Homology Medicines Presents Data from Gene Therapy and Gene Editing Programs and Manufacturing Capabilities at ASGCT Meeting

- Homology’s Scalable HEK293 Suspension Manufacturing Process for AAVHSCs Demonstrated Superiority to a Baculovirus System and AAVHSC15 Showed Improved In Vivo Efficacy Compared to AAV5 in PKU Model -

- Non-clinical Tolerability Results of HMI-102 PKU Gene Therapy Candidate Support Start of Phase 1/2 Clinical Trial with Initial Data Expected This Year -

- PKU Gene Editing Data Showed Reduction of Phe to Therapeutic Levels and Efficient and Selective Editing in Disease Models -

- Data Shows AAVHSCs Crossed the Blood-Brain Barrier and Achieved Therapeutic Enzyme Levels in MLD Disease Model -

BEDFORD, Mass., May 2, 2019 – Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the presentation of data highlighting its gene therapy and gene editing platform and manufacturing capabilities at the 22nd Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT).

New data presented at ASGCT showed that Homology’s Manufacturing Platform, including serum-free suspension transfection, is scalable and an optimized approach to manufacture Homology’s novel adeno-associated virus vectors (AAVHSCs), resulting in superior in vitro infectivity and in vivo efficacy compared to a baculovirus process. Importantly, Homology’s AAVHSC15 vector showed a greater reduction in phenylalanine (18-fold) when compared to an AAV5 vector carrying the identical DNA construct in the phenylketonuria (PKU) murine model tested at the same doses.

“We have a great sense of urgency to advance our gene therapy and gene editing programs with the goal of bringing transformative treatments and potential cures to patients with rare genetic diseases,” said Albert Seymour, Ph.D., Chief Scientific Officer of Homology Medicines. “We are pleased to share the progress that we have made across our PKU and MLD development programs, as well as demonstrate the scalability, quality and superiority of our manufacturing process for our human-derived AAVHSCs. We are carrying this momentum forward in our IND-enabling studies in MLD and in our gene editing program for PKU and look forward to starting our Phase 1/2 pheNIX trial in adults with PKU and reporting initial clinical data this year.”

Additional data presented on HMI-102 came from a 5-year retrospective study of PKU patients and non-clinical data supporting the initiation of the pheNIX gene therapy trial, for which Homology recently received IND clearance. Data presented on HMI-103, Homology’s gene editing candidate for PKU, demonstrated that Homology’s proprietary AAVHSCs achieved precise, nuclease-free in vivo gene editing at levels that corrected the phenotype in a disease model. Homology’s AAVHSCs crossed the blood-brain barrier (BBB) with a single intravenous dose of HMI-202, which resulted in efficient transduction in biologically relevant regions of the brain and reached therapeutic enzyme activity levels in a murine model of metachromatic leukodystrophy (MLD).

Presentation Highlights from ASGCT

The presentation, “Development of a Scalable Platform for GMP Production of High Quality, Novel Clade F rAAV Vectors Following Comparison of HEK293 Mammalian and the SF9-Baculovirus Systems,” compared manufacturing processes to determine the optimal approach for AAVHSCs. The studies showed:

  • An 18-fold improvement of in vivo activity when an AAVHSC PKU vector was produced using transfection of HEK293 cells compared to a baculovirus-produced vector
  • Linear scalability of Homology’s proprietary transfection process as measured by vector genome productivity up to 400 liters, which is the scale used to supply the Phase 1/2 PKU gene therapy trial
  • Reduced serum Phe levels to normal in the PKU murine model using the AAVHSC PKU vector compared to minimal reduction with an AAV5 PKU vector

In the oral presentation, “Novel AAVHSCs Demonstrate Efficient Crossing of the Blood-Brain Barrier and Potential in Gene Therapy for Metachromatic Leukodystrophy (MLD),” studies evaluated the ability of AAVHSCs to cross the blood-brain barrier in preclinical models. The presentation also highlighted the effect of HMI-202 gene therapy on the murine model of MLD. The data demonstrated that:

  • A single intravenous dose of AAVHSC crossed the BBB in non-human primates and in the MLD murine model
  • HMI-202 targeted the lysosomes and numerous other MLD-relevant regions of the central and peripheral nervous systems
  • HMI-202 exceeded the therapeutic target levels of 10-15% of human ARSA expression in the brain of the MLD murine model

Three additional presentations focused on PKU, and highlighted Homology’s gene therapy and gene editing programs.

