THU-193
DIFFERENTIAL REDUCTIONS IN VIRAL ANTIGENS EXPRESSED
FROM CCCDNAVS INTEGRATED DNA IN TREATMENT NAÏVE HBEAG
POSITIVE AND NEGATIVE PATIENTS WITH CHRONIC HBVAFTER
RNA INTERFERENCE THERAPY WITH ARC-520
M.-F. Yuen1, H.L.Y. Chan2, K. Liu1, B.D. Given3, T. Schluep3, J. Hamilton3,
C.-L. Lai1, S.A. Locarnini4, J.Y.N. Lau1,5, C. Ferrari6, R.G. Gish7,8. 1The
University of Hong Kong; 2The Chinese University of Hong Kong, Hong
Kong, China; 3Arrowhead Research Corporation, Pasadena, United
States; 4Victorian Infectious Diseases Reference Laboratory, Victoria,
Australia; 5Hong Kong Polytechnic University, Hong Kong, China;
6University of Parma, Parma, Italy; 7Stanford University, Palo Alto;
8Hepatitis B Foundation, Doylestown, United States
E-mail: [email protected]
Background and Aims: ARC-520 (ARC), a RNA interference drug,
targets cccDNA-derived mRNA in chronic hepatitis B patients (CHB);
we previously reported safety and activity of ARC in entecavir (ETV)
experienced CHB and preliminary results in treatment-naïve CHB
enrolled in a single dose phase 2a study; herein we report full safety
and activity against multiple viral antigens and DNA in naïve CHB.
Methods: 58 CHB (48 ARC, 10 placebo) were accrued to 7 cohorts, of
which 46 were ETV experienced and 12 (6 HBeAg-neg, 6 HBeAg-pos)
were treatment naïve. Naïve CHB received a single IV dose of 4 mg/kg
ARC and started daily oral ETV on the same day. Viral DNA and
antigen knockdown (KD) were measured over 85 days [qHBsAg, HB
core-related antigen (qHBcrAg) in all, qHBeAg in HBeAg-pos].
Results: ARCwaswell tolerated – 23% reported a mild or mod adverse
event (AE) with no AE rated serious, severe, drug-related or causing
withdrawal. For naïve CHB, 5 of 6 HBeAg-neg and 1 of 6 HBeAg-pos
achieved HBV DNA BLOQ within a mean of 11 days. HBeAg-pos above
LLOQ had a max DNA reduction of 5.0 log (mean max 4.2). Two
distinct patterns of qHBsAg KD were seen: an immediate, direct ARC
antiviral effect in 5/6 HBeAg-pos and a delayed response several
weeks after treatment in 5/6 HBeAg-neg. One transitional CHB
became HBeAg neg early during therapy and had an intermediate
qHBsAg response. In HBeAg-pos maximum reduction of antigenswas
1.9 log (mean max 1.5) for qHBsAg, 1.8 log (mean max 1.4) for
qHBcrAg, and 2.0 log (mean max 1.6) for qHBeAg. In HBeAg-neg
max reductionwas 0.4 log (mean max 0.3) for qHBsAg. 5 of 6 HBeAgneg
had HBcrAg BLOQ; 1 with measurable levels had a 0.7 log
decline. Duration of qHBsAg decline was >57 days after a single dosein all CHB.
Conclusions: 1) ARC was well tolerated 2) ARC + ETV acted
synergistically to produce rapid DNA suppression 3) ARC effectively
inhibited cccDNA-derived mRNAwith protein KD up to 2.0 logs (99%)
observed 4) In HBeAg-pos naïve CHB all viral antigens were
effectively suppressed, while in HBeAg-neg less KD in qHBsAg was
observed compared to qHBcrAg. 5) These findings are consistent with
more cccDNA-driven antigen production in naïve HBeAg-pos and a
higher fraction of qHBsAg production from integrated DNA in HBeAgneg
6) These variations in viral protein KD are consistent with ARC
data from chimps showing higher fractions of integrated DNAderived
viral mRNA in HBeAg-neg 7) Chronic ARC studies aimed at
producing HBsAg seroclearance are ongoing.