AVROBIO Reports Favorable Data on Use of Combined State-of-the-art In Vitro Cell-based Assays to Identify Potential Genotoxicity Risk of Integrating Vectors During Preclinical Development

AVROBIO leading industry in combining use of two safety assays to evaluate genotoxicity risk prior to moving into clinical trials

New safety assay uses machine learning algorithms and transcriptional profile data designed to assess the genotoxicity risk of integrating vectors

AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene therapy company working to free people from a lifetime of genetic disease, today reported favorable data on the combined use of two state-of-the-art assays to evaluate the genotoxicity risk of integrating vectors used in hematopoietic stem cell (HSC) gene therapy prior to clinical use, at the 29^th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT), Oct. 11-14, 2022 in Edinburgh, Scotland.

In collaboration with Professor Axel Schambach, Ph.D., Institute of Experimental Hematology, Hannover Medical School, Germany, AVROBIO is pioneering the use of two advanced preclinical cell-based assays -- in vitro immortalization (IVIM) assay and the novel surrogate assay for genotoxicity assessment (SAGA) -- to evaluate viral vectors before they move into clinical programs. Together these assays are designed to assess which vectors are less likely to exhibit genotoxic behavior and monitor if these vectors activate proto-oncogenes (genes that may lead to cancer).

“Our work provides insight into the early molecular events of genotoxicity following HSC transduction with integrating vectors and presents a powerful machine-learning approach to prospectively estimate the genotoxicity risk of integrating vectors for gene therapy,” said Professor Schambach, also associated with the Division of Hematology/Oncology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, whose work includes data on more than 30 commonly used vectors. “These assays enable preclinical risk assessment of gene therapy vectors, potentially paving the way for safer gene therapy vectors used in clinical trials.”

AVROBIO uses these assays to inform vector selection during preclinical development. In addition, to date, AVROBIO has seen no cases of insertional oncogenesis in any of its clinical programs.

“Safety is at the forefront of our work at AVROBIO and incorporated in the development of our plato® platform, which includes our advanced vector design, optimized for safety as well as transgene expression and protein uptake,” said AVROBIO President and CEO Geoff MacKay. “Combining these assays helps assess vector genotoxicity risk early in preclinical development and further reaffirms that not all lentiviral vectors are designed the same.”

IVIM/SAGA as screening tools during lentiviral vector selection

In its research, AVROBIO used the two assays in combination to determine the potential genotoxicity risk of six lentiviral vectors. Five of the vectors used the EF1 α short promoter (EFS), while the sixth vector used the modified enhancer/promoter of the murine myeloproliferative sarcoma virus, or MND, promoter. Vectors were compared to a non-transduced mock control and a positive genotoxic control, the non-SIN gamma-retroviral vector (RSF91).

The in vitro immortalization (IVIM) assay quantifies the risk of vector-induced cellular transformation. The technique assesses genotoxicity by determining how likely a vector is to insert near and activate proto-oncogenes, such as MECOM, and lead to an over-proliferation of cells. In this study, to quantify the risk of vector-induced cellular transformation, mouse hematopoietic stem and progenitor cell (HSPC) proliferation was monitored after transduction. IVIM determined that the five EFS vectors drove cell growth in a manner indistinguishable from non-transduced cells. The vector using the MND promoter, however, exhibited cell growth that was statistically significantly different from non-transduced cells and similar to the positive genotoxic control.

The second and newer assay assesses genotoxicity more directly. The novel surrogate assay for genotoxicity assessment (SAGA) relies on the observation that genotoxic vectors induce a unique gene expression signature that is linked to stemness and oncogenesis in mouse HSPCs. Machine learning algorithms developed from transcriptional data of known genotoxic vectors are used to estimate the transformational potential of candidate vectors. The SAGA assay can evaluate vectors with known genotoxic potential with an accuracy of 90.9%. In this study, SAGA data showed that the five vectors with EFS promoters were statistically distinct from the genotoxic positive control and therefore displayed lower genotoxic risk, whereas four of nine (44%) samples from cells transduced with a lentiviral vector containing an MND internal promoter had gene enrichment scores associated with insertional oncogenesis.

These findings enable the estimation of clinically translatable insertional oncogenesis risk of integrating vectors during preclinical development. AVROBIO uses the EFS promoter in its clinical programs.

The Hannover Medical School team working with Professor Schambach and Michael Rothe, Ph.D., has previously published their data in Molecular Therapy.

About AVROBIO

Our vision is to bring personalized gene therapy to the world. We target the root cause of genetic disease by introducing a functional copy of the affected gene into patients’ own hematopoietic stem cells (HSCs), with the goal to durably express the therapeutic protein throughout the body, including the central nervous system. Our first-in-class pipeline includes clinical programs for cystinosis and Gaucher disease type 1, as well as preclinical programs for Gaucher disease type 3, Hunter syndrome and Pompe disease. Our proprietary plato® gene therapy platform is designed to be scaled to support late-stage clinical development and commercialization globally. We are headquartered in Cambridge, Mass. For additional information, visit avrobio.com, and follow us on Twitter and LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “aims,” “anticipates,” “believes,” “could,” “designed to,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our preclinical and clinical product candidates, the potential benefits of the IVIM/SAGA preclinical assays, including the potential to evaluate or assess possible genotoxicity risk during preclinical development and in vector selection, statements regarding preclinical or clinical trial results, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, the expected benefits and results of our implementation of the plato platform in our clinical trials and gene therapy programs, and the expected safety profile of our preclinical and investigational gene therapies. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Results in preclinical or early-stage clinical trials may not be indicative of results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.

Any forward-looking statements in this press release are based on AVROBIO’s current expectations, estimates and projections about our industry as well as management’s current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of AVROBIO’s product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators, the risk that AVROBIO may not successfully recruit or enroll a sufficient number of patients for our clinical trials, the risk that AVROBIO may not realize the intended benefits of our gene therapy platform, including the features of our plato^® platform, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving AVROBIO’s product candidates, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and growth potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third-party suppliers and manufacturers, risks regarding the accuracy of our estimates of expenses and future revenue, risks relating to our capital requirements and needs for additional financing, risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our enrollment and development timelines and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIO’s actual results to differ materially and adversely from those contained in the forward-looking statements, see the section entitled “Risk Factors” in AVROBIO’s most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

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