- Molecular Methods Quantified Precision and Efficiency of Nuclease-Free Gene Editing for PKU -
- Manufacturing Enhancements Led to Improved Productivity, Quality and Scalability of Commercial Process, Confirmed in 2,000L Bioreactor -
- Data Highlight Unique Characteristics of AAVHSC Genetic Medicines Platform -
BEDFORD, Mass., May 12, 2020 – Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the presentation of data at the American Society of Gene & Cell Therapy (ASGCT) 23rd Annual Meeting. Among Homology’s seven presentations are data from its in vivo nuclease-free gene editing program for phenylketonuria (PKU) and in vivo gene therapy program for metachromatic leukodystrophy (MLD), both of which are in IND-enabling studies. Presentations also focus on the Company’s commercial manufacturing platform, as well as data on the differentiating characteristics of Homology’s family of AAVHSC vectors, particularly when compared to other AAVs, which highlight the potential of the Company’s dual gene therapy and editing platform.
“Homology has made substantial progress in understanding the unique properties of our AAVHSC-based technology and this enables us to move our dual genetic medicines platform forward to develop potential treatments, or cures, for patients,” stated Albert Seymour, Ph.D., Chief Scientific Officer of Homology Medicines. “We are pleased to share data here that describe the molecular methods we have developed to characterize in vivo, nuclease-free gene editing efficiency and precision at the DNA level. Additional data from our in vivo MLD gene therapy program demonstrates the impact on key biomarkers in two species, as well as the durability of effect in the murine model of disease with data out to 52 weeks. Underpinning all our programs is our internal GMP process and manufacturing capabilities, where we have now confirmed our commercial HEK293 suspension platform at the 2,000-liter scale, bringing our total internal capacity to 3,500 liters. Additionally, we are presenting data showing improved AAVHSC packaging as compared to the non-Clade F vector AAV5.”
Highlights from Homology’s 2020 ASGCT Presentations
The presentation, “Molecular Characterization of Precise In Vivo Targeted Gene Editing in Human Cells using AAVHSC15, a New AAV Derived from Hematopoietic Stem Cells (AAVHSC),” describes quantitative molecular methods to measure efficiency and precision of nuclease-free, homologous recombination-based gene editing. The studies, which used a single I.V. administration of a gene editing construct to insert the human PAH gene, which is mutated in people with phenylketonuria (PKU), in a humanized liver murine model, show:
- Precise gene editing with no unintended on-target mutations or viral integration, supportive of the homologous recombination pathway
- Six percent gene editing efficiency using two independent molecular assays. This level of editing is an improvement over the efficiencies published in others’ nuclease-free gene editing studies, and it has been shown to be sufficient to normalize Phe levels in the murine model.
Two posters related to Homology’s internal commercial manufacturing platform will be presented. In “Molecular Design and Characterization of Packaging Plasmid Sequences for Improved production of Novel Clade F AAVHSCs,” the data demonstrate:
- AAVHSCs were suitable for packaging a wide range of AAV genome sizes and yielded more intact packaged genomes than AAV5, a non-Clade F serotype
- Improved productivity and optimized upstream process following enhancements to the packaging plasmid sequences
In “Development and Scalability of Transfection-Based Production and Purification of Novel Clade F Adeno-Associated Viruses Isolated from Human Hematopoietic Stem Cells (AAVHSCs),” Homology describes high-quality productivity and scalability of its mammalian, suspension-based manufacturing, including:
- Executed 2,000-liter bioreactor scale using Homology’s commercial process, with comparable productivity and product quality to smaller scale runs
- Improved product quality using anion exchange purification, which can be leveraged across Homology’s family of AAVHSC vectors and product candidates
Related to Homology’s HMI-202 investigational gene therapy for MLD, the presentation, “Gene Therapy for Metachromatic Leukodystrophy (MLD) That Crosses the Blood-Nerve and Blood-Brain Barriers in Mice and Non-Human Primates,” details that a single I.V. administration:
- Crossed the blood-brain-barrier and blood-nerve barriers in the MLD murine model and in non-human primates, with human ARSA (hARSA) enzyme detected in both species
- Showed hARSA biodistribution in the murine model that resembled endogenous murine ARSA in age-matched controls
- Produced durable hARSA levels in the murine model meeting or exceeding normal human brain ARSA activity levels out to 52 weeks
- Positively impacted key MLD biomarkers, including reducing sulfatides and LAMP-1 (lysosomal-associated membrane protein 1), as well as increased MAL (myelin and lymphocyte protein)
In collaboration with Children’s Hospital of Philadelphia (CHOP), Homology also presents, “In Vivo Transduction of Murine Hematopoietic Stem Cells after Intravenous Injection of AAVHSC15 and AAVHSC17,” which shows:
- AAVHSC15 and AAVHSC17 - two of Homology’s family of 15 AAVHSCs that were tested in the studies - can target murine hematopoietic stem cells in vivo
- Transduced cells were viable, self-renewed and actively contributed to hematopoiesis over time
As Homology has advanced its AAVHSC technology, it is presenting mechanistic data on the platform, including the following two presentations. In “Role of Terminal Galactose in Cellular Uptake, Intracellular Trafficking, and Tissue Tropism Using Adeno-Associated Viruses Isolated from Human Stem Cells (AAVHSCs),” the data show:
- AAVHSC transduction efficiency improved with increased galactose binding, a finding that has been previously described with Clade F vector AAV9
- Nucleotide differences in AAVHSCs led to differences in transduction efficiencies related to galactose binding
In “AAVHSCs Transduction Does Not Significantly Elicit p53-Mediated Apoptosis or Alter Cell Cycle in Human iPSCs and Primary Cells When Compared to Non-Clade F AAV Vectors,” the studies demonstrate that AAVHSCs:
- Have differentiating properties than those vectors in Clades 1-8, and did not induce p53 or CHK2 activation, which are responsible for apoptosis (cell death)
- Even at high multiplicities of infection (MOI), AAVHSCs did not elicit cell death or alter cell cycle
For more information about the presentations, visit Homology’s website at www.homologymedicines.com/publications.
About Homology Medicines, Inc.
Homology Medicines, Inc. is a genetic medicines company dedicated to transforming the lives of patients suffering from rare genetic diseases with significant unmet medical needs by curing the underlying cause of the disease. Homology’s proprietary platform is designed to utilize its human hematopoietic stem cell-derived adeno-associated virus vectors (AAVHSCs) to precisely and efficiently deliver genetic medicines in vivo either through a gene therapy or nuclease-free gene editing modality across a broad range of genetic disorders. Homology has a management team with a successful track record of discovering, developing and commercializing therapeutics with a particular focus on rare diseases, and intellectual property covering its suite of 15 AAVHSCs. Homology believes that its compelling preclinical data, scientific expertise, product development strategy, manufacturing capabilities and intellectual property position it as a leader in the development of genetic medicines. For more information, please visit www.homologymedicines.com.
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; our beliefs regarding our manufacturing capabilities; 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 capabilities of our manufacturing facility; risks relating to the regulatory approval process; 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; 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; failure to attract, retain and motivate qualified personnel; the possibility of system failures or security breaches; risks relating to intellectual property and significant costs 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 quarterly period ended March 31, 2020 and our other filings with the 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.