P394

1. Introduction EPIC was a Phase IIb, 96 week, randomized, open-label, multicenter, parallel-group, repeat-dose study conducted in HIV-1 infected, ART naïve subjects designed to define a dosage regimen to be evaluated in subsequent Phase III trials by assessing safety, pharmacokinetics (PK) and antiviral activity of different oral doses of APL in combination with LPV/r. Primary • The proportion of responders with vRNA <400 copies/mL at Week 12 • To assess short-term safety, and tolerability of different oral doses of APL Secondary • To assess the HIV-1 RNA decay rate over the initial weeks of treatment • To assess the long-term safety and antiviral activity of APL Methods • Therapy-naïve, HIV-1 infected, male or female subjects aged 18 years or older with screening vRNA 50,000 copies/mL, CD4+ cell count ≥100 cells/mm3,and HIV-1 harboring cellular chemokine receptor 5 (CCR5) R5-tropic or R5/X4 tropic virus based on viral tropism assessment were randomized 2:2:2:1 to APL 200mg BID, APL 400mg BID, APL 800mg QD or ZDV/3TC each in combination with LPV/r. • The Treatment Phase included all data collected while the subjects were on randomized treatment, and data collected through 30 days following treatment discontinuation when additional ARVs could have been initiated. • The Safety Population was defined as all randomized subjects with documented evidence of having received at least one dose of randomized treatment. Subjects were analyzed according to the actual treatments received. • Efficacy data presented herein are for the Modified Intent To Treat population (M-ITT) which eliminates any subjects who did not have the opportunity to complete 12 weeks of treatment, and the ITT population which includes all subjects. The primary efficacy analysis was based on the M-ITT Population, and was the proportion of responders at Week 12 as defined by the TLOVR algorithm. Study Population A total of 193 subjects harboring R5 tropic or R5/X4 tropic virus were enrolled from 36 centers in the United States (US), five centers in Canada and 38 sites in the European Union (EU). Of these, 191 subjects received at least one dose of study medication (the Safety Population); 174 subjects (91%) had additional data that was included in the Follow-up Phase. A total of 141 subjects initiated treatment early enough to have been able to complete 12 weeks of treatment, while the remaining 50 started treatment too late to have been able to complete 12 weeks on treatment prior to study termination (15 September 2005). A total of 133 of the 141 subjects in the M-ITT Population (94%) completed the 12-week Treatment Phase. Figure 1. Proportion of HIV-1 RNA <400c/mL for Modified ITT by Week Discussion The study was terminated due to treatment-emergent hepatotoxicity that occurred among some subjects receiving APL. One subject had a combined increase in ALT and total bilirubin consistent with Hy’s Law [FDA Working Group, 2000]. The reasons for the observed hepatotoxicity with APL are currently unknown; preliminary data suggest that hepatotoxicity was not associated with APL exposure. Genetic predictors of APL-associated hepatotoxicity are currently undergoing investigation. Gastrointestinal AEs appeared to be associated with APL. An apparent dose response relationship was noted in the incidence of diarrhea, with subjects in the 400mg BID and 800mg QD arms demonstrating a higher incidence of diarrhea than the 200mg BID arm. The control arm had the lowest rate of diarrhea. However, these GI events were rarely treatment-limiting. Antiviral response rates were similar between the APL dosage regimens; however, a moderately diminished response relative to COM + LPV/r was noted overall. Protocol-defined virologic failure was infrequent in this study (6%) and was not associated with the development of resistance to APL at the population level or a change in tropism readout (Kitrinos et al, 2006). Short-term immunologic responses (increases in CD4+ cell counts) were similar and observed across all treatment groups. Though APL demonstrated nonlinear PK with high intersubject variability (the increase in APL area under the curve [AUC (0-)] and Cmax was more than proportional to the increase in dose), there was not a significant relationship between APL exposure and antiviral response. Further exploration of predictors for response to APL-containing regimens (e.g., pharmacogenetic analysis) is underway. Conclusions While not powered to show significant differences between treatments, a trend towards lower activity of the dual combination of APL+LPV/r when compared to COM+LPV/r was seen. The occurrence of idiosyncratic hepatotoxicity precluded further study of APL. GSK remains committed to the development of HIV entry inhibitors, and will continue to explore additional/new compounds for clinical development. Acknowledgements The authors would like to