Transcript Title of presentation

STARTVerso 4:
High rates of early virologic response in HCV
genotype 1/HIV-co-infected patients treated
with faldaprevir plus pegIFN and RBV
Douglas Dieterich,1 Vicente Soriano,2 Mark Nelson,3
Jürgen Kurt Rockstroh,4 Keikawus Arastéh,5 Sanjay Bhagani,6
Andrew Talal,7 Cristina Tural,8 Richard Vinisko,9 and Jens Kort 9
1Mount
Sinai School of Medicine, New York, NY, USA; 2Hospital Carlos III, Madrid, Spain; 3Chelsea and Westminster
Hospital, London, UK; 4University of Bonn, Bonn, Germany; 5EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin,
Germany; 6Royal Free Hospital, London, UK; 7State University of New York, Buffalo, NY, USA; 8Hospital Universitari
Germans Trias i Pujol, Barcelona, Spain; 9Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013
Presenter disclosure
Douglas Dieterich, MD
Mount Sinai School of Medicine,
New York, USA
I have had financial relationships within the last
12 months relevant to my presentation with:
Boehringer Ingelheim Pharmaceuticals
AND
My presentation includes information on
faldaprevir, which is an investigational
compound and is not yet approved
Introduction to faldaprevir
•
Faldaprevir is a potent and selective
inhibitor of the HCV NS3/A4 protease
‒ The pharmacokinetics of FDV allow
oral once daily administration
•
Phase IIb data demonstrated potent
antiviral activity against HCV GT-1 for:
‒ Faldaprevir combined with pegIFN/RBV
‒ An IFN-free combination of faldaprevir
Faldaprevir: Interaction with
NS3/4A protease
Green = hydrophobic
Blue = mildly polar
Purple = H bonding
GT, genotype; HCV, hepatitis C virus;
IFN, interferon alpha; RBV, ribavirin;
BI 207127, a non-nucleoside inhibitor of HCV RNA polymerase
with BI 207127 and RBV
•
Phase III trials are ongoing for the
iFree and iBased faldaprevir clinical
development programs
Llinàs-Brunet M, et al. J Med Chem 2010;53:6466–6476;
Lemke CT, et al. J Biol Chem 2011;286:11434–11443;
Sulkowski MS, et al. Hepatology 2013 Jan 28 [Epub ahead of print];
Zeuzem S, et al. AASLD Congress November 9–13, 2012 [Abstract No. 232].
STARTVerso 4: Study design (1)
Phase III open-label, sponsor-blinded study in treatment-naïve and relapser
patients with chronic HCV GT-1 and HIV infection
Interim data
Primary endpoint: SVR12
Faldaprevir 240 mg QD
+ pegIFN/RBV
Faldaprevir 240 mg QD
+ pegIFN/RBV
pegIFN/RBV
pegIFN/RBV
Randomization 1:1
pegIFN/RBV
Faldaprevir 120 mg QD
+ pegIFN/RBV
Day 1
Week 12
Week 24
Week 48
Patients with HCV RNA below LLoQ, at Week 4, and HCV RNA below LLoQ target not detected at Week 8 (=ETS)
will be re-randomized 1:1 at week 24 to stop treatment or continue pegIFN/RBV through week 48
Patients who did not achieve ETS will continue pegIFN/RBV through week 48
LLoQ, lower limit of quantification <25 IU/mL HCV RNA; pegIFN: pegylated interferon alfa-2a 180 µg once weekly; QD, once daily; SVR, sustained
virologic response at 12 weeks after end of treatment.; ETS, early treatment success
RBV: ribavirin 1000 or 1200 mg daily dose for body weight <75 kg or ≥75 kg, respectively
STARTVerso 4: Study design (2)
•
HCV GT-1 infection, including compensated cirrhosis
‒
HCV treatment-naive or relapsers
ART
regimen
No ART
Raltegravir or
maraviroc
based
Efavirenz
based
RANDOMIZED
Faldaprevir
dosage
120 or 240 mg QD
ART, antiretroviral therapy; QD, once daily
Darunavir/ritonavir or
atazanavir/ritonavir
based
ALLOCATED
240 mg QD
120 mg QD
STARTVerso 4: Patient disposition
(Week 12 interim data)
Screened
(N=453)
Screen failure
(N=143)
Allocated/Randomized
(N=153/N=157)
HCV treatment-naïve
(N=239)
Faldaprevir (120 or 240 mg QD)
