HAYWARD, Calif., Feb. 24, 2021 /PRNewswire/ --
Highlights from the Interim Analysis:
- Biologically significant, highly-consistent, dose-dependent
levels of BB-301 tissue transduction (i.e. delivery of the
multi-functional genetic construct into the target pharyngeal
muscle cells)
-
- BB-301 copy numbers ranging from 1.7 copies per cell up to 8.6
copies per cell were achieved in the respective pharyngeal muscles
after a single administration of increasing doses of BB-301
- Durable, broad-based, dose-dependent expression within the
pharyngeal muscle cells of the three distinct genes comprising the
BB-301 gene construct (i.e., siRNA13, siRNA17, and codon optimized
PABPN1)
- Durable and biologically significant levels of target gene
knock-down (i.e., inhibition of the expression of the gene of
interest) within the pharyngeal muscle cells
-
- Low-Dose, Intermediate-Dose, and High-Dose BB-301
administration achieved similar levels of inhibition, with an
average of 74% inhibition of PABPN1 expression observed across all
doses
- BB-301 has been evaluated in prior non-clinical studies in
animals that express mutant PABPN1 and manifest the key signs and
symptoms of Oculopharyngeal Muscular Dystrophy (OPMD) and, in these
animal models of OPMD, the achievement of PABPN1 silencing levels
of 31% inhibition or higher led to complete resolution of OPMD
disease symptoms and correction of the histological hallmarks of
OPMD
- Finally, it is critical to highlight the key distinctions
between the current BB-301 Pilot Dosing Study in Beagle dogs
conducted by Benitec and the prior Beagle dog dosing study carried
out independently by the previous BB-301 licensee of Benitec
-
- The Benitec team optimized the route and method of
administration for BB-301 and refined the core analytical methods
employed following the completion of dosing
- Following these methodological improvements, Benitec
demonstrated a 248-fold improvement (+24,650%) and a 111-fold
improvement (+11,027%) in BB-301 transduction of the two key
pharyngeal muscles relative to the levels of BB-301 transduction
observed in the analogous Beagle dog study conducted by the
previous BB-301 licensee
- Benitec has scheduled a Scientific Advice Meeting in
France in May 2021 to review the interim data and the Phase
1 clinical trial design, and the Company continues to plan for the
initiation of the first-in-human clinical study of BB-301 in OPMD
patients in 2022
- Robust validation of Benitec's proprietary
"Silence-and-Replace" approach has been achieved
-
- The data derived from the interim analysis validate the promise
of the "Silence-and-Replace" approach to disease management, and
Benitec plans to provide additional pipeline updates in 2H
2021
Benitec Biopharma Inc. (NASDAQ: BNTC), a development-stage
biotechnology company focused on the advancement of novel genetic
medicines, today announced the successful results of the interim
analysis of the BB-301 Pilot Dosing Study. In addition to the
data summarized below, please see the accompanying slide
presentation available at www.benitec.com and accessible here.
The proprietary DNA-directed RNA interference (ddRNAi) platform
combines RNA interference (RNAi) with classical AAV-based gene
therapy. Through the use of the ddRNAi platform Benitec's
goal is to create genetic medicines that, following a single
administration, will enable target tissues to perpetually produce
siRNA molecules which facilitate the sustained silencing of
disease-causing genes. Importantly, the ddRNAi platform also
allows for concomitant delivery of wild type replacement genes, and
these distinct genetic elements work in concert to silence the
expression of disease-causing mutant genes and to simultaneously
replace the mutant genes with normal (wild type) genes to restore
the natural underlying physiology of the diseased tissues.
BB-301, the most advanced genetic medicine currently under
development by Benitec, employs the proprietary platform, which
allows for a "Silence and Replace" approach to the treatment of
Oculopharyngeal Muscular Dystrophy (OPMD).
BB-301 is a first-in-class genetic medicine employing the
"Silence and Replace" approach for the treatment of OPMD.
OPMD is a chronic, life-threatening genetic disorder affecting
approximately 15,000 patients in the
United States, Canada,
Western Europe, and Israel.
