ARC520 Late-breaker at AASLD 2015

[StephenCastlecrag]

LB-9
ARC-520 produces deep and durable knockdown of
viral antigens and DNA in a phase II study in patients
with chronic hepatitis B
Man-Fung Yuen1, Henry Lik-Yuen Chan2
, Sze Hang Kevin Liu1, Bruce Given3, Thomas Schluep3, James Hamilton3, Ching-Lung Lai1, Stephen Locarnini4, Johnson Y. Lau5, Carlo Ferrari6, Robert Gish7,8
; 1The University of Hong Kong, Hong Kong, China;
2The Chinese University of Hong Kong, Hong Kong, China;
3Arrowhead Research Corp., Pasadena, CA;
4Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia;
5Hong Kong Polytechnic University, Hong Kong, China;
6University of Parma, Parma, Italy;
7Stanford University, Palo Alto, CA;
8Hepatitis B Foundation, Doylestown, PA
Chronic hepatitis B (CHB) has become an important target for drug development. ARC-520 (ARC), the first RNA interference-based drug to reach patients (pts), targets ccc-DNA-derived mRNA; herein we report results in CHB.
Methods:
58 CHB pts (48 ARC, 10 placebo (PL), mean age 41 yrs (range 23-59) were included. 38 pts were HBeAg-neg and 20 HBeAg-pos. At entry, 32 of 38 HBeAg-neg and 14 of 20 HBeAg-
pos had taken entecavir (ETV) for mean of 5 yrs (range 2-8) and were on ETV throughout the study. 12 treatment naïve pts
(6 HBeAg-neg, 6 HBeAg-pos) started on ETV during the trial.
All pts received a single dose IV of ARC or PL (6 HBeAg-pos received a divided dose of ARC separated by 2 wks) and had viral parameter knockdown (KD) measured over 85 days [qHBsAg, HB core-related antigen (qHBcrAg) and viral DNA in all, qHBeAg in HBeAg-pos]. Doses were 1-4 mg/kg in HBeAg-neg. All HBeAg-pos received 4 mg/kg. 15 pts are continuing in follow-up.
Results:
ARC therapy was well tolerated - 23%
reported a mild or mod adverse event (AE) with no AE rated serious, severe, drug-related or causing withdrawal from the trial. Viral DNA was below level of quantitation in all chronic ETV pts at study entry. Naïve pts reduced viral DNA up to 4.3
log (mean 2.2 log) after ARC and ETV. ARC reduced viral antigens with qHBeAg best KD of 1.7 log (mean max 1.2 log)
following a single 4 mg/kg dose. In naïve pts, best qHBsAg KD of 1.9 log (mean max 1.1 log) in HBeAg-pos and 0.7 log
(mean max 0.2 log) in HBeAg-neg were observed. qHBcrAg showed a dose response in HBeAg-neg with best KD at 1 mg/kg of 0.18 log (mean max 0.15 log) and 1.1 log (mean max 0.9 log) with 4 mg/kg. HBeAg-pos showed best KD of 1.1 log
(mean max 0.92 log). The qHBsAg dose response was less deep in chronic ETV pts with best observed reduction of 0.3
log (mean max 0.2 log) observed at 1 mg/kg vs 0.5 log (mean max 0.4 log) at 4 mg/kg in HBeAg-neg. Best qHBsAg KD in
chronic ETV treated HBeAg-pos was 0.7 log (mean max 0.3 log). Divided doses at 4 mg/kg did not increase antigen KD.
Duration of qHBsAg KD was typically 8 wks with 2 distinct KD patterns of qHBsAg seen: an immediate, direct ARC antiviral effect (~70% of pts) and a delayed response several weeks after treatment (~30% of pts).
Conclusions:
1) These findings are consistent with more cccDNA-driven antigen production
in HBeAg-pos. 2) ARC was well tolerated 3) ARC effectively inhibited cccDNA-derived mRNA with protein KD up to 1.9
logs (99%) observed 4) These variations in viral protein KD are consistent with ARC data in chimps and previously reported
chronic ETV reductions in pts for cccDNA 5) Chronic ARC studies aimed at producing HBsAg seroclearance are underway.

Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline,
Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer,
GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD, Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and Teaching: Echosens
Bruce Given - Employment: Arrowhead Research Corp; Stock Shareholder: Icon plc
Thomas Schluep - Employment: Arrowhead Research Corp.
James Hamilton - Employment: Arrowhead Research Corp
Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc;
Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc
Stephen Locarnini - Consulting: Gilead, Arrowhead; Employment: Melbourne Health
Johnson Y. Lau - Advisory Committees or Review Panels: Arrowhead Research;
Management Position: Kinex Pharmaceuticals, Avalon BioMedical Management; Speaking and Teaching: Hong Kong Polytechnic University, University of Hong Kong, Southwestern Hospital
Carlo Ferrari - Advisory Committees or Review Panels: Gilead, Roche, Abbvie, BMS, Merck, Arrowhead; Grant/Research Support: Gilead, Roche, Janssen
Robert Gish - Advisory Committees or Review Panels: Gilead, AbbVie, Arrowhead; Consulting: Eiger, Isis, Genentech; Speaking and Teaching: Gilead, AbbVie; Stock Shareholder: Arrowhead
The following people have nothing to disclose: Sze Hang Kevin Liu

[Royal36]

Ufff what a complicated disease we have!

[studyforhope]

The hbsag reductions seem way to small to achieve the hopeful immune activation by elimination of surface antigen. I wish they would report absolute levels after KD, it would be more obvious to estimate this possibility.
replicors trials showed that a reduction below 1 iU/ml is needed to have a strong effect.
The reduction of the other proteins is interesting. If core formation could be inhibited this way, then a synergistic action with antivirals might be possible, to reduce reinfection rate, just like one could hope for the capsid inhibitors. This apparantly did not happen to a meaningful extent in the chimp multi dosing study.

Fundamentally,  the inhibition of viral proteins will reduce viral activity and related immune action while on drug, which was also shown in the chimp model, with alt lowering. But from the point of view to achieve the functional cure, switching off the viral proteins also removes the epitopes and other signals that a cell is infected. This should lead to less recognition and elimination of infected cells. Therefore,  after ending therapy,  rebound and not cure is likely. That is exactly what happened to the chimps that were treated for almost a year, they rebounded back into the billion virions per ml quite quickly, as can be seen by Christine  woodells poster at the molecular biology meeting a few weeks ago, available at the arrowhead website. One e ag positiv chimp seroconverted in the entecavir pretreatment phase.

I also heard that the side effects were quite intense inflammation, with the need to give steroids to mitigate those. This would not be good in terms of inducing immune mediated clearing, as is hoped for.

[sorte]

StephenCastlecrag: is ARC521 ready for the trials or for now it's just the concept ?

[March06]

we are tired of "produces deep and durable
knockdown of blah blah "                                                           so far this hbv community support  produces more HBsag loss  than all these trials.

[StephenCastlecrag]

Results are similar to those in chimps. In chimps, they tried ARC521 in HbeAg negative chimps and obtained better knock down. Of course, they have not yet tried ARC521 in HbeAg negative human patients.
The big question remains whether their explanation about high level of hbvdna integration holds water?
But I am impressed that Carlo Ferrari is part of their team.

[Aduiski]

It seems to me worser results than for chimps at least for hbeag - people...mean max reduction of hbsag of 0.2-0.3 logs after a single dose. Repeating doses shall increase hbsag knockdown but not much, maybe 0.4 at its nadir from the baseline (that's on average but some will benefit more).

Combining this with both entecavir and interferon, as it will be done in the announced trial, shall help those who are need an extra little push to clear the virus, but in my own estimate won't help the majority.

above relates to hbeag -

What are your thoughts Steven, studyforhope?

[StephenCastlecrag]

Carlo Ferrari is one of the authors.