Homology Medicines Presents Details of Optimized HMI-103 Nuclease-Free Gene Editing Candidate Featuring Integrated Liver-Specific Promoter to Maximize Long-Term Expression

Rhea-AI Summary

Homology Medicines (FIXX) showcased groundbreaking data at the ASGCT Annual Meeting on May 18, 2022, revealing the optimization of its gene editing candidate HMI-103 for phenylketonuria (PKU). This nuclease-free approach utilizes homologous recombination to permanently correct the PAH gene, demonstrating on-target integration and no off-target events in preclinical models. New findings on AAVHSC capsids suggest potential for targeting various disorders with lower liver tropism. These advancements affirm Homology's commitment to innovative genetic therapies for rare diseases.

Positive

• HMI-103 demonstrates on-target integration and no off-target effects, enhancing its therapeutic potential for PKU.
• New AAVHSC capsids identified may allow targeting of diseases with reduced liver tropism, expanding treatment options.
• Successful preclinical results suggest sustained correction of phenylalanine levels, beneficial for young PKU patients.

Negative

• None.

- Additional Data at ASGCT Annual Meeting Demonstrate Precision of HR-Based Approach with Genome-Wide Integration Assays Confirming On-Target Editing and No Off-Target Events -

- New Data from GTx-mAb Platform Support Potential for Targeting Many
Complement-Related Disorders -

- Further Characterization of Homology’s Naturally Derived AAVHSC Capsids Highlight Their Broad Biodistribution and a Novel Discovery Revealed One Capsid with Low Tropism to the Liver, a Key Functional Benefit for Selecting New Disease Indications -

- Homology Symposium to be Held Today, May 18, at 7:30 a.m. ET -

BEDFORD, Mass., May 18, 2022 (GLOBE NEWSWIRE) --  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-103
For 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 Pah^enu2 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 Program
Homology 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 Platform
There 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 Strategy
In 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 Webcast
Homology 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 McNeely
Chief Communications Officer
and Patient Advocate
tmcneely@homologymedicines.com
781-301-7277

Media Contact:
Cara Mayfield
Vice President, Patient Advocacy
and Corporate Communications
cmayfield@homologymedicines.com
781-691-3510

 

FAQ

What is HMI-103 in relation to FIXX?

HMI-103 is a nuclease-free gene editing candidate for phenylketonuria (PKU) developed by Homology Medicines (FIXX), showing promising preclinical results.

What were the key findings presented at the ASGCT Annual Meeting by FIXX?

Key findings included the successful optimization of HMI-103, showcasing on-target integration with no off-target events, and new data on AAVHSC capsids indicating potential for targeting various disorders.

How does FIXX's gene editing approach work?

FIXX's gene editing approach utilizes homologous recombination to insert a functional PAH gene copy, aiming for a permanent DNA correction in PKU patients.

What significance does the low liver tropism of AAVHSC capsids have for FIXX?

The low liver tropism of certain AAVHSC capsids may expand treatment applications for gene therapies targeting tissues like the CNS and muscle, potentially reducing side effects.