In the oral presentation, “Nuclease-Free and Promoter-Less AAVHSC-Mediated Genome Editing In Vivo Corrects the Disease Phenotype in a Mouse Model of Phenylketonuria,” data from Homology’s PKU gene editing program demonstrated:

  • Proof-of-concept for nuclease-free, promoter-less in vivo gene editing with editing and expression of luciferase detectable and stable one-year following a single dose
  • Luciferase expression and editing levels stabilized after liver repopulation following partial hepatectomy in the murine model
  • A single IV dose of the murine PKU editing construct reduced serum Phe levels over 12 weeks post-dosing and increased melanin production, a key marker for biochemical pathway restoration
  • A single IV dose of Homology’s human PKU gene editing construct (HMI-103) selectively edited human cells in a humanized murine model comprised of human and murine hepatocytes
  • HMI-103 leverages Homology’s manufacturing platform of serum-free suspension transfection and produced therapeutic levels of human PAH, as measured by edited mRNA expression of greater than 10% in the humanized murine model

In an additional oral presentation, “Biodistribution and Tolerability of HMI-102, a Novel AAVHSC15 Encoding Human Phenylalanine Hydroxylase, in Cynomolgus Monkeys,” Homology presented data with its PKU gene therapy candidate, which is expected to enter a Phase 1/2 clinical trial this year, which showed:

  • HMI-102 was well-tolerated in non-human primates at doses within the expected clinical range with no adverse findings
  • Support for 1:1 weight-based dosing from murine and non-human primate models to human clinical trials

In the presentation, “A 5-Year Retrospective Study of Individuals with Phenylketonuria (PKU) Treated at Two Specialized Clinics,” Homology and its academic partners presented findings from a chart review of PKU patients, which demonstrated:

  • Phenylalanine levels remained elevated above the threshold considered well-controlled under current standard of care, which is a restricted diet
  • A high unmet medical need for new treatment options to address the underlying genetic defect in PKU

For more information about the presentations, visit Homology’s website at www.homologymedicines.com/publications.

About Phenylketonuria (PKU)
PKU is a rare, inherited inborn error of metabolism caused by mutations in the PAH gene. The current standard of care is a highly restrictive diet, but it is not always effective, and there are currently no treatments available that address the genetic defect in PKU. If left untreated, PKU can result in progressive and severe neurological impairment. PKU affects approximately 15,000 people in the U.S., and an estimated 300 newborns are diagnosed each year.

About Metachromatic Leukodystrophy (MLD)
MLD is a rare lysosomal storage disorder caused by mutations in the ARSA gene. ARSA is responsible for the creation of the arylsulfatase A (ARSA) protein, which is required for the breakdown of cellular components. In MLD, these cellular components accumulate and destroy myelin-producing cells in the peripheral and central nervous system leading to progressive and serious neurological deterioration. The late infantile form of the disorder is estimated to affect 1 in 40,000 people, and it is fatal within 5-10 years after onset.

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.

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 statements regarding our expectations surrounding the initiation and timing of clinical trials for our PKU gene therapy program and related manufacturing supply; the anticipated timing of the release of clinical data for the Phase 1/2 pheNIX clinical trial; the potential for HMI-102 to address the underlying genetic cause of PKU; advancing our novel gene therapy and gene editing technology platform and pipeline; the scalability, quality and potential superiority of our supply and manufacturing capabilities; our goal of improving the lives of patients with rare genetic diseases; beliefs about preclinical data; and our position as a leader in the development of genetic medicines. 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 fact that 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 marketable products; the early stage of our development efforts; our failure or the failure of our collaborators to successfully develop and commercialize drug candidates; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the capabilities and potential expansion 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; the inability to obtain orphan drug exclusivity; 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; the price of our common stock may be volatile; significant costs as a result of operating as a public company; and any securities class action litigation. These and other important factors discussed under the caption “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2018 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.

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