AVROBIO Presents Positive Initial Data for its Investigational Cystinosis Program and plato TM Platform, as well as Positive Data Out to 32 Months for its Ongoing Investigational Fabry Program Early data trends from firs

AVROBIO Presents Positive Initial Data for its Investigational Cystinosis Program and plato

TM Platform, as well as Positive Data Out to 32 Months for its Ongoing Investigational Fabry Program

Early data trends from

first patient dosed in the AVR-RD-04 investigational gene therapy program for cystinosis show improvements across multiple measures

Data from the Phase 1 and Phase 2 trials of AVR-RD-01

support potential long-term engraftment and durable, endogenous production of functional enzyme in patients with Fabry disease

First Phase 2 Fabry patient treated using plato gene therapy platform shows plasma enzyme activity at one month 4.0 times higher than mean

activity of other Phase 2 patients treated using academic platform at same timepoint

Analyst and investor event will be webcast

today, Feb. 10, 2020, at 7:00 p.m. ET, in conjunction with WORLDSymposiumTM

CAMBRIDGE, Mass., Feb. 10, 2020 AVROBIO, Inc. (NASDAQ: AVRO), a

leading clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, today announced new initial data from the first patient dosed in the investigational gene therapy program for cystinosis, showing

improvements in early measures at three months compared to baseline. The company also unveiled new clinical data showcasing a sustained biomarker response in patients for up to 32 months after receiving the company s investigational gene

therapy for Fabry disease across metrics including vector copy number (VCN), substrate levels and enzyme activity. Additionally, the company reported on the clinical debut of its platoTM gene

therapy platform. These data showed improved enzyme activity, transduction efficiency and VCN in drug product manufactured using plato compared with drug product produced using the academic platform, as well as higher in vivo enzyme activity at one

month in the first patient treated with plato, as compared to other patients treated using the academic platform. All these data will be presented today, during the 16th Annual

WORLDSymposiumTM in Orlando, Fla.

We have now dosed 10 patients across three trials for

two lysosomal disorders and we re delighted with the data we re seeing. We have followed six patients in our Fabry trial for more than a year and one for nearly three years, and they are consistently producing the functional enzyme that

was missing as a consequence of their genetic disease, suggesting a potentially durable effect from a single dose, said Geoff MacKay, AVROBIO s president and CEO. Furthermore, we believe that early data from the first clinical

application of plato support our decision to invest heavily from AVROBIO s earliest days in this state-of-the-art gene

therapy platform. We believe these data collectively indicate that we re making exciting progress toward our goal of freeing patients and families from the life-limiting symptoms and relentless progression of lysosomal disorders.

Three-month data from first patient in investigational AVR-RD-04 trial in cystinosis

AVROBIO reported initial data from the first patient dosed in the

investigator-sponsored Phase 1/2 trial of the company s AVR-RD-04 investigational gene therapy for cystinosis, a progressive disease marked by the accumulation of

cystine crystals in cellular organelles known as lysosomes. Patients with cystinosis accumulate the amino acid cystine, which can lead to crystal formation in the lysosomes of cells, causing debilitating symptoms including corneal damage, difficulty

breathing and kidney failure, often leading to a shortened lifespan. The current standard of care for cystinosis, a burdensome treatment regimen that can amount to dozens of pills a day, may not prevent overall progression of the disease.

As of the safety data cut-off date of Jan. 27, 2020, which was approximately three months following administration of

the investigational gene therapy to the first patient in the AVR-RD-04 program, there have been no reports of safety events attributed to the investigational drug

product. In addition, no serious adverse events (SAEs) have been reported as of the safety data cut-off date. Adverse events did not suggest any unexpected safety signals or trends.

Three months following administration of AVR-RD-04, the first patient had a

VCN of 2.0. VCN measures the average number of copies of the lentiviral-vector inserted transgene integrated into the genome of a cell and can be used to help assess the durability of a gene therapy. Initial data on another biomarker show that the

patient s average granulocyte cystine level one of the trial s primary endpoints decreased from 7.8 nmol half cystine/mg protein two weeks after cysteamine discontinuation, to 1.5 at three months post-gene therapy.

