studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 225A
vitro, using reporter constructs representative of genotypes A-J.
In HepG2.2.15 cells, ALN-HBV mediates viral transcript silencing
with ED 50
s of 12-19 pM, as determined for amplicons in
the P and S ORFs. In vivo, in an AAV-HBV mouse model, a
single 3 mg/kg SC dose of ANL-HBV resulted in mean 1.6
log 10
reduction in plasma HBsAg (3.6 log 10
max reduction) at
10-15 days post dosing. After 3 weekly doses of 3 mg/kg SC,
mean HBsAg silencing >2.9 log 10
was observed, with several
animals being below the level of quantitation (100 days after the last dose.
In vitro metabolic stability, and mouse and rat pharmacokinetics
and liver exposure were consistent with ESC chemistry
which enables the long-lived pharmacologic response. Exploratory
toxicology and histopathology were performed in rats
sacrificed 24 hr after 3 weekly doses of 30 and 100 mg/kg
SC, and revealed excellent tolerability. Additional pharmacology
studies are in progress, including combination studies
with ALN-PDL, an RNAi drug targeting PD-L1 in hepatocytes.
ALN-PDL is expected to result in augmentation of HBV-specific
cellular immunity in the liver, thereby improving immunological
control of HBV infection locally, while avoiding the immunotoxicity
of systemic immune checkpoint blockade. Conclusion:
ALN-HBV is a single, hepatocyte-targeted siRNA conjugate
targeting a highly conserved region in the HBV genome. It
mediates specific, potent and durable silencing of HBV viral
transcripts and HBsAg expression. ALN-HBV is being developed
as finite treatment in combination with standard-of-care
nucleos(t)ide analogs as a means for inducing a functional cure
in CHB patients. A CTA filing is planned for late 2015.
Disclosures:
Laura Sepp-Lorenzino - Employment: Alnylam
Andrew G. Sprague - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Tuyen M. Nguyen - Employment: Alnylam Pharmaceutical; Stock Shareholder:
Alnylam Pharmaceutical
Svetlana Shulga Morskaya - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Stuart Milstein - Employment: Alnylam
Greg Hinkle - Employment: Alnylam Pharmaceuticals
Richard G. Duncan - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Krishna C. Aluri - Employment: Alnylam Pharmaceuticals
Husain Attarwala - Employment: Alnylam Pharmaceuticals
Renta M. Hutabarat - Employment: Alnylam Pharmaceuticals
Ju Liu - Employment: Alnylam
Benjamin S. Brigham - Employment: Alnylam Pharmaceuticals
Akin Akinc - Employment: Alnylam Pharmaceuticals
Klaus B. Charisse - Employment: Alnylam Pharmaceuticals
Vasant Jadhav - Employment: Alnylam Pharmaceuticals
Satya Kuchimanchi - Employment: Alnylam Pharmaceuticals
Martin A. Maier - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Muthiah Manoharan - Employment: Alnylam
Rachel Meyers - Employment: Alnylam Pharmaceuticals
Haroon Hashmi - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Daniel Freedman - Employment: Alnylam Pharmaceuticals
Tanya P. Sengupta - Employment: Alnylam Pharmaceuticals
Karin Galil - Consulting: Alnylam Pharmaceuticals
Eoin Coakley - Employment: AbbVie; Stock Shareholder: AbbVie
Patrick Haslett - Employment: Alnylam Pharmaceuticals
The following authors have nothing to disclose: Tara Mayo, Huilei Xu, Pia
Kasperkovitz, Natalie Keirstead, Brenda Carito, Lauren Moran, Prasoon
Chaturvedi, Chris Tran, Qianfan Wang, Tadeusz Wyrzykiewicz, Julie Donovan,
Tim Mooney
37
Safety and efficacy of daclatasvir plus sofosbuvir with
or without ribavirin for the treatment of chronic HCV
genotype 3 infection: Interim results of a multicenter
European compassionate use program
Tania M. Welzel 1 , Joerg Petersen 2 , Peter Ferenci 3 , Michael
Gschwantler 4 , Kerstin Herzer 5 , Markus Cornberg 6 , Eckart Schott 7 ,
Thomas Berg 8 , Ulrich Spengler 9 , Ola Weiland 10 , Marc van der
Valk 11 , Andreas Geier 12 , Jürgen K. Rockstroh 9 , Markus Peck-Radosavljevic
3 , Yue Zhao 13 , Maria Jesus Jimenez Exposito 14 , Stefan
Zeuzem 1 ; 1 Universitätsklinikum der Johann Wolfgang Goethe
Universität, Frankfurt, Germany; 2 IFI Institut für Interdisziplinäre
Medizin, Hamburg, Germany; 3 Medizinische Universität Wien,
Vienna, Austria; 4 Wilhelminenspital, Vienna, Austria; 5 Universitätsklinikum
Essen (AöR), Essen, Germany; 6 Medizinische
Hochschule Hannover, Hannover, Germany; 7 Charité Universitätmedizin
Berlin, Berlin, Germany; 8 Universitätsklinikum Leipzig,
Leipzig, Germany; 9 Universitätsklinikum Bonn, Bonn, Germany;
10 Karolinska Institutet, Solna, Sweden; 11 Academic Medical Center,
Amsterdam, Netherlands; 12 Universitätsklinikum Würzburg,
Würzburg, Germany; 13 Bristol-Myers Squibb, Hopewell, NJ;
14 Bristol-Myers Squibb, Princeton, NJ
BACKGROUND: Despite progress in the development of well
tolerated, all-oral, interferon-free therapies, the treatment of
HCV genotype (GT) 3 infection remains challenging. Current
treatment options are limited, and debate continues regarding
the optimal regimen and duration of treatment, especially for
treatment-experienced patients with liver cirrhosis. Here we
report interim results on the combination daclatasvir (DCV) plus
sofosbuvir (SOF) with or without ribavirin (RBV) for the treatment
of GT3-infected patients from a European compassionate use
program (CUP). METHODS: This CUP enrolled adult patients
with chronic HCV infection who were at a high risk of hepatic
decompensation or death within 12 months if left untreated,
and who had no available treatment options. Patients received
DCV 60mg + SOF 400mg QD, with RBV added at the physician’s
discretion. Recommended duration of treatment was
24 weeks. This interim analysis includes 101 GT 3-infected
patients enrolled in the CUP with available data on March 16,
2015, of whom 24 patients have available SVR12 data to
date. RESULTS: Most patients were male (68%), white (90%);
median age: 54 years (31–75). Fifty-nine (58%) were treatment
experienced. Most patients had cirrhosis (81%); 46 of them
(56%) were Child-Pugh class B/C; and 13 (16%) had MELD
scores ≥15. Seven patients were liver transplant recipients; 15
were HIV/HCV coinfected. Median baseline HCV RNA was
5.6 log 10
IU/mL. Overall, SVR12 rates among GT3-infected
patients with HCV RNA available data were 92% (22/24).
One patient meets criteria for relapse. SVR12 rates among
sub-groups are presented in the Table. Updated SVR12 data
will be presented. Twenty-two patients experienced at least one
serious adverse event (AE); 5 patients discontinued therapy due
to AEs (pneumonia/multi-organ failure, physical deterioration,
hepatic encephalopathy, syncope, undetermined); 2 patients
died (multi-organ failure, liver related). CONCLUSION: In this
preliminary analysis, DCV in combination with SOF±RBV led
to high SVR12 rates in HCV GT3-infected patients, regardless
of cirrhosis status, and was well tolerated. The use of RBV did
not affect efficacy outcomes.