV type-1 (HIV-1) isolates. Methods: A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 1 days of SCH53276 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients. Results: The study enrolled males with CD4 + T-cell count >1 cells/µl. Median (range) CD4 + T-cell count was 327 cells/µl (117 1,8), HIV-1 RNA was 4.6 log 1 copies/ml (3.8 5.5) and patients had phenotypically confirmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1 RNA at days 1 and 15 (4 days off SCH53276) were -1.31 log 1 copies/ ml (-1.6-1.) and -1.62 log 1 copies/ml (-2. -1.3), respectively. Day 1 median (range) time to maximum plasma concentration, mean (±sd) effective half-life and mean (±sd) trough concentration were 1.4 h (1. 4.), 39.4 h (±14.5) and 178 ng/ml (±34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported 1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug. Conclusions: Overall, SCH53276 with RTV was safe, generally well tolerated and active against HIV-1 over 1 days of dosing. In this setting, SCH53276 trough concentrations exceed the mean in vitro IC 9 (1.1 ng/ml) by >3-fold (after correction for 8% plasma protein binding) and provide a PK rationale for the observed efficacy. Introduction Chemokine receptor-5 (CCR5) and CXCR4 are key coreceptors for HIV type-1 (HIV-1) entry [1]. Clinical studies have confirmed the antiviral activity of the CCR5 antagonists maraviroc [2,3] and vicriviroc [4,5]; the former has gained approval for use in patients with multidrug-resistant R5-tropic HIV-1. Vicriviroc is in Phase III clinical development. SCH53276 is a new small molecule CCR5 antagonist with high potency and bioavailability. In vitro data show that SCH53276 inhibits the replication of 3 different HIV-1 isolates, with a mean 9% inhibitory concentration (IC 9 ) value of 1.1 ng/ml; resistance to SCH53276 is still currently under investigation. A rising single-dose study of SCH53276 (5 2, mg) in healthy volunteers found that the drug was rapidly absorbed with a time to maximum plasma concentration (T max ) of 1 2 h and a halflife (t ½ ) of 8 11 h (unpublished data). A rising multidose (RMD) study in healthy volunteers randomized to 5 days of SCH53276 (1, 15, 6 or 15 mg twice daily) found all doses were well tolerated. Maximum plasma drug concentration (C max ) and area under the plasma concentration time curve (AUC) increased in a greater-than-dose proportional manner on days 1 and 5. In vitro and animal studies indicate that SCH53276 29 International Medical Press 1359-6535 111

SL Pett et al. elimination is via hepatic oxidative metabolism by the cytochrome P45 enzyme CYP3A4 followed by conjugation (chiefly glucuronidation; unpublished data). In vitro inhibition of UGT1A1 by SCH53276 has not been assessed. Therefore, the potential for an interaction of raltegravir, a UGT1A1 substrate, is unknown. These data suggest that ritonavir (RTV) would augment the pharmacokinetic (PK) profile of SCH53276 via CYP3A4 inhibition [6]. This was confirmed in those RMD volunteers on the 6 mg twice daily arm who received a further 1 days of SCH53276 with RTV (1 mg once daily). Mean SCH53276 C max increased sixfold (49 296 ng/ml), AUC increased 11-fold (252 2,88 ng/h/ml), minimum plasma concentration (C min ) increased 18-fold (1.3 1,89 ng/ml) and t ½ had a twofold increase ( 26 h; unpublished data). The Phase I study described here enrolled HIV-1- infected individuals who were about to start or resume combination antiretroviral therapy. It was designed to further examine the safety, antiviral activity and PK of SCH53276 (6 mg twice daily) coadministered with RTV. The study was designed to provide a proof of concept with a single dosing regimen of SCH53276 with RTV coadministration. Because inhibition of baseline HIV-1 viral load has been shown to correlate well with the trough levels of CCR5 inhibitors, a twice-daily dosing regimen with RTV coadministration was selected over a once-daily dosing regimen to produce higher trough level concentrations of SCH53276 at steady state. The safety of this dosing regimen was confirmed previously in the RMD study in healthy volunteers. Methods This study was a single-centre, open-label, nonrandomized trial of SCH53276 with concurrent RTV. Study drug (6 mg every h) was given for 1 days as an oral solution (3 ml per dose). RTV (1 mg capsule) was administered once daily. Following the 1-day dosing period, patients received no treatment for 14 days (the washout) and commenced combination antiretroviral therapy on day 25. The study was open to currently untreated HIV-1- infected patients with R5-tropic virus only. Participants were antiretroviral-naive or had had a 3-month treatment interruption. Other key inclusion criteria were age 18 65 years, body mass index (BMI) 19 35 kg/ m 2, CD4 + T-cell count 1 cells/µl and plasma HIV-1 RNA 5, copies/ml. Key exclusion criteria were resistance to 2 classes of antiretroviral agents, prior CCR5 antagonist use, an active AIDS-defining illness and detectable dual-tropic or X4-tropic virus. The primary endpoint was