OPMD is caused by a mutation in the gene encoding poly(A) binding
protein nuclear 1 (PABPN1). Patients with OPMD lose the
ability to swallow liquids and solids, and the natural history of
the disorder is characterized by chronic malnutrition, aspiration,
and fatal episodes of aspiration pneumonia. Currently, no
therapeutic agents are approved for the treatment of OPMD.
Additionally, no surgical interventions capable of altering the
long-term natural history of OPMD are available. BB-301 has
received Orphan Drug Designation in the
United States and the European Union which provides
commercial exclusivity (independent of intellectual property
protection) and opportunities for efficient pathways for regulatory
review and approval. While OPMD is a rare (Orphan) disorder,
the commercial opportunity for a safe and efficacious therapeutic
agent in this indication exceeds $1
billion over the course of the commercial life of the
product.
Benitec has previously outlined the core IND-enabling studies
required by global regulatory agencies to support the initiation of
BB-301 clinical trials in OPMD patients, and these IND-enabling
studies include a BB-301 Pilot Dosing Study in large animals and a
classical 12-week GLP Toxicology and Biodistribution Study. BB-301
is directly injected into the pharyngeal muscles known to underlie
the morbidity and mortality characterizing the natural history of
OPMD. Against this backdrop, the BB-301 Pilot Dosing Study in
large animal subjects was conducted to demonstrate that direct
intramuscular injection of BB-301 via the use of a proprietary
dosing device in an open surgical procedure could safely achieve
the following goals:
- Biologically significant, highly-consistent, dose-dependent
levels of BB-301 tissue transduction (i.e., delivery of the
multi-functional genetic construct into the target pharyngeal
muscle cells)
- Durable, broad-based, dose-dependent expression within the
pharyngeal muscle cells of the three distinct genes comprising the
BB-301 gene construct
- Durable and biologically significant levels of target gene
knock-down (i.e., inhibition of the expression of the gene of
interest) within the pharyngeal muscle cells
The Pilot Dosing Study evaluated the safety and biological
activity of two concentrations of BB-301 (1.0+E13 vg/mL and 3.0+E13
vg/mL) across three distinct doses (1.0+E13 vg/mL, 3.0+E13 vg/mL
with a low injection volume, and 3.0+E13 vg/mL with a high
injection volume) following direct intramuscular injection into the
Hypopharyngeus (HP) muscles and the Thyropharyngeus (TP) muscles of
Beagle dogs via the use of a proprietary delivery device employed
in an open surgical procedure. The HP muscle in Beagle dogs
corresponds to the Middle Pharyngeal Constrictor muscle in Human
subjects, and the TP muscle in Beagle dogs corresponds to the
Inferior Pharyngeal Constrictor muscle in Human subjects. BB-301
was injected only on Day 1 of the Pilot Dosing Study, and the
corresponding canine pharyngeal muscles were harvested for analysis
after 8 weeks on study. BB-301 dosing was carried out by both
a veterinary surgeon and a practicing Otolaryngologist who has
extensive experience with the provision of palliative surgical care
for OPMD patients.
Further data analyses are ongoing for the canine subjects
treated in the BB-301 Pilot Dosing Study, and the interim
data-points highlighted today are derived from completed analyses
of pharyngeal muscle tissues isolated from the 6 Beagle dog
subjects to date (of the 24-subject study population). The
data-set and the initial conclusions will be updated as additional
subjects are analyzed. The key preliminary results are
summarized at the end of this announcement.
Finally, it is critical to highlight the key methodological
distinctions between the current BB-301 Pilot Dosing Study in
Beagle dogs conducted by Benitec and the prior Beagle dog dosing
study carried out independently by the previous BB-301 licensee of
Benitec. The BB-301 dosing study conducted by the prior
BB-301 licensee employed non-ideal routes and methods of BB-301
administration to the target pharyngeal muscle tissues and employed
similarly limited analytical methods at the completion of the
dosing phase of the study. The Benitec team worked to
optimize the route and method of administration of BB-301 and to
refine the core analytical methods employed following the
completion of dosing.
Following these methodological improvements, Benitec
demonstrated a 248-fold improvement (+24,650%) in BB-301
transduction of the HP muscle and a 111-fold improvement (+11,027%)
in BB-301 transduction of the TP muscle relative to the levels of
BB-301 transduction observed by the previous BB-301 licensee.