+ pegIFN/RBV
(N=308)
Not available (N=18)
Discontinued (N=45)
15 Due to AE
12 Lack of efficacya
18 Other reasonb
Completed 12 weeks of treatment
(N=176)
Not treated
(N=2)
Relapser
(N=69)
Not available (N=4)
Discontinued (N=7)
3 Due to AE
1 Lack of efficacya
3 Other reasonb
Completed 12 weeks of treatment
(N=58)
viral rebound ≥1 log10 HCV RNA from previous undetected level; lack of HCV RNA reduction from baseline by ≥ 2 log10 at Week 12;
lack of viral response at Week 24. bIncludes: protocol violation, withdrawal by subject, or other reasons
AE, adverse event; ATZ, atazanavir; DRV, darunavir; EFV, efavirenz; r, ritonavir
aIncludes:
STARTVerso 4: Baseline characteristics
Treatment-naïve
(N=239)
Relapser
(N=69)
Total
(N=308)
47
47
47
184 (77)
64 (93)
80
179 (75)
39 (16)
21 (9)
63 (91)
2 (3)
4 (6)
79
13
8
67 (28)
60 (25)
105 (44)
7 (3)
17 (25)
7 (10)
41 (59)
4 (6)
84 (27)
67 (22)
146 (47)
11 (4)
Mean baseline CD4+ T cell count, cells/µL
544
549
545
Baseline HCV RNA ≥800 000 IU/mL, n (%)
197 (82)
49 (71)
246 (80)
HCV Genotype-1a, n (%)
184 (77)
55 (80)
239 (78)
Cirrhosis F4 or FibroScan >13 kPa, n (%)
40 (17)
11 (16)
51 (17)
Age, years (mean)
Male, n (%)
Race, n (%)
White
Black or African American
Othera
ART, n (%)
EFV-based
ATZ/r- or DRV/r-based
Ral-based and otherb
No ART (ARV-naïve), n (%)
aIncludes
Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and missing data.
1 patient taking maraviroc plus emtricitabine/tenofovir disoproxil fumarate, 1 patient taking emtricitabine/tenofovir disoproxil fumarate only.
Ral, raltegravir
bIncludes
STARTVerso 4: Interim safety and tolerability
Most frequent AEs in >20% of patients
Nausea
Fatigue
Diarrhea
Headache
Asthenia
Other AEs of interest
Anemia
Neutropenia
Rash
Loss of HIV suppressiona
Most frequent serious AEs (>1 patient)
Pyrexia
Abdominal pain
Diarrhea
Gastroenteritis
Vomiting
Anemia
Rash
Dehydration
aIncrease
No. of patients (%)
113 (37)
102 (33)
83 (27)
71 (23)
68 (22)
No. of patients (%)
55 (18)
49 (16)
55 (18)
0
No. of patients (%)
4 (1)
3 (<1)
3 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
of HIV plasma RNA >200 copies/mL on two consecutive measurements from prior <40 copies/mL
Three deaths: dyspnea; hemorrhage, cerebrovascular accident; Drug reaction with eosinophilia and systemic symptoms
Early virologic response in HIV/HCV co-infected patients:
HCV treatment-naïve
Treatment-naïve <LLoQ
Treatment-naïve <LLoQ TND
100
Proportion of patients (%)
86
80
80
82
60
60
40
20
191/
239
143/
239
206/
239
195/
239
0
Week 4
TND target not detected
Week 12
Early virologic response in HIV/HCV co-infected patients:
HCV treatment-naïve and relapsers
Treatment-naïve <LLoQ
Treatment-naïve <LLoQ TND
Relapser <LLoQ
Relapser <LLoQ TND
Proportion of patients (%)
100
80
91
86
80
93
91
64/
69
63/
69
82
74
60
60
40
20
191/
239
143/
239
63/
69
51/
69
206/
239
195/
239
0
Week 4
Week 12
Early virologic response in HIV/HCV co-infected patients:
comparison with HCV mono-infected patients
Treatment-naïve <LLoQ
Treatment-naïve <LLoQ TND
Relapser <LLoQ
Relapser <LLoQ TND
Proportion of patients (%)
100
80
91
Mono-infected patients, SILEN-C1 study:
Treatment-naïve <LLoQ TND
86
80
a
74
76
51/
69
108/
142
a
93
91
93
64/
69
63/
69
132/
142
82
60
60
40
20
191/
239
143/
239
63/
69
206/
239
195/
239
0
Week 4
aSILEN-C1
Week 12
study arm of 240mg QD FDV plus pegIFN/RBV in HCV GT1 treatment-naïve monoinfected patients without cirrhosis; data on file
Response guided therapy criteria (ETS) in
STARTVerso 4
Treatment-naïve
Relapser
100
Proportion of patients (%)
88
80
missing for 4 patients.