change in plasma HIV-1 RNA from baseline to day 1 of treatment. Clinical and laboratory evaluations Screening assessments included CD4 + T-cell count, plasma HIV-1 RNA, tropism, HIV-1 genotype (Trugene HIV-1 Guidelines TM Rules 1., Bayer Health Care, Tarrytown, NY, USA), haematological, renal (estimated glomerular filtration rate) and hepatic safety laboratories, a urinary drug screen and pregnancy test (as applicable). Plasma HIV-1 RNA, CD4 + T-cell count, safety laboratories and HIV-1 tropism were repeated on the day prior to receipt of study drug. Plasma HIV-1 RNA was determined with the Roche Amplicor assay (Roche Molecular Diagnostics, Pleasanton, CA, USA) on days 1, 3, 5, 7, 1, 15, 2 and 25. CD4 + T-cell count was quantified on days 1 and 25. Tropism assays were performed at four time points: at screening and at days -1, 1 and 25 using the Viro- Tect Tropism assay (Invirion Diagnostics, Oak Brook, IL, USA), a flow cytometric technique with a sensitivity cutoff of 1% for detection of CCR5- and CXCR4- infected cells. Laboratory tests were performed on days 5, 1 and 25. Vital signs were assessed on days 1 and 1 of dosing, and on day 25. Resting electrocardiograms (ECGs) were performed at days 1 and 25 only. The National Cancer Institute s Common Terminology Criteria for Adverse Events version 3. [7] was used for toxicity grading. Intensive PK sampling was performed on day 1, immediately pre-dosing, and at.5, 1, 1.5, 2, 4, 6 and h after dosing. This PK sampling schedule was repeated on day 1. All patients were confined for 14 h on days 1 and 1. Trough (pre-dose) PK samples were also obtained on days 3, 5 and 7. PK samples were analysed using a validated liquid chromatographic-tandem mass spectrometric method with a calibration range of.5 1, ng/ml. Statistical and pharmacokinetic data analyses Data from all enrolled patients were included in the tabular and graphical summaries of change in HIV-1 RNA from baseline over time. In addition, the proportion of patients with plasma HIV-1 RNA<5 copies/ ml and the proportion of patients with a decrease in plasma HIV-1 RNA of 1 log 1 copies/ml were calculated at day 1. The C max and T max were determined by observation of the plasma concentration time data. The AUC up to the last measured concentration following the first dose of SCH53276 and RTV were calculated using the linear trapezoidal method. Plasma samples were drawn for a h post-dose period on days 1 and 1. This allowed estimation of exposure over the dosing interval (τ) and also calculation of the accumulation ratio (steady state AUC/first dose AUC), while keeping patient blood sampling burden low. Characterization of terminal elimination phase was not possible 1 29 International Medical Press

SCH53276 in HIV type-1-infected patients Figure 1. HIV-1 RNA evolution during receipt of SCH53276 with ritonavir (days 1 1), no therapy (days 11 24) and commencement of combination antiretroviral therapy (day 25) Plasma HIV-1 RNA change from baseline, log 1 copies/ml Viral load <5 copies/ml.5 -.5-1 -1.5-1.3 (-1.6-1.) -1.6 (-2. -1.3) -.4 (-.8 -.1) -2 Period of dosing -2.5-1 1 2 3 4 5 6 7 8 9 1 11 13 14 15 16 17 18 19 2 21 22 23 24 25 Days n 1 2 1 Data points are mean change in HIV type-1 (HIV-1) viral load (95% confidence interval). because of the relatively short blood sampling period. However, effective t ½ was calculated based on the accumulation ratio, as previously described [8]. The apparent steady state total body clearance was calculated as dose/auc τ. Results The study enrolled Caucasian male participants. Median age was 36 years (range 3 52) and median BMI was 24.3 kg/m 2 (range 2 28). Median CD4 + T-cell count and plasma HIV-1 RNA were 327 cells/µl (range 17 1,8) and 4.6 log 1 copies/ml (range 3.8 5.5), respectively. Four patients were antiretroviral-naive and eight were treatment-experienced, but off therapy for a median of 32 months (range 3 71). Mean (95% confidence interval [CI]) changes from baseline plasma HIV-1 RNA at days 1 and 15 (4 days after study drug ceased) were -1.31 log 1 copies/ml (-1.6-1.) and -1.62 log 1 copies/ml (-2. 1.3), respectively (Figure 1). Overall, 1 of (83%) patients exhibited a decrease of 1 log 1 copies/ ml in plasma HIV-1 RNA at day 1 (Table 1). Two patients at day 15 and one at day 2 achieved plasma HIV-1 RNA<5 copies/ml. All virus isolates remained R5-tropic throughout the study period. There was an increase in CD4 + T-cell count between days -1 and 1 (mean increase of 59 cells/µl). CD4 + T-cell count had returned to baseline by day 25. The mean steady state C min, C max and AUC τ values in HIV-1-infected individuals (Table 2) were comparable with those observed in healthy seronegative volunteers. The mean effective t ½ was calculated at 39.4 h, which was considerably longer than the h dosing period. In total, 11 (92%) patients reported 1 treatmentemergent adverse events (AEs), most commonly gastrointestinal upset (67%), that is, diarrhoea (33%) and abdominal pain (25%). Gastrointestinal disorders reported in <1% were abdominal