Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines
company, unveiled today the mechanism of action (MOA) and
optimization of HMI-103, the nuclease-free gene editing candidate
currently in a Phase 1 trial for phenylketonuria (PKU). HMI-103
utilizes the body’s natural DNA repair process of homologous
recombination (HR) to insert a functional copy of the PAH gene into
a specific region of the genome. It is designed to provide a
permanent DNA correction for PKU by replacing at least one
disease-causing allele with a normal gene sequence in edited cells.
HMI-103 was optimized to integrate the PAH gene and a
liver-specific promoter into the genome and to maximize enzyme
expression in all transduced cells.
“Our dedication to providing new solutions for patients living
with PKU led us to develop an AAV-based nuclease-free gene editing
vector with a new MOA,” said Albert Seymour, Ph.D., President and
Chief Scientific Officer of Homology Medicines. “We believe an
innovative approach that combines a permanent correction in the
genome while providing expression in all cells that are transduced
will be an important advance in the field of gene editing.
Preclinical data from our optimized HMI-103 in PKU showed Phe
normalization and durability of expression, which is the ultimate
goal for treating younger patients whose livers are still growing
and dividing.”
Also at the American Society of Gene and Cell Therapy (ASGCT)
Annual Meeting, Homology presented data from its long-read,
genome-wide integration assays, which confirmed the precision of
HR-based integration of HMI-103, including no off-target editing in
human hepatocytes in a humanized murine liver model. In addition,
Homology shared new data from its GTx-mAb platform showing
sustained antibody levels in murine and humanized models. The
characterization of AAVHSC16 that has low tropism to the liver was
also presented, which is a novel finding that provides
opportunities to target additional diseases with a potentially
lower immunogenicity profile.
“AAVs are ideal gene delivery vehicles for many disorders;
however, the high liver tropism that many exhibit can limit their
use in certain diseases,” continued Dr. Seymour. “Our family of 15
AAVHSC capsids have unique properties, and we have been focused on
characterizing and leveraging them across our platform. We believe
the new discovery that AAVHSC16 was able to target key tissues such
as the CNS, muscle and cardiac tissue following a single I.V.
administration, while having a very low affinity for the liver, may
enable us to expand into new disease areas.”
Highlights from Homology’s 2022 ASGCT
Presentations
In Vivo, Nuclease-Free Gene Editing Candidate HMI-103For the
first time, Homology will present data on the optimization of
HMI-103 and its MOA in the presentation, “Sustained Correction of a
Murine Model of Phenylketonuria and Integration into the Genome
Following a Single Administration of an AAVHSC15 Phenylalanine
Hydroxylase Gene Editing Vector.” The data show that a single I.V.
administration of the optimized gene editing vector led to:
- Dose-responsive phenylalanine (Phe) reduction and integration
in Pahenu2 mice;
- On-target integration at the target human PAH locus with no
evidence of off-target integration; and
- Supported clearance of the IND for the HMI-103 pheEDIT clinical
trial.
Also related to Homology’s HMI-103 program, the Company
presented, “Genome-Wide and Directed Integration Assays Identify
and Quantify rAAV In Vivo Gene Editing Sites in Mice with
Humanized Livers,” which showed:
- The use of long-read sequencing is critical to ensure genomic
DNA is analyzed and does not include episomal DNA; and
- When evaluating across the genome using long-read sequencing,
the only site of DNA integration detected with HMI-103 was at the
desired human PAH location.
GTx-mAb ProgramHomology presented new data in the poster,
“Sustained Expression of C5mAb in Presence of Murine and Human
FcRn,” including:
- Sustained expression of C5 mAb observed in the presence of
murine and human FcRn; and
- Utility of the GTx-mAb approach for paroxysmal nocturnal
hemoglobinuria (PNH) and other complement-mediated disorders.
AAVHSC PlatformThere were three presentations related to
Homology’s family of 15 AAVHSCs, including the poster, “Naturally
Occurring Variations at the 501 and 706 Residues on AAVHSC16
Contribute to Reduced Liver Tropism and Slower Serum Clearance.”
This poster focused on the characterization and screening of
AAVHSCs that led to identifying AAVHSC16’s substantially reduced
liver tropism after I.V. administration, which could be meaningful
for diseases focused on cardiac tissue, muscle or the CNS. Related,
in “The Structure of the 501 Residue on AAVHSC16 is Imperative to
the Functional Binding to Cell Surface Glycans, Which is a Key Step
in Successful Transduction,” the data showed:
- The 501 unique residue is key for the lack of galactose binding
for AAVHSC16; and
- The amino acid at this location is key for the glycan binding
and functional transduction of the vector.
In an oral session, Homology presented, “rAAV Vector Breakpoints
Determined Using Single-Molecule, Modified Base Sequencing,” that
demonstrated the ability to identify, resolve and redesign rAAV
vectors with the assistance of the long-read sequencing
technology.
