Background: Aplaviroc (APL), a CCR5 antagonist, has demonstrated potent anti-HIV activity (a mean 1.66 log10 copies/mL at nadir decrease in viral load from baseline was observed in the highest dosage arm in the 10-day monotherapy study [Lalezari]) and

1
P392
Safety and Antiviral Activity of the Novel CCR5
Antagonist Aplaviroc in Combination with
ZidovudineLamivudine in HIV-Infected Therapy
Naive Subjects
Judith Currier, MD1, Adriano Lazzarin, MD2,
Jörg-Peter Kleim, PhD3, Helen Steel, MD3, Judith
Millard, PhD4, Tab Bonny, MS4 and the ASCENT
study team1UCLA Center for Care, Los Angeles,
United States 2San Raffaele Vita-Salute
University, Milan, Italy 3GSK, Greenford, United
Kingdom and 4GSK, RTP, NC, United States
Abstract
Table 1. Summary of Common Drug Related Grade
2-4 Adverse Events (gt2)
Table 2. Adverse Events Leading to Premature
Discontinuation1 of Study Drug
Background Aplaviroc (APL), a CCR5 antagonist,
has demonstrated potent anti-HIV activity (a mean
1.66 log10 copies/mL at nadir decrease in viral
load from baseline was observed in the highest
dosage arm in the 10-day monotherapy study
Lalezari) and long receptor occupancy (gt100
hrs). This phase IIb study explored the
combination of APLZDV/3TC (COM). The
idiosyncratic hepatotoxicity that led to
premature termination of APL development has been
previously reported. Previously unreported
efficacy data are presented. Methods 145
therapy naive subjects harboring R5-tropic virus,
with screening vRNA gt10,000 c/mL and CD4 100
cells/mm3, were randomized 221 to receive APL
600mg BID, APL 800mg BID, or EFV 600mg QD. All
subjects received COM BID. Summary of Results
Of the 145 subjects entered, 83 were male, 25
were non-white and 8 were co-infected with HBV
or HCV. Median BL vRNA and CD4 cell counts were
well matched. One subject withdrew due to hepatic
cytolysis. The most common clinical AEs on APL
and EFV respectively were gastrointestinal and
CNS related events. Laboratory elevations seen on
APL were largely related to liver enzyme
increases. 142 subjects (98) were randomized at
least 12 weeks prior to study termination, 115
(79) completed 12 weeks of treatment. The
proportion of subjects with vRNA lt400 c/mL at
Week 12 (ITT) was 53 (95 CI 40, 67) for APL
600 mg BID, 50 (37, 63) for APL 800 mg BID and
66 (46, 82) for COMEFV. Similar CD4 cell
increases were seen across groups. Conclusions
While target plasma concentrations of APL were
achieved, the antiviral activity of APL as part
of a triple drug regimen did not appear to be
comparable to COMEFV. However, the occurrence of
idiosyncratic hepatotoxicity precluded further
investigation of APL.
APL 600 BID N58 APL 800 BID N58 COMEFV N29
Any event 30 (52) 29 (50) 14 (48)
Diarrhea 13 (22) 15 (26) 0
Nausea 7 (12) 8 (14) 2 (7)
Fatigue 3 (5) 4 (7) 3 (10)
Vomiting 4 (7) 4 (7) 0
Anemia 4 (7) 1 (2) 1 (3)
Dyspepsia 2 (3) 2 (3) 1 (3)
Abdominal pain 1 (2) 3 (5) 0
Dizziness 2 (3) 1 (2) 1 (3)
Headache 3 (5) 0 1 (3)
Neutropenia 2 (3) 1 (2) 1 (3)
Rash 1 (2) 0 3 (10)
APL 600 BID N58 APL 800 BID N58 COMEFV N29
Any Event 8 (14) 9 (16) 8 (28)
Nausea 2 (3) 5 (9) 1 (3)
Diarrhea 0 4 (7) 1 (3)
Anemia 4 (7) 0 1 (3)
Abdominal pain 0 2 (3) 1 (3)
Dyspepsia 0 1 (2) 1 (3)
Vomiting 2 (3) 0 0
Insomnia 0 1 (2) 1 (3)
Fatigue 0 2 (3) 1 (3)
Pyrexia 1 (2) 1 (2) 0
Dizziness 0 2 (3) 1 (3)
1Treatment Phase Safety Population

• One subject withdrew due to hepatic cytolysis.
  This was the sentinel case that subsequently led
  to termination of the APL program. (Data
  previously presented 2005 EACS, Ireland.)
• The most common clinical AEs (all grades, all
  causalities) on APL and EFV respectively were
  gastrointestinal and CNS related events. The most
  commonly reported drug-related Grade 2 to Grade 4
  AEs during the Treatment Phase were diarrhea,
  nausea, fatigue, and vomiting Table 1. Similar
  numbers of subjects were withdrawn from treatment
  due to AEs (Table 2). The most common AEs
  leading to treatment discontinuation were GI
  events, including nausea and diarrhea. These
  events were more common for the APL treatment
  groups and there was a suggestion that more
  patients withdrew from APL due to GI events on
  the APL 800mg BID group than the APL 600mg BID
  group.
• Laboratory elevations seen on APL were largely
  related to liver enzyme increases (see Table 3).