distension, nausea, abdominal pain (upper and lower) and frequent bowel movement. Overall, 75% of AEs were graded as mild; 58% were considered by clinicians at the site to be likely related to RTV [6] and unlikely related to SCH53276. One serious AE was recorded in a 32-year-old male, who reported chest pain and mild dyspnoea on day 23 (13 days after last receiving study drug). Pericarditis (grade 2) was diagnosed based on ECG changes, although it was not confirmed by echocardiogram. In the absence of a confirmed aetiology, the event was considered possibly related to the study drug. All symptoms and ECG changes resolved without sequelae after 4 days; the patient did not require hospital admission and was treated with 4 days of overthe- counter simple analgaesia. None of the changes in haematological and biochemical parameters was considered clinically significant by clinicians at the site. The median change in QTc interval at day 1 from baseline was ms (range -36 6). Discussion Ten days of dosing with SCH53276 coadministered with RTV demonstrated potent antiretroviral activity in this small study. The maximum reductions in plasma HIV-1 RNA observed at day 15 (4 days after last receipt Antiviral Therapy 14.1 113

SL Pett et al. of study drug) are similar to those previously observed with two other small molecule CCR5 antagonists, maraviroc [2] and vicriviroc [4,5]. In addition, the mean C min level of SCH53276 (178 ng/ml) in this study was above the 1 ng/ml C min value shown to correlate with better virological suppression in both maraviroc [9] and vicriviroc [1] trials. CXCR4-using virus was not detected during this brief, 1-day treatment. SCH53276 was generally well tolerated with no signature adverse reactions. The patient diagnosed with pericarditis 13 days after last dosing of study drug recovered quickly and without sequelae. Relationship of this event to SCH53276 was considered possible, despite the length of time between last receipt of study drug and onset of symptoms. Small molecule CCR5 antagonists are becoming an important addition to the antiretroviral armamentarium. SCH53276 represents a promising future treatment option. The high virological efficacy of this drug is supported by the finding that the trough concentrations of SCH53276, when dosed with concurrent RTV, exceed the in vitro IC 9 (1.1 ng/ml) by >3-fold (after correction for 8% plasma protein binding). In addition, the long t ½ justifies once-daily dosing. Acknowledgements In addition to all the patients who participated in this study, we would like to acknowledge John McAllister, Mark Lacey, Martina Rafferty and Brett Sinclair of the HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent s Hospital, Sydney, Australia; Linda Hotong, Kate Towers and Jane Donnelly of the Clinical Trials Pharmacy Unit, St Vincent s Hospital; Fiona Peet and Erika O Dea of the Clinical Trials Centre, St Vincent s Hospital; and Jack Tseng of Schering Plough Research Institute (SPRI), Kenilworth, NJ, USA. The study was coordinated by the National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia and conducted at St Vincent s Hospital. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, University of New South Wales, Darlinghurst, Sydney, Australia. The trial was conducted in accordance with the ICH Good Clinical Practice guidelines. Informed consent was obtained from all patients. The study was approved by the St Vincent s Hospital and the University of New South Wales Human Research Ethics Committees using the human experimentation guidelines in the National Statement on Ethical Conduct in Research Involving Humans issued by the National Health and Medical Research Council, Commonwealth of Australia. Disclosure statement This study was supported with funds from SPRI. MM, AT and JMS are employees of SPRI. The Biostatistical Unit of SPRI provided data analyses. Table 1. Distribution of HIV type-1 RNA log 1 copies/ml decrease by time interval Day of study n <, n (%) to <1, n (%) 1 to <2, n (%) 2, n (%) Receipt of study drug Day 3 1 a 5 (5) 5 (5) () () Day 5 1 (8) 1 (83) 1 (8) () Day 7 () 6 (5) 6 (5) () Day 1 () 2 (17) 9 (75) 1 (8) Washout (no drug) Day 15 () 1 (8) 7 (58) 4 (33) Day 2 1 (8) 6 (5) 3 (25) 2 (17) Day 25 1 (8) 9 (75) 2 (17) () a Missing data for two patients. Table 2. Pharmacokinetic parameters of SCH53276 on days 1 and 1 Day of study C max, ng/ml C min, ng/ml Median T max, h (range) AUC h, ng h/ml Cl ss /F, l/h Effective t ½, h Day 1 8.7 (37) 35.6 (26) 1.5 (1. 6.) 586 (27) NA NA Day 1 295 (15) 178 (19) 1.4 (1. 4.) 2,78 (16) 17.7 (15) 39.4 (37) Data are means (coefficient of variation %) unless otherwise indicated. AUC h, area under the plasma concentration time curve from baseline to h; Cl ss /F, apparent steady state total body clearance; C max, maximum plasma drug concentration; C min, minimum plasma drug concentration at pre-dose; NA, not applicable; T max, time to maximum concentration, t 1/2, half-life. 114 29 International Medical Press

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