The ongoing open-label, single-arm Phase 1/2 clinical trial evaluating the safety and efficacy of AVR-RD-04 is sponsored by AVROBIO s academic collaborators at the University of California San Diego (UCSD), led by Stephanie Cherqui, Ph.D. The trial is actively

enrolling up to six participants at UCSD.

Interim data continue to support potential first line use of AVR-RD-01 in Fabry disease

Four patients have been dosed in the Phase 2 trial

(FAB-201), and five patients in the Phase 1 investigator-led trial of AVR-RD-01 in Fabry

VCN data continue to be stable at 32 months following AVR-RD-01

treatment for the first patient in the Phase 1 trial, suggesting successful engraftment, which is critical to the long-term success of investigational ex vivo lentiviral gene therapies. The VCN data trend was generally consistent across the seven

other Phase 1 and Phase 2 trial participants out six to 24 months.

The first three AVR-RD-01

Phase 2 patients entered the study with minimal endogenous enzyme activity. At nine, 12 and 18 months after dosing, data from these three patients indicate sustained increased leukocyte and plasma enzyme activity, suggesting that they are now

producing an endogenous supply of functional alpha-galactosidase (AGA) enzyme. This enzyme is essential for breaking down globotriaosylceramide (Gb3) in cells; without it, a toxic metabolite, lyso-Gb3, may

accumulate, potentially causing cardiac and kidney damage and other symptoms.

For two Phase 2 patients, data indicate that their decreased plasma lyso-Gb3 levels, a key biomarker for monitoring Fabry disease, have been sustained below their baseline at six and 18 months after dosing. The third Phase 2 patient, a cardiac variant who does not have classic Fabry

disease, did not show a decrease in plasma lyso-Gb3 levels, as expected. Cardiac and kidney function measures in the Phase 2 trial remained within normal range for patients who had available 12-month data.

As previously reported, a kidney biopsy taken at 12 months post-treatment for the first patient in the

Phase 2 trial showed an 87-percent reduction in Gb3 inclusions per peritubular capillary. The company believes this data point, the primary efficacy endpoint for the Phase 2 trial, supports the potential of AVR-RD-01 to reduce Gb3 levels in tissue, including in the kidney.

1 trial of AVR-RD-01, four of the five patients had their plasma lyso-Gb3 levels reduced between 26 and 47 percent compared

to their pre-treatment baseline levels. Data from the other patient in the trial, who remains off enzyme replacement therapy (ERT), through month six showed an initial decline and at month 12 showed a 23-percent increase in lyso-Gb3 levels, as compared to pre-treatment levels. This patient s

lyso-Gb3 levels remain within the range for the Fabry disease patients on ERT observed in this study.

three of the five Phase 1 patients have discontinued ERT and all three remain off ERT for six, 14 and 15 months.

As of the safety data cut-off date of Nov. 26, 2019, there have been no safety events attributed to AVR-RD-01 drug product in either the Phase 1 or Phase 2

trial. Through the safety data cut-off date, four SAEs have been reported in the FAB-201 trial and two SAEs in the Phase 1 trial. The fourth Phase 2 patient, who was

dosed after the safety data cut-off date, has reported an SAE, which was not attributed to AVR-RD-01 and which subsequently

resolved. Across both studies, each of the SAEs has been consistent with the conditioning regimen, stem cell mobilization, underlying disease or pre-existing conditions.

Pre-existing low anti-AGA antibody titers have been detected in four patients in the Phase 1 trial and a transient low titer was observed but not detectable in

subsequent measures in one patient in the Phase 2 trial.

The Phase 1 trial is fully enrolled. AVROBIO continues to actively enroll the Phase 2 trial in Australia,

Canada and the U.S. The FAB-201 trial is an ongoing open-label, single-arm Phase 2 clinical trial evaluating the efficacy and safety of AVR-RD-01 in eight to 12 treatment-na ve patients with Fabry disease.

Successful clinical debut of platoTM gene therapy platform

AVROBIO also shared preliminary results from the first two patients to receive busulfan conditioning. Conditioning is an essential step in ex vivo lentiviral

gene therapy designed to clear space in the bone marrow for the cells carrying the therapeutic transgene to engraft. The conditioning regimen developed as part of AVROBIO s plato platform includes therapeutic dose monitoring to assess how

rapidly the individual patient metabolizes busulfan so physicians can adjust the dose as needed, with a goal of minimizing side effects while maximizing the potential of durable engraftment.