ETS, early treatment success
a
ETS criteria:
Wk 4 HCV RNA <LLoQ,
+ Wk 8 <LLOQ, TND
60
YES
40
20
184/
239
0
aData
77
61/
69
50% Stop treatment at week 24
50% continue with pegIFN/RBV
through week 48
Summary and conclusions
• AEs were comparable to those with faldaprevir and pegIFN/RBV
in HCV mono-infected patients
• ETS was observed in 80% of patients
‒ Half of these patients will stop treatment at Week 24
• 12-week data show high rates of early virologic response to
faldaprevir + pegIFN/RBV
Overall reductions in HCV RNA
Week 4 <LLoQ :
Week 12 <LLoQ TND:
Treatment-naïve
80%
82%
Relapsers
91%
91%
• Interim data compare well with early response rates in
mono-infected patients
• Sustained virologic response data will be used to determine the
feasibility of response-guided therapy with faldaprevir
Acknowledgments
•
Patients, and study investigators and site staff at 67 study centers:
Brazil
•
•
Josep Mallolas
Chloe Orkin
Marina Nunez
Carlos Eduardo Brandão Mello Arastéh Keikawus
Juan Antonio Pineda
Alison Uriel
Gerald Pierone
Raymundo Ferreira Filho
Hartwig Klinker
Daniel Podzamczer
United States
Michael Saag
Paulo Ferreira
Jürgen Kurt Rockstroh
Cristina Tural
John Baxter
Michael Somero
Juvencio Furtado
Italy
Jorge Vergas
Maurizio Bonacini
Richard Sterling
Beatriz Grinsztejn
Giacchino Angarano,
Switzerland
Cynthia Brinson
Mark Sulkowski
Jose Madruga
Andrea Antinori
Manuel Battegay
Douglas Dieterich
Andrew Talal
France
Giovanni Di Perri
Enos Bernasconi
Richard Elion
Kristen Marks
Marc Bourliere
Gaetano Filice
Jan Fehr
Jerome Ernst
Laurent Cotte
Francesco Mazzotta
Andri Rauch
Douglas G. Fish
Pierre-Marie Girard
Paola Nasta
United Kingdom
Federico Hinestrosa
Caroline Lascoux-Combe
Massimo Puoti
Kosh Agarwal
Mamta Jain
Marc-Antoine Valantin
Spain
Sanjay Bhagani
Anthony LaMarca
Germany
Francisco Blanco
Martin Fisher
Eric Lawitz
Johannes Bogner
Manuel Crespo,
Ranjababu Kulasegaram Cheryl McDonald
Christian Hoffmann
Josep Guardiola
Clifford Leen
Karam Mounzer
Patrick Ingiliz
Juan Carlos Lopez
Mark Nelson
Ronald Nahass
Hans Jäger
Boehringer Ingelheim for sponsoring the study and the Boehringer Ingelheim
1220.19 team
The external Data Monitoring Committee