Benitec has scheduled a Scientific Advice Meeting in
France in May 2021 to review the interim data and the Phase
1 clinical trial design, and the Company continues to plan for the
initiation of the first-in-human clinical study of BB-301 in OPMD
patients in 2022. The interim data validate the promise of the
"Silence and Replace" approach to disease management, and Benitec
plans to provide additional pipeline updates in 2H2021.
Preliminary Results of the Pilot Dosing Study:
Regarding Pharyngeal Muscle Tissue Transduction Levels
Observed for BB-301:
In the HP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved a vector copy number
of 1.7 copies per cell
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved a
vector copy number of 3.5 copies per cell
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved a vector
copy number of 7.2 copies per cell
In the TP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved a vector copy number
of 2.0 copies per cell
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved a
vector copy number of 2.3 copies per cell
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved a vector
copy number of 8.6 copies per cell
Regarding Gene Expression Levels Observed for BB-301 Within
the Pharyngeal Muscle Tissues:
BB-301 encodes 2 distinct siRNA species (i.e. siRNA13 and
siRNA17) which are each, independently, capable of inhibiting (i.e.
"silencing") the expression of the mutant form of the PABPN1
protein and the wild type (i.e. endogenous) form of the PABPN1
protein (importantly, the mutant form of the PABPN1 protein
underlies the development and progression of OPMD)
BB-301 also codes for a wild type version of the PABPN1
protein whose intracellular expression is unaffected by the
inhibitory activities of siRNA13 and siRNA17, and this codon
optimized PABPN1 protein (i.e. coPABPN1) serves to replenish the
endogenous form of the PABPN1 protein and to replace the mutant
form of PABPN1 that underlies the development and progression of
OPMD in diseased tissues
For comparative purposes, is should be noted that the average
level of expression for wild type PABPN1 within the pharyngeal
muscle cells of Beagle dogs is 4.5 copies per cell to 7.8 copies
per cell
In the HP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved siRNA13, siRNA17, and
coPABPN1 copy numbers of 161,358 copies per cell, 26,652 copies per
cell, and 21 copies per cell, respectively
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved
siRNA13, siRNA17, and coPABPN1 copy numbers of 256,928 copies per
cell, 47,944 copies per cell, and 24 copies per cell,
respectively
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved siRNA13,
siRNA17, and coPABPN1 copy numbers of 374,324 copies per cell,
57,126 copies per cell, and 52 copies per cell, respectively
In the TP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved siRNA13, siRNA17, and
coPABPN1 copy numbers of 195,182 copies per cell, 40,106 copies per
cell, and 15 copies per cell, respectively
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved
siRNA13, siRNA17, and coPABPN1 copy numbers of 293,597 copies per
cell, 57,969 copies per cell, and 43 copies per cell,
respectively
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved siRNA13,
siRNA17, and coPABPN1 copy numbers of 751,484 copies per cell,
173,211 copies per cell, and 100 copies per cell, respectively
Regarding Wild Type PABPN1 Silencing (i.e. target
"knock-down") Observed for BB-301 Within the Pharyngeal Muscle
Tissues:
As noted above, BB-301 encodes 2 distinct siRNA species (i.e.
siRNA13 and siRNA17) which are each, independently, capable of
inhibiting (i.e. "silencing") the expression of all forms of the
PABPN1 protein (siRNA13 and siRNA17 silence the expression of both
wild type PABPN1 [wtPABPN1] and mutant PABPN1)
While the Beagle dog subjects treated in the current BB-301
Pilot Dosing Study do not express mutant PABPN1, the level of
BB-301-driven gene silencing for the PABPN1 target can be
accurately assessed due to the equivalent inhibitory effects of
siRNA13 and siRNA17 on both wtPABPN1 and mutant PABPN1
Thus, the wtPABPN1 silencing activity observed in the current
BB-301 Pilot Dosing Study serves as a surrogate for the activity
that would be anticipated in the presence of mutant PABPN1
BB-301 has been evaluated in prior non-clinical studies in
animals that express mutant PABPN1 and manifest the key signs and
symptoms of OPMD and, in these animal models of OPMD, the
achievement of PABPN1 silencing levels of 31% inhibition or higher
led to complete resolution of OPMD disease symptoms and correction
of the histological hallmarks of OPMD
In the HP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved 74% inhibition of
wtPABPN1 expression
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved
80% inhibition of wtPABPN1 expression
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved 78%
inhibition of wtPABPN1 expression
In the TP muscle:
- Low-Dose BB-301 (1.0E+13 vg/mL) achieved 72% inhibition of
wtPABPN1 expression
- Intermediate-Dose BB-301 (3.0E+13 vg/mL, low volume) achieved
61% inhibition of wtPABPN1 expression
- High-Dose BB-301 (3.0E+13 vg/mL, high volume) achieved 79%
inhibition of wtPABPN1 expression
About Benitec Biopharma, Inc.
