Animal Efficacy Studies
in Chronically-Infected Woodchucks and Clinical Trial Results in
Hepatitis C Patients Provide Support for Targeting RIG-I and NOD2
Sentinel Proteins to Restore Host Antiviral Defense
MILFORD, MA, USA I April 27, 2015 I
Spring Bank Pharmaceuticals, Inc., a clinical-stage biopharmaceutical
company developing novel therapeutics for the treatment of viral
infections, today announced the presentation of scientific data from its
Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) programs at The
International Liver Congress™ 2015, 50th annual meeting of the European Association for the Study of the Liver (EASL), April 22-26, in Vienna, Austria.
"The data presented at EASL on Saturday, April 25,
continue to expand our understanding of the mechanism of action of SB
9200, an oral dinucleotide prodrug derived from our proprietary Small
Molecule Nucleic Acid Hybrid (SMNH) technology platform," stated
Radhakrishnan (Kris) Iyer, Ph.D., Chief Scientific Officer of Spring Bank.
"Our studies demonstrate that SB 9200 activates the cell's innate
immune response triggering Interferon production which causes the death
of the infected cell thereby removing the virus while also providing
protection for uninfected cells. Based on the results reported of a
preclinical study in chronic hepatitis-carrier woodchucks and a Phase I
study in HCV-infected patients, we are excited about the potential of SB
9200 for the treatment of HBV and HCV."
SB 9200 is an oral antiviral agent that uniquely acts by modulating
the host immune response to viral infections through activation of host
antiviral sensor proteins, RIG-I and NOD2. RIG-1 and NOD2 are cytosolic
viral sensors that are important for the regulation of the innate
immune response and activation of intracellular interferon (IFN)
signaling pathways in response to viral RNA. Data presented from a Phase
I clinical study in HCV-infected patients with SB 9200 demonstrate
safety, positive PK/PD characteristics and dose-dependent antiviral
activity consistent with host immune modulation within infected cells.
Data presented from a 12-week study in the chronic woodchuck model of
HBV infection demonstrate significant reductions in viral loads, surface
antigen and cccDNA along with a strong safety profile, suggesting the
potential of SB 9200 as a next generation HBV therapy in combination
with currently available, direct acting HBV antiviral drugs as well as
other agents in development.
"The data presented at EASL continue to build upon a growing body of
scientific evidence supporting the development of SB 9200 in the
treatment in HBV, HCV and other of viral diseases," said Douglas J. Jensen, President and CEO of Spring Bank.
"Collectively, these data are helping to elucidate the underlying
mechanisms that are the foundation for our research and development
efforts with SB 9200. Based on the body of evidence we have assembled to
date, we are advancing SB 9200 into Phase II clinical trials in
patients with HBV this year and evaluating opportunities to partner for
Phase II combination studies in HCV."
A summary of the data presented by Spring Bank at the conference is below:
Poster Presentations
Title: Antiviral Efficacy and Induction of Host
Immune Responses with SB 9200, an Oral Prodrug of the Dinucleotide SB
9000, in the Woodchuck Model of Chronic Hepatitis B Virus (HBV)
Infection
Date and Time: Saturday, April 25, 12:30 pm to 1:00 pm (CEST)
Location: Hall B ePoster Area
Abstract Number: PO636
Session: Viral hepatitis: Hepatitis B & D – c. Clinical (Therapy, new compounds, resistance)
An oral presentation of the poster was made by Dr. Stephan Menne, Research Associate Professor at the Department of Microbiology & Immunology, Georgetown University Medical Center
Summary: The study was a 12-week study in two groups
of woodchucks with chronic woodchuck hepatitis virus (WHV) infection
(the gold standard for HBV drug development). WHV carrier woodchucks
(n=5/group) were treated orally, once daily, with SB 9200 for 12 weeks
at doses of 15 or 30 mg/kg. Endpoints included PK, PD, tolerability, and
efficacy determined by changes in serum levels of viral DNA, surface
antigen (WHsAg), and antibody against WHsAg (anti-WHs). Efficacy in
liver was evaluated by changes in levels of viral DNA, RNA, and
antigens.
Treatment with SB 9200 at two select dose levels resulted in up to
4.2 and 2.2 log10 reductions in serum WHV DNA or WHsAg loads,
respectively, from pretreatment levels. Treatment was also associated
with reduced hepatic levels of WHV DNA replicative intermediate (RI) (up
to 41%), WHV covalently-closed circular (ccc) DNA (up to 32%), and WHV
RNA (up to 50%), lower hepatic expression of WHV core and surface
antigens, and reduced liver disease progression. Following cessation of
SB 9200 treatment, recrudescence of WHV replication was observed in all
woodchucks treated with 15 mg/kg, whereas woodchucks administered 30
mg/kg had delays in the relapse of serum WHV DNA and WHsAg. The
development of an anti-WHs antibody response was not observed in any of
the woodchucks. Furthermore, the antiviral effects were associated with
the dose-dependent induction of type I IFNs (IFN-α and IFN-β), ISGs
(OAS-1, CXCL10, and ISG15), and cytokine (IL-6) in blood and liver.