Table 3. Treatment Emergent Clinical Chemistries
of Special Interest Max on Treatment1
Figure 3. APL PK Parameters (Intensive Week
12) Achieving Less lt or 400 copies/mL
    APL 600 BID n58 APL 800 BID n58 COMEFV BID n29
ALT Grade 1 Grade 2 Grade 3 Grade 4 2 (3) 2 (3) 0 0 5 (9) 4 (7) 1 (2) 1 (2) 6 (21) 0 0 0
AST Grade 1 Grade 2 Grade 3 Grade 4 6 (10) 0 0 0 7 (12) 2 (5) 1 (2) 1 (2) 0 1 (3) 0 0
Total bilirubin Grade 1 Grade 2 Grade 3 Grade 4 3 (5) 4 (7) 4 (7) 1 (2) 6 (10) 2 (3) 0 2 (3) 0 1 (3) 0 0
APL PK Parameter APL600 BID N15 APL800 BID N18
AUC (0- ?) ng.h/mL 1184 923,1517 (47.2) 2733 1468,5088 (137)
Cmax (ng/mL) 314 240,411 (51.6) 853 418,1740 (174)
C ? (ng/mL) 11.8 8.01,17.5 (80.5) 16.91 9.16,31.3 (124)
25000
20000
15000
Aplaviroc AUC(0-tau) ng.h/mL
10000
5000
0
lt400
gt400
Responders HIV-1 RNAlt400 cp/mL
1n12
1Includes 30 days post treatment discontinuation

• APL demonstrated nonlinear PK. The increase in
  APL AUC(0-?), Cmax and C? parameters was more
  than proportional to the increase in dose (data
  not shown).

Figure 1. Demographic and Baseline
Characteristics
Discussion
APL 600 BID N58 APL800 BID N58 COMEFV N29 Total N145
Median Age (range), years 40 (22 65) 37 (20 63) 36 (21 62) 38 (20 65)
Gender, n ()
Male 46 (79) 48 (83) 26 (90) 120 (83)
Female 12 (21) 10 (17) 3 (10) 25 (17)
Race, n ()
African American/African Heritage 11 (19) 12 (21) 7 (24) 30 (21)
White 45 (78) 43 (74) 21 (72) 109 (75)
Other 3 3 (5) 1(3) 7 (lt1)
Ethnicity, n ()
Hispanic or Latino 9 (16) 12 (21) 10 (34) 31 (21)
Not Hispanic or Latino 49 (84) 46 (79) 19 (66) 114 (79)
CDC classification, n ()
Class A asymptomatic 50 (86) 43 (74) 23 (79) 116 (80)
Class B symptomatic, not AIDS 7 (12) 10 (17) 2 (7) 19 (13)
Class C AIDS 1 (2) 5 (9) 4 (14) 10 (7)
Baseline plasma HIV-1 RNA
Median, range, log10 copies/mL 4.98 3.95 - 6.63 5.07 4.00 - 6.29 5.08 3.80 - 6.20 5.03 3.80 - 6.63
lt100,000 copies/mL, n () 28 (48) 27 (47) 14 (48) 69 (48)
?100,000 copies/mL, n () 30 (52) 31 (53) 15 (52) 76 (52)
Baseline CD4 cell counts
Median, cells/mm3 (range) 265.0 87 - 477 227.0 89 - 663 264.0 133 - 633 256.0 87 - 663
Hepatitis C (n) 2 (3) 3 (5) 2 (7) 7 (5)

