Passage Bio, Inc. (NASDAQ: PASG), a genetic medicines company
focused on developing transformative therapies for rare, monogenic
central nervous system disorders, today announced publication of
data supporting development of its gene therapy PBFTO2 for patients
with frontotemporal dementia caused by mutations in the granulin
gene (FTD-GRN). In the study, a single administration of an
optimized adeno-associated virus (AAV) containing the GRN gene
resulted in elevated levels of progranulin (PGRN) in the brain and
cerebral spinal fluid (CSF), reduced lysosomal storage lesions,
normalized lysosomal enzyme expression and corrected microgliosis
in a mouse model of progranulin deficiency. These data were
published online September 16 in the peer-reviewed scientific
journal Annals of Clinical and Translational Neurology (ACTN).
To identify a vector capable of achieving optimal expression
levels of GRN, the study also evaluated three AAV serotypes (1, 5,
and hu68) in non-human primates. Following a single intra-cisterna
magna (ICM) injection of the AAV-GRN vectors, all non-human
primates, regardless of AAV serotype, showed increased PGRN levels
in the CSF. The injections were also well tolerated across
serotypes. However, a single administration of an optimized
AAV1-GRN vector (PBFT02) showed the greatest CSF expression levels,
reaching more than 50-fold the normal expression level. AAV1 also
appeared to demonstrate extensive transduction of the ependymal
cells that line the ventricles of the brain and are involved in the
production of CSF.
“These findings suggest that the highly transduced ependymal
cells achieved with AAV1 could be the primary source of PGRN in the
CSF, which also could make it the ideal choice for GRN gene
therapy,” said James Wilson, M.D., Ph.D., director of the Gene
Therapy Program at the University of Pennsylvania and chief
scientific advisor of Passage Bio. “Of course, more study is
needed, which is why we look forward to Passage Bio’s clinical
development of PBFT02 for patients with FTD-GRN.”
FTD is one of the more common causes of early-onset (midlife)
dementia, causing impairment in behavior, language and executive
function, and occurs at similar frequency to Alzheimer’s disease in
patients younger than 65 years. In approximately 5% to 10% of
individuals with FTD, the disease occurs because of mutations in
the GRN gene, causing a deficiency of PGRN. PGRN is a complex and
highly conserved protein thought to have multiple roles in cell
biology, development and inflammation. Emerging evidence suggests
that PGRN’s pathogenic contribution to FTD and other
neurodegenerative disorders relates to its critical role in
lysosomal function.
“This study also demonstrates that the route of administration –
ICM – that we plan to use for PBFT02 in our clinical studies was
minimally invasive and well tolerated in animal models,” said Bruce
Goldsmith, Ph.D., CEO of Passage Bio. “Using this approach with
PBFT02 may allow us to determine empirically the levels of brain
progranulin required to overcome intracellular lysosomal
deficiency. Based on the encouraging pre-clinical data, we plan to
initiate a Phase 1/2 trial in the first half of 2021. Our aim is to
one day offer a transformative therapy to patients with FTD-GRN,
who currently suffer profound impairments and have no treatment
options available to them.”
Results of the PBFT02 preclinical study were reported in the
paper titled, “Adeno-associated virus serotype 1-based gene therapy
for FTD caused by GRN mutations,” by Christian Hinderer, M.D.,
Ph.D., and colleagues, including Dr. Wilson, from the Gene Therapy
Program, Department of Medicine, University of Pennsylvania Perlman
School of Medicine, Philadelphia, PA., an expert in gene transfer
technologies. ACTN is an Official Journal of the American
Neurological Association. Click here to read the full-text
article.
About PBFT02 Passage Bio is developing PBFT02
to treat FTD-GRN with a single dose of PBFT02 by intra-cisterna
magna injection. PBFT02 is a gene therapy that utilizes an AAV1
viral vector to deliver a modified DNA encoding the granulin (GRN)
gene to a patient's cells. The goal of this vector and delivery
approach is to provide higher than normal levels of progranulin
(PGRN) to the central nervous system to overcome the progranulin
deficiency in GRN mutation carriers, who have been observed to have
reduced cerebrospinal fluid PGRN levels ranging from 30% to 50% of
the PGRN levels observed in normal, mutation non-carriers.
About Passage Bio
Passage Bio is a genetic medicines company focused on developing
transformative therapies for rare, monogenic central nervous system
disorders with limited or no approved treatment options. The
company is based in Philadelphia, PA and has a research,
collaboration and license agreement with the University of
Pennsylvania and its Gene Therapy Program (GTP). The GTP conducts
discovery and IND-enabling preclinical work and Passage Bio
conducts all clinical development, regulatory strategy and
commercialization activities under the agreement. The company has a
development portfolio of six product candidates, with the option to
license eleven more, with lead programs in GM1 gangliosidosis,
frontotemporal dementia and Krabbe disease.
Penn Financial Disclosure
Dr. Wilson is a Penn faculty member and also a scientific
collaborator, consultant and co-founder of Passage Bio. As such, he
holds an equity stake in the Company, receives sponsored research
funding from Passage Bio, and as an inventor of certain Penn
intellectual property that is licensed to Passage Bio, he may
receive additional financial benefits under the license in the
future. The University of Pennsylvania also holds equity and
licensing interests in Passage Bio.
Forward-Looking Statements This press release
contains “forward-looking statements” within the meaning of, and
made pursuant to the safe harbor provisions of, the Private
Securities Litigation Reform Act of 1995, including, but not
limited to: our expectations about timing and execution of
anticipated milestones, including our planned IND submissions,
initiation of clinical trials and the availability of clinical data
from such trials; our expectations about our collaborators’ and
partners’ ability to execute key initiatives; our expectations
about manufacturing plans and strategies; our expectations about
cash runway; and the ability of our lead product candidates to
treat the underlying causes of their respective target monogenic
CNS disorders. These forward-looking statements may be accompanied
by such words as “aim,” “anticipate,” “believe,” “could,”
“estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,”
“plan,” “potential,” “possible,” “will,” “would,” and other words
and terms of similar meaning. These statements involve risks and
uncertainties that could cause actual results to differ materially
from those reflected in such statements, including: our ability to
develop and obtain regulatory approval for our product candidates;
the timing and results of preclinical studies and clinical trials;
risks associated with clinical trials, including our ability to
adequately manage clinical activities, unexpected concerns that may
arise from additional data or analysis obtained during clinical
trials, regulatory authorities may require additional information
or further studies, or may fail to approve or may delay approval of
our drug candidates; the occurrence of adverse safety events; the
risk that positive results in a preclinical study or clinical trial
may not be replicated in subsequent trials or success in early
stage clinical trials may not be predictive of results in later
stage clinical trials; gene therapies are novel, complex and
difficult to manufacture; failure to protect and enforce our
intellectual property, and other proprietary rights; our dependence
on collaborators and other third parties for the development and
manufacture of product candidates and other aspects of our
business, which are outside of our full control; risks associated
with current and potential delays, work stoppages, or supply chain
disruptions caused by the coronavirus pandemic; and the other risks
and uncertainties that are described in the Risk Factors section in
documents the company files from time to time with
the Securities and Exchange Commission (SEC), and other
reports as filed with the SEC. Passage Bio undertakes no
obligation to publicly update any forward-looking statement,
whether written or oral, that may be made from time to time,
whether as a result of new information, future developments or
otherwise.
For further information, please contact:
Investors:Sarah McCabe and Zofia MitaStern Investor Relations,
Inc.sarah.mccabe@sternir.com zofia.mita@sternir.com
Media:Gwen FisherPassage
Bio215.407.1548gfisher@passagebio.com
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