Prolonged SB 9200 administration at both dose levels was well tolerated
with CBC, hematology and serum biochemistry parameters all appearing
normal through the treatment period.
During this study, once-daily oral administration of SB 9200 in
woodchucks with chronic WHV infection resulted in marked reductions in
serum and hepatic levels of viral DNA, RNA, and antigens that were
associated with (or were a result of) the induction of host immune
responses. These results suggest that SB 9200 can induce an antiviral
immune response during chronic active hepadnaviral infection that has
the potential for a functional cure in the treatment of chronic
hepatitis B, most likely in combination with approved anti-HBV drugs.
Title: SB 9200, A Novel Immunomodulator for Patients with Viral Hepatitis: Phase 1 MAD Study in
Patients with Hepatitis C Virus (HCV) Infection
Date and Time: Saturday, April 25, 2015, 3:30 pm to 4:00 pm (CEST)
Location: Hall B ePoster Area
Session: Late Breaker
Summary: This was a first in man randomized,
placebo-controlled, multiple ascending dose study of SB 9200 in
treatment-naïve, HCV-infected adults. Subjects were randomized 6:2 to SB
9200 or placebo for 7 days. Doses evaluated were 200 mg (N=8), 400 mg
(N=8), 900 mg (N=8 HCV-1, N=6 HCV-3). The results showed that increases
in SB 9200 AUC0-t and Cmax were dose-proportional. The terminal plasma
half-life (t1/2) on Days 1 and 7 ranged from 0.684 to 1.07 hours for SB
9200, and was slightly longer for the metabolites: Sp-SB 9000 t1/2 was
4.65-8.90 hours, Rp-SB 9000 t1/2 was 4.31-5.94 hours. SB 9200 Cmax
ranged from 0.531 to 6.66 ng/mL at 0.817 and 3.00 hours. Sp-SB 9000 Cmax
ranged from 7.13 to 22.0 ng/mL at 1.00 and 12.0 hours. Rp-SB 9000 Cmax
ranged from 4.32 to 14.7 ng/mL at 1.00 and 12.0 hours. Peak individual
viral load drop improved from 1.5 to 1.9 log10 when the dose increased
from 200 to 400 mg. Further dose increases did not result in response
increases. Inter-individual variability in antiviral response was
observed.
A significant relationship between SB 9200 Cmax and maximum
suppression of HCV RNA on Day 7 was observed (p=0.015) after exclusion
of two subjects with extreme Cmax values for SB 9200. Seventy-three
adverse events (AEs) were reported by 25 subjects (83.3%), mostly mild
in severity. No dose limiting toxicities or systemic interferon-like
side effects were observed and no serious adverse events were reported.
There was no relationship between incidences, severity or relationship
of AEs and dose of SB 9200 received or placebo. Results of this study
suggest an anti-viral effect similar to interferon but without systemic
side effects. Based on the reported HCV data, Spring Bank believes SB9200 merits further evaluation in combination trials with direct-acting antivirals (DAAs).
About SB 9200
SB 9200, derived from Spring Bank's
proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology
platform, is a novel anti-viral agent that uniquely acts by modulating
the host immune response to viral infections through activation of the
intracellular sentinel proteins RIG-I and NOD2. SB 9200 is being
developed for the treatment of chronic Hepatitis B and C and other viral
infections.
About Spring Bank Pharmaceuticals
Spring Bank Pharmaceuticals is a clinical stage biopharmaceutical company. Based on its proprietary SMNH chemistry platform, Spring Bank
is developing a pipeline of products representing a new class of
pharmaceuticals with a wide range of applications. These rationally
designed molecules combine the selectivity of naturally occurring
nucleotides with the drug-like properties of classical pharmaceuticals.
The SMNHs have the properties of oral delivery, good pharmacokinetic
profile, low side effects and ease of manufacture. The Company's most
advanced clinical candidate, SB 9200, is a potential breakthrough drug
for the treatment for HBV, HCV and other viral diseases. SB 9200 has a
novel mechanism of action that involves modulation of the host immune
response in the presence of viral infection.
Note Regarding NIH-Funded Research
Certain studies mentioned in this press release were partly supported
by the National Institute of Allergy and Infectious Diseases of the
National Institutes of Health under Award Number R01AI094469 and NIAID
contract laboratories. The content of this press release is solely the
responsibility of Spring Bank Pharmaceuticals and does not necessarily
represent the official views of the National Institutes of Health.
SOURCE: Spring Bank PharmaceuticalsLabels: EASL 2015, SB 9200, Spring Bank