thank the study participants, clinical investigators, study coordinators, and GlaxoSmithKline staff who participated in this study. Daniel S. Berger MD, Anthony LaMarca MD, Robert Heglar MD, Stephen L. Green MD, Patricia D. Salvato MD, Luis F. López Cortés MD, Eugénio Teófilo MD, Paul J. Cimoch MD, Stefan Schneider MD, Knud Schewe MD, Leslie Diaz MD, Prof Jacques Reynes, MD, Prof Adriano Lazzarin, Winkler Weinberg MD, Fiona Smaill MD, José M Gatell MD, Prof Schlomo Staszewski MD, Bonaventura Clotet MD, Prof Gilles Pialoux MD, Dirk Schürmann MD, José Vera MD, Roger Trinh MD, Lewis Hall McCurdy MD, Gian Marco Vigevani MD, Michael Hill MD, Bruce S. Rashbaum MD, Benjamin Young MD, F. Brobson Lutz Jr MD, E Wilkins MD, Edwin DeJesus MD, Sharon Walmsley MD, Brian Conway MD, Prof Pierre-Marie Girard MD, Prof Guy-Patrick Yeni MD, Prof Andreas Plettenberg MD, Prof Jürgen Rockstroh MD, Johnson MD, Jorge E. Rodriguez MD, Melanie A. Thompson MD, William James Towner MD, Prof Christine Katlama MD, Prof François Raffi, MD, Prof Jean-Michel Molina MD, Prof Gerd Fätkenheuer MD, Prof Mauro Moroni MD, C Orkin MD, Trevor Hawkins MD, James Sampson MD, Peter Sklar MD, MPH, Ulf Fritz Bredeek MD, Robert Schwartz MD, Bienvenido G. Yangco MD, MPH, Jonathan Angel MD, Jan Gerstoft MD, Prof Jean-François Delfraissy MD, Yazdan Yazdanpanah MD, Marie-Aude Khuong-Josses MD, Véronique Bergerol MD, Prof Giovanni Di Perri MD, K Radcliffe MD, Martin Fisher MD, Robert A. Myers,MD, Lars Mathiesen MD, María J. Pérez Elías MD, Dominique Salmon-Ceron MD, Prof Hervé Gallais MD, Jan Willem Mulder MD, PhD, Michael R. Byer, MD, Timothy Friel MD, Princy N. Kumar MD, Tanya Schreibman MD, Anthony Mills MD, Gervais Frechette MD, Sylvie Trottier MD, Miguel Salavert MD, Stephen L. Becker MD, Donna Sweet MD, Robert C. Scott MD, Thomas T. Jefferson MD References • FDA Working Group. CDER-PhRMAAASLD Conference 2000: clinical white paper on drug-induced hepatotoxicity, November 2000. (Accessed July 5, 2006, at http://www.fda.gov/cder/livertox/clinical.pdf.) • Lalezari J, Thompson M, Kumar P et al. Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults. AIDS 2005;19:1443-8. • Nichols WG, Steel HM, Bonny TM, Min SS, Curtis L, Kabeya K, Clumeck N. Hepatotoxicity observed in clinical trials of aplaviroc (APL, 873140). Special Oral Communication, 2005 EACS, Dublin, Ireland. • Kitrinos, KM, Irlbeck, DM, LaBranche, CC, Madsen, HA, and Demarest, JF. 2006. Virologic characterization of treatment naive subjects failing an aplaviroc-based regimen with either lamivudine/zidovudine or lopinavir/ritonavir. XV International Drug Resistance Workshop, June 13-17, Sitges, Spain. Abstract # 21 P394 Safety and Antiviral Activity of the Novel CCR5 Antagonist Aplaviroc in Combination with Lopinavir/ritonavir in HIV-Infected Therapy Naive Subjects Patrick Yeni, MD1, Jűrgen Rockstroh, MD2*, Anthony LaMarca, MD3, Sam Madison, MSc4, Garrett Nichols, MD5, Judith Millard, PhD4, Deb McCarty4, Tab Bonny, MS4 and the EPIC study team1University Hospital Bichat, Paris, France; 2Bonn University, Germany; 3Therafirst Medical Center, Ft.Lauderdale, Florida, United States; 4GSK, RTP, NC, United States and 5GSK, Greenford, United Kingdom. Abstract Table 2. CD4+ Cell Change From Baseline Table 3. Summary of Common Drug Related Grade 2-4 Adverse Events (>2% Safety Population) Background: Aplaviroc (APL), a CCR5 antagonist has demonstrated potent anti-HIV activity and long receptor occupancy (>100 hrs). This phase IIb study explored the combination of APL+LPV/r. All APL studies were prematurely terminated due to idiosyncratic hepatotoxicity. Methods: 191 therapy naive subjects with R5 or R5/X4-tropic virus, vRNA 50,000 c/mL and CD4+ ≥100 cells/mm3, were randomized 2:2:2:1 to APL 200mg BID, APL 400mg BID, APL 800mg QD, or ZDV/3TC (COM). All subjects received LPV/r BID. Previously unreported efficacy data and final safety data are presented. Summary of Results: Of the 191 subjects entered, 90% harbored only R5-tropic virus, 85% were male, 81% were white and 12% were co-infected with HBV or HCV. Median BL vRNA and CD4+ counts were well matched. Common clinical AEs were diarrhea, nausea, headache, fatigue and vomiting. 