AAVHSC Capsid Selection StrategyIn the presentation titled,
“Capsid Selection Strategy for the Development of Gene Therapies
Based on Structural and Functional Analyses of a Panel of AAVHSCs,”
data supported Homology’s approach to leverage the most
advantageous capsid for each specific disease the Company
targets.
Homology Symposium and WebcastHomology will be
hosting a symposium today at 7:30 a.m. ET, including guest speaker
Jerry Vockley, Ph.D., M.D., FACMG, Division Director, Genetic and
Genomic Medicine, Professor of Pediatrics and Human Genetics, and
Director, Center for Rare Disease Therapy at the University of
Pittsburgh, and Lead Principal Investigator for the pheEDIT
clinical trial. A live webcast of the symposium will be accessible
on Homology’s website in the Investors section, and the replay will
be available on the website for 90 days following the
presentation.
About Homology Medicines, Inc.Homology
Medicines, Inc. is a clinical-stage genetic medicines company
dedicated to transforming the lives of patients suffering from rare
diseases by addressing the underlying cause of the disease. The
Company’s clinical programs include HMI-102, an investigational
gene therapy for adults with phenylketonuria (PKU); HMI-103, a gene
editing candidate for PKU; and HMI-203, an investigational gene
therapy for Hunter syndrome. Additional programs focus on
metachromatic leukodystrophy (MLD), paroxysmal nocturnal
hemoglobinuria (PNH) and other diseases. Homology’s proprietary
platform is designed to utilize its family of 15 human
hematopoietic stem cell-derived adeno-associated virus (AAVHSCs)
vectors to precisely and efficiently deliver genetic medicines in
vivo through a gene therapy or nuclease-free gene editing modality,
as well as to deliver one-time gene therapy to produce antibodies
throughout the body through the GTx-mAb platform. Homology has a
management team with a successful track record of discovering,
developing and commercializing therapeutics with a focus on rare
diseases. Homology believes its initial clinical data and
compelling preclinical data, scientific and product development
expertise and broad intellectual property position the Company as a
leader in genetic medicines. For more information, visit
www.homologymedicines.com.
Forward-Looking Statements This press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. All statements
contained in this press release that do not relate to matters of
historical fact should be considered forward-looking statements,
including, without limitation, statements regarding our
expectations surrounding the potential, safety, efficacy, and
regulatory and clinical progress of our product candidates; the
potential of our gene therapy and gene editing platforms; our
position as a leader in the development of genetic medicines; and
our participation in upcoming presentations and conferences. These
statements are neither promises nor guarantees, but involve known
and unknown risks, uncertainties and other important factors that
may cause our actual results, performance or achievements to be
materially different from any future results, performance or
achievements expressed or implied by the forward-looking
statements, including, but not limited to, the following: the
impact of the COVID-19 pandemic on our business and operations,
including our preclinical studies and clinical trials, and on
general economic conditions; we have and expect to continue to
incur significant losses; our need for additional funding, which
may not be available; failure to identify additional product
candidates and develop or commercialize marketable products; the
early stage of our development efforts; potential unforeseen events
during clinical trials could cause delays or other adverse
consequences; risks relating to the regulatory approval process;
interim, topline and preliminary data may change as more patient
data become available, and are subject to audit and verification
procedures that could result in material changes in the final data;
our product candidates may cause serious adverse side effects;
inability to maintain our collaborations, or the failure of these
collaborations; our reliance on third parties, including for the
manufacture of materials for our research programs, preclinical and
clinical studies; failure to obtain U.S. or international marketing
approval; ongoing regulatory obligations; effects of significant
competition; unfavorable pricing regulations, third-party
reimbursement practices or healthcare reform initiatives; product
liability lawsuits; securities class action litigation; failure to
attract, retain and motivate qualified personnel; the possibility
of system failures or security breaches; risks relating to
intellectual property; risks associated with international
operations, such as political and economic instability, including
in light of the conflict between Russia and Ukraine; and
significant costs incurred as a result of operating as a public
company. These and other important factors discussed under the
caption “Risk Factors” in our Quarterly Report on Form 10-Q for the
quarter ended March 31, 2022, and our other filings with the
Securities and Exchange Commission (SEC) could cause actual results
to differ materially from those indicated by the forward-looking
statements made in this press release. Any such forward-looking
statements represent management’s estimates as of the date of this
press release. While we may elect to update such forward-looking
statements at some point in the future, we disclaim any obligation
to do so, even if subsequent events cause our views to change.
Company Contacts:Theresa McNeelyChief
Communications Officer and Patient
Advocatetmcneely@homologymedicines.com781-301-7277Media
Contact:Cara Mayfield Vice President, Patient Advocacy and
Corporate Communications cmayfield@homologymedicines.com
781-691-3510
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