• In general for the primary endpoint analysis,
  antiviral response rates were similar between the
  APL dosage regimens however, a moderately
  diminished response relative to COMEFV was noted
  overall, especially in the higher viral load
  stratum. 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. Resistance to
  3TC may have been a component of virologic
  failure for subjects receiving an APL-containing
  regimen. (Data not presented here Kitrinos,
  etal.)
• The mechanisms for APL-induced hepatotoxicity are
  unclear at this time but did not appear to be
  associated with APL exposure. The observed
  clinical pattern might suggest hepatotoxicity is
  one of hepatocellular rather than cholestatic
  injury, given the high transaminase
  concentrations and absence of increases in
  alkaline phosphatase. The absence of significant
  preclinical liver signals and relatively low
  proportion of affected individuals among those
  treated are also consistent with idiosyncratic
  drug hepatotoxicity. Genetic predictors of
  APL-associated hepatotoxicity are currently
  undergoing investigation.
• Substantially more subjects treated with both APL
  regimens experienced GI AEs than did subjects
  treated with COMEFV. Specifically, diarrhea,
  nausea, and vomiting were each more than twice as
  likely to be observed in the APL treatment arms.
  Dizziness and rash were more common events for
  the COMEFV arm (data not shown).
• Although substantial differences were not
  observed in the frequency of adverse events
  between the APL dosage regimens (600mg BID vs.
  800mg BID), there were more subjects with Grade
  2-4 diarrhea and vomiting in both APL arms than
  in the control arm. However, these GI events
  were rarely treatment-limiting. Also, a higher
  proportion of subjects treated with APL
  experienced at least one Grade 2-4 AE during the
  treatment phase of the study (data not shown).
• One subject died due to Burkitts lymphoma, not
  considered to be attributable to APL.
• Inter-subject variability in APL PK parameters
  was high, especially for the 800mg BID group.
  There was not a significant relationship between
  APL exposure and antiretroviral response.
  Further exploration of predictors for response to
  APL-containing regimens (eg. Pharmacogenetic) are
  underway.
• There was no increased risk of infections on APL
  (data not shown).

Figure 1. HIV-1 RNA Change from Baseline in (ITT)
Conclusions

• While target plasma concentrations of APL were
  achieved, the antiviral activity of APL as the
  third agent in a triple drug regimen did not
  appear to be comparable to COMEFV.
• More subjects treated with both APL regimens
  experienced treatment emergent GI AEs (all
  grades) than did subjects treated with COMEFV.
  Had the program continued, close monitoring of GI
  toxicity would have been a priority in further
  studies.

Figure 2. Week 12 Proportion with HIV-1 RNA lt400
c/mL by Strata
lt100,000 c/mL
gt100,000 c/mL
Acknowledgements
67 47 45
64 61 56
The authors would like to thank the study
participants, study coordinators, GlaxoSmithKline
staff and the clinical investigators (Prof.
Adriano Lazzarin, Louis Sloan, MD, Prof. Clumeck,
Jihad Slim MD, Nicholaos Bellos MD Allan
Rodriguez MD, Douglas Ward MD, PD Dr. Keikawus
Arastéh, Prof. Giampiero Carosi Professeur RAFFI
François, Prof. Dr. Schlomo Staszewski, Jerry
Cade MD, Frank Rhame MD, M. Keith Rawlings MD
Kilby, Donald MD, Rachlis Anita MD, Prof. Mauro
Moroni, Prof. Dr. Saraiva da Cunha, Dr K
Radcliffe, Dr G Moyle, Phyllis Cohen MD, Dorece
Norris MD, Baril, Jean-Guy MD, Dr. Pere Domingo,
Docteur COTTE Laurent, Docteur FORCE Gilles,
Professeur Guy-Patrick Yeni, Dr C Orkin, Roberto
Corales DO, Judith Currier MD, Franco Felizarta
MD, Kunthavi Sathasivam MD, Sally Williams MD,
Thomas Jefferson MD, Julia Torres MD, Sylvie
Vezina MD, Dr. Vicente Soriano Vázquez, Prof. Dr.
Gerd Fätkenheuer, Prof. Dr. Hartwig Klinker,
Prof. Dr. Reinhold E. Schmidt, Dr. Gian Marco
Vigevani, Dr. Teresa Branco, Prof. Dr. António
Mota Miranda, Dr Martin Fisher, Dr E Wilkins,John
David Brand, M Richard Cazen MD, Edwin DeJesus
MD, William Harley MD, David A. McDonough MD,
Miguel Mogyoros MD, Karam Mounzer MD, Gerald
Pierone, MD, Andrew Zolopa MD) who participated
in this study.
Percentage of Subjects
Percentage of Subjects
Study Week
Study Week
ITT, TLOVR algorithm
ITT, TLOVR algorithm
References

• 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.
• 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 2005191443-8.
• 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.

• The proportion of subjects with vRNA lt400 c/mL at
  Week 12 (ITT) was 53 (95 CI 40, 67) for APL
  600 mg BID, 50 (37, 63) for APL 800 mg BID and
  66 (46, 82) for COMEFV (data not shown). For
  the change from baseline in plasma HIV-1 RNA,
  approximately a mean 3 log10 copies/mL decline
  was seen across all treatment groups at the Week
  12 time point. However, there was greater
  variability in response in the two APL treatment
  arms relative to the control as evidenced by the
  range of responses observed (Figure 1).