Download 8 th International Congress on Drug Therapy in HIV

P392
Safety and Antiviral Activity of the Novel CCR5 Antagonist
Aplaviroc in Combination with Zidovudine+Lamivudine 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 team
1UCLA
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
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
(>100 hrs). This phase IIb study explored the combination of APL+ZDV/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 >10,000 c/mL and CD4+≥ 100 cells/mm3, were
randomized 2:2:1 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 <400 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 COM+EFV. 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 COM+EFV. However, the occurrence of idiosyncratic hepatotoxicity precluded further investigation of APL.
Table 1. Summary of Common Drug Related
Grade 2-4 Adverse Events (>2%)
APL 600 BID
N=58
APL 800 BID
N=58
COM+EFV
N=29
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
Introduction
ASCENT was a Phase IIb, randomized, partially double-blinded, multicenter, parallel-group, repeat-dose study conducted in
HIV-1 infected, ART naïve subjects to select an APL dose for further evaluation based on comparison of the short-term
antiviral activity, safety and tolerability of different oral doses of APL in combination with COM over 96 weeks.
1 (2%)
3 (5%)
0
Table 2. Adverse Events Leading to
Premature Discontinuation1 of Study Drug
APL 600 BID
N=58
APL 800 BID
N=58
COM+EFV
N=29
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%)
0
2 (3%)
1 (3%)
1 (3%)
Abdominal pain
Dyspepsia
0
1 (2%)
Vomiting
2 (3%)
0
0
Insomnia
0
1 (2%)
1 (3%)
1 (3%)
Dizziness
2 (3%)
1 (2%)
1 (3%)
Headache
3 (5%)
0
1 (3%)
Fatigue
0
2 (3%)
Neutropenia
2 (3%)
1 (2%)
1 (3%)
Pyrexia
1 (2%)
1 (2%)
0
Rash
1 (2%)
0
3 (10%)
Dizziness
0
2 (3%)
1 (3%)
1Treatment
Primary
Phase; Safety Population
 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
 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].)
Secondary
 To assess the HIV-1 RNA decay rate over the initial weeks of treatment
 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.
Methods
 Therapy-naïve, HIV-1 infected, male or female subjects aged 18 years or older with screening vRNA ≥10,000 copies/mL,
CD4+ cell count ≥100 cells/mm3, and HIV-1 utilizing cellular CC chemokine receptor 5 (CCR5) (R5-tropic) based on viral
tropism assessment, and no reverse transcriptase (RT) drug resistance mutations were randomized 2:2:1 to APL 600mg
BID, APL 800mg BID or efavirenz (EFV) each in combination with COM.
 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.
 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
APL 600 BID
n=58
 Efficacy data presented here are for the Intent-to-Treat (ITT) population which included all subjects who received at least
one dose of randomized treatment. The primary efficacy analysis was based on the ITT Population, and was the proportion
of responders at Week 12 as defined by the TLOVR algorithm.
147 subjects harboring R5-tropic virus were enrolled from 24 sites in the European Union, 33 sites in the United States and 4
sites in Canada. The ITT population includes 145 subjects as 2 subjects were randomized but never received study medication.
AST
Results
Final results through the study termination date (15 September 2005) are presented:
 142/145 subjects (98%) were randomized at least 12 weeks prior to study termination, 115 (79%) completed 12 weeks of
treatment.
Total
bilirubin
 Demographic characteristics were similar across treatment groups; the mean age was 39 years; the majority of subjects
were 35 years of age or older (68%), white (75%), and male (83%)
 Baseline characteristics were similar across treatment groups. Similar numbers of subjects in the study population had
baseline plasma HIV-1 RNA <100,000 and >100,000 copies/mL (48% vs 52%). Most subjects were CDC Class A (80%), had
homosexual contact as the primary HIV risk factor (65%), and were negative for Hepatitis B and C co-infection (90% to
95%). The majority of subjects had stable tropism readouts, with 140 of 145 subjects testing R5-tropic at screening and
remaining R5-tropic at Baseline.
 Similar CD4+ cell increases were seen across groups (data not shown).
 The geometric mean plasma APL AUC(0- ) values (Table 5) of 1184 and 2733ng.h/mL for the 600mg and 800mg BID dose
groups, respectively, met or exceeded the antiviral target AUC (0-24) of 1900 ng.h/mL determined in the 10-day
monotherapy study (Lalezari etal, 2005, data not shown).
Figure 1. HIV-1 RNA Change from Baseline in (ITT)
Randomized Treatment Group=COM + APL 600mg BID
COM+EFV BID
n=29
600mg BID + COM
800mg BID + COM
25000
ALT
Study Population
APL 800 BID
n=58
Figure 3. APL PK Parameters (Intensive
Week 12) Achieving Less < or ≥ 400 copies/mL
1Includes

Grade
Grade
Grade
Grade
1
2
3
4
2 (3%)
2 (3%)
0
0
5 (9%)
4 (7%)
1 (2%)
1 (2%)
6 (21%)
0
0
0
Grade
Grade
Grade
Grade
1
2
3
4
6 (10%)
0
0
0
7 (12%)
2 (5%)
1 (2%)
1 (2%)
0
1 (3%)
0
0
Grade
Grade
Grade
Grade
1
2
3
4
3 (5%)
4 (7%)
4 (7%)
1 (2%)
6 (10%)
2 (3%)
0
2 (3%)
0
1 (3%)
0
0
Aplaviroc AUC(0-tau); ng.h/mL
 To assess the long-term safety and antiviral activity of APL
20000
15000
10000
5000
0
<400
>400
Responders HIV-1 RNA<400 cp/mL
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).
Discussion
 In general for the primary endpoint analysis, antiviral response rates were similar between the APL dosage regimens;
however, a moderately diminished response relative to COM+EFV 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.
Randomized Treatment Group=COM + APL 800mg BID
 Substantially more subjects treated with both APL regimens experienced GI AEs than did subjects treated with COM+EFV.
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 COM+EFV 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).
Randomized Treatment Group=COM + EFV
 One subject died due to Burkitt’s 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 APLcontaining regimens (eg. Pharmacogenetic) are underway.
 There was no increased risk of infections on APL (data not shown).
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 COM+EFV.
Figure 2. Week 12: Proportion with HIV-1 RNA <400 c/mL by Strata
Percentage of Subjects
APL 600 BID, n= 58
100
90
80
70
60
50
40
30
20
10
0
APL 800 BID, n=58
<100,000 c/mL
64%
61%
56%
0
ITT, TLOVR algorithm
2
4
8
COM/EFV, n=29
100
90
80
70
60
50
40
30
20
10
0
12
 More subjects treated with both APL regimens experienced treatment emergent GI AEs (all grades) than did
subjects treated with COM+EFV. Had the program continued, close monitoring of GI toxicity would have been
a priority in further studies.
>100,000 c/mL
67%
47%
45%
0
2
4
8
Acknowledgements
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.
12
Study Week
 The proportion of subjects with vRNA <400 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 COM+EFV (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).
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 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.
8th International Congress on Drug Therapy in HIV Infection, 12–16 November 2006, Glasgow, UK