141 subjects (74%) were randomized ≥12 weeks prior to study termination, 133 (70%) completed 12 weeks of treatment. The proportion of subjects with vRNA <400 c/mL at Week 12 (ITT R5 population) was 38% (95% CI: 24%, 53%) for APL 200mg BID, 35% (22%, 50%) for APL 400mg BID, 38% (25%, 53%) for APL 800mg QD and 54% (33%, 74%) for COM+LPV/r. Similar CD4+ cell increases were seen across all dose groups. Antiviral activity was also seen in the limited number of subjects in the R5/X4-tropic cohort. Conclusions: While not powered to show significant differences between treatments, a trend towards less activity of the dual combination of APL+LPV/r than COM+LPV/r was seen. The occurrence of idiosyncratic hepatotoxicity precluded further study of APL. 1ITT Observed Population, median (min, max) Safety • The mean duration of exposure was similar across the treatment arms (~14 weeks mean duration). • More subjects treated with APL experienced treatment emergent gastrointestinal (GI) AEs (all grades) than subjects in the control arm. An apparent dose response relationship was noted in the incidence of diarrhea, with subjects in the 400mg BID (79%) and 800mg QD (76%) arms demonstrating a higher incidence than those in the 200mg BID (59%) or COM (42%) arms. However, these events were rarely treatment-limiting. • GI events accounted for the majority of Grade 2-4 AEs; these appeared to be most prevalent in the APL 800 QD dosing arm (Table 3). • The Treatment Phase includes all data on treatment as well as events with onset up to 30 days following the discontinuation of treatment. • One subject died approximately four months after discontinuing APL as a result of end-stage liver failure (alcoholic cirrhosis, hepatitis C and portal hypertension with ascites, all of which predated treatment with APL). This event was thus not considered by the investigator to be attributable to APL. Laboratory parameters • The majority of subjects had no treatment emergent clinical chemistry abnormalities (Table 4). • The APL clinical development program was discontinued due to treatment-emergent hepatotoxicity seen in some subjects treated with APL. The combination of increases in ALT (>5x the upper limits of normal (ULN)) and total bilirubin (>2.5 x ULN) occurred in one subject; this subject has been described previously (Nichols WG et al, 2005). Interestingly, the rate of Grade 2-4 ALT was similar between groups; observed rates were 9/165 (5.5%) of APL-treated subjects, compared with 2/26 (7.7%) of COM+LPV/r subjects, while Grade 2-4 increases in total bilirubin were reported for 16/165 (9.7%) of APL-treated subjects vs. 3/26 (11.5%) of COM+LPV/r-treated subjects. Table 4. Emergent Clinical Chemistries of Special Interest: Maximum DAIDS Grade on Treatment1 Table 5. APL PK Summary (Geometric Mean [95% CI] (%CVb) Results • Final results through the study termination date (15 September 2005) are presented • Demographic characteristics were well balanced across treatment groups. The mean age was 38 years; the majority of subjects were 35-65 years of age (58%), white (81%), and male (85%). More subjects in the R5-tropic group had baseline plasma HIV-1 RNA 100,000 copies/mL compared to <100,000 copies/mL (62% vs 28%). Most subjects were CDC Class A (85%), had homosexual contact as their primary HIV risk factor (73%), and were negative for Hepatitis B and C (95% and 88%, respectively). 1includes 30 days post treatment discontinuation • Data presented are geometric mean [95% CI] (%CVb) • =12h for BID regimens; =24h for QD regimen • AUC(0-24) estimated as 2 x AUC(0-) for twice daily regimens 4.N=12; AUC and C could not be estimated for Subject 612. 5.N=14 6.N=12 Antiviral and Immunologic Efficacy A total of 133 of the 141 subjects (94%) in the M-ITT Population completed the 12-week Treatment Phase. The proportion of subjects with vRNA <400 c/mL at Week 12 (M-ITT R5 only) was similar between the APL dosage regimens; however, a moderately diminished response relative to COM + LPV/r was noted overall (Figure 1). APL and LPV/r Pharmacokinetics • The geometric mean plasma APL AUC(0-24) values (Table 5) met or exceeded the target AUC(0-24) of 1900ng.h/mL determined in the 10-day monotherapy study (Lalezari et al, 2005). LPV and RTV PK parameters were consistent with previously reported values (Data not shown) • No consistent relationships between APL AUC(0- ), Cmax or C and measures of antiviral response were detected in the subset of subjects who participated in Week 12 Intensive PK (data not shown). 72%54%53%49% • The change from baseline in HIV-1 RNA was more variable in the APL treatment arms relative to the control. This is illustrated in Figure 2 which shows the change from baseline over time for the entire ITT population. Figure 2. HIV-1 RNA Change From Baseline Randomized Treatment Group=APL 200mg BID + LPV/r Randomized Treatment Group=APL 200mg BID + LPV/r Randomized Treatment Group=APL 400mg BID + LPV/r 200 BID 400 BID Randomized Treatment Group=APL 800mg QD + LPV/r Randomized Treatment Group=COM + LPV/r 800 QD COM+LPV/r • Protocol-defined virologic failure was infrequent in this study (6%) and was not associated with the development of resistance to APL or a change in tropism readout (Kitrinos et al, 2006). • A limited number of subjects harboring R5X4-tropic virus were enrolled. These subjects did appear to respond to treatment but due to small numbers and the limited duration of follow up no meaningful conclusions could be drawn. • Similar increases in CD4+ cell counts were observed across all treatment groups (Table 2).