Benitec Biopharma, Inc. ("Benitec" or the "Company") is a
development-stage biotechnology company focused on the advancement
of novel genetic medicines with its headquarters in Hayward, California. The proprietary platform,
called DNA-directed RNA interference, or ddRNAi, combines RNA
interference, or RNAi, with gene therapy to create medicines that
facilitate sustained silencing of disease-causing genes following a
single administration. The Company is developing ddRNAi-based
therapeutics for chronic and life-threatening human conditions
including Oculopharyngeal Muscular Dystrophy (OPMD), and Chronic
Hepatitis B. A comprehensive overview of the Company can be found
on Benitec's website at www.benitec.com.
Forward Looking Statements
Except for the historical information set forth herein, the
matters set forth in this press release represent forward-looking
statements, including statements regarding BB-301, Benitec's plans
to develop and commercialize its product candidates, the timing of
the initiation and completion of preclinical and clinical trials,
the timing of patient enrolment and dosing in clinical trials, the
timing of expected regulatory filings, the clinical utility and
potential attributes and benefits of ddRNAi and Benitec's product
candidates, potential future out-licenses and collaborations, the
intellectual property position and the ability to procure
additional sources of financing, and other forward-looking
statements. In addition, preliminary results or other preliminary
analyses do not in any way ensure that later or final results in a
clinical trial or in similar clinical trials will replicate those
interim results.
These forward-looking statements are based on the Company's
current expectations and subject to risks and uncertainties that
may cause actual results to differ materially Some of the
risks and uncertainties that may cause our actual results,
performance or achievements to differ materially from those
expressed or implied by forward-looking statements include the
following:
- the success of our plans to develop and potentially
commercialize our product candidates;
- the timing of the initiation and completion of preclinical
studies and clinical trials;
- the timing of the availability of data from clinical
trials;
- the timing and outcome of regulatory filings and
approvals;
- unanticipated delays;
- sales, marketing, manufacturing and distribution
requirements;
- market competition and the acceptance of our products in the
marketplace;
- regulatory developments in the United
States;
- the development of novel AAV vectors;
- the plans of licensees of our technology;
- the clinical utility and potential attributes and benefits of
ddRNAi and our product candidates;
- the timing and sufficiency of patient enrollment and dosing in
any future clinical trials;
- including the potential duration of treatment effects and the
potential for a "one shot" cure;
- our dependence on our relationships with collaborators and
other third parties;
- expenses, ongoing losses, future revenue, capital needs and
needs for additional financing;
- the length of time over which we expect our cash and cash
equivalents to be sufficient to execute on our business plan;
- our intellectual property position and the duration of our
patent portfolio;
- the impact of local, regional, and national and international
economic conditions and events; and
- the impact of the current COVID-19 pandemic, the
disease caused by the SARS-CoV-2 virus, which
may adversely impact our business and preclinical and future
clinical trials;
as well as other risks detailed under the caption "Risk Factors"
in our reports filed with the SEC from time to time. Any
forward-looking statements in this release speak only as of the
date on which it was made. We undertake no obligation to publicly
update or revise any forward-looking statement, whether as a result
of new information, future events or otherwise.
Media & Investor Relations Contact:
Jay A. Morakis
CEO of M Group Strategic Communications (for Benitec Biopharma,
Inc.)
Phone: 646-859-5951
Email: jmorakis@mgroupsc.com
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