AVROBIO is implementing its precision dosing conditioning regimen across its company-sponsored clinical trials as part of the plato platform. The fourth

patient in AVROBIO s Phase 2 Fabry trial received a precision dosing conditioning regimen with busulfan as part of the plato platform, while the first patient in the investigator-led cystinosis trial

received busulfan but not as part of the plato platform.

These two patients both had rapid neutrophil and platelet count recovery, with a trajectory that

was similar to the patients who enrolled earlier in the Fabry trials and who received a melphalan conditioning regimen. Side effects, which included nausea, mucositis, fever, rash and hair loss, developed eight to 10 days after dosing with busulfan

and then resolved quickly.

The company also reported preliminary data from the first drug product produced using the plato gene therapy platform, which

was used to dose the fourth patient in the Phase 2 Fabry trial (FAB-201). Early data indicate that enzyme activity and transduction efficiency for the drug product used to dose the fourth patient were 2.2

times higher than the mean of the drug product used to dose the first three patients in FAB-201. VCN for the drug product used to dose the fourth patient was 1.8 times higher than the mean of the drug product

for the first three patients dosed in FAB-201. The drug product for the first three patients in FAB-201 was manufactured using a manual process first developed by

AVROBIO s academic collaborators. The automated manufacturing embedded in plato leverages optimized processes developed at AVROBIO.

following administration of the plato-produced investigational gene therapy for the fourth patient in the Phase 2 Fabry trial, initial data show the patient s plasma enzyme activity level to be 4.0 times higher than the mean activity level of

the first three patients in the Phase 2 Fabry trial at the same timepoint.

The investigational drug product used to dose the first patient in the AVR-RD-04 program for cystinosis, which included a four-plasmid vector but not plato s automated manufacturing process, also showed increased performance in line with the increased performance recorded

for the drug product in the Fabry trial. The investigational drug product and VCN assay are different for each trial.

We believe these data are an

early, but exciting, validation of our decision to invest in technological innovation rather than build expensive bricks-and-mortar manufacturing facilities, said

MacKay. The plato platform gives us control over the production and scaling of our investigational gene therapies through an efficient, automated manufacturing system that is designed to be deployed in standard contracted sites around the

world. The four-plasmid vector, conditioning regimen with precision dosing and other elements of plato are designed to optimize the safety, potency and durability of our investigational lentiviral gene therapies.

About AVROBIO s ex vivo approach to gene therapy

Our investigational ex vivo gene therapies start with the patient s own stem cells. In the manufacturing facility, a lentiviral vector is used to insert a

therapeutic gene designed to enable the patient to produce a functional supply of the protein they lack. These cells are then infused back into the patient, where they are expected to engraft in the bone marrow and produce generations of daughter

cells, each containing the therapeutic gene. This approach is designed to drive durable production of the functional protein throughout the patient s body, including

hard-to-reach tissues such as the brain, muscle and bone. It is a distinguishing feature of this type of gene therapy that the corrected cells are expected to cross the

blood-brain barrier and thereby potentially address symptoms originating in the central nervous system.

Lentiviral vectors are differentiated from other

delivery mechanisms because of their large cargo capacity and their ability to integrate the therapeutic gene directly into the patient s chromosomes. This integration is designed to maintain the transgene s presence as the patient s

cells divide, which may improve the expected durability of the therapy and potentially enable dosing of pediatric patients, whose cells divide rapidly as they grow. Because the transgene is integrated ex vivo into patients stem cells, patients

are not excluded from receiving the investigational therapy due to pre-existing antibodies to the viral vector.

Analyst and investor event and webcast information

AVROBIO will host an analyst and investor event today, Monday, Feb. 10, 2020, in conjunction with the WORLDSymposiumTM, an annual scientific meeting dedicated to lysosomal disorders, in Orlando, FL. The presentation at the event will be webcast beginning at 7:00 p.m. ET. The webcast and accompanying slides will

be available under Events and Presentations in the Investors & Media section of the company s website at www.avrobio.com. An archived webcast recording of the event will be available on the website for approximately 30

Our mission is to free people from a lifetime of genetic disease with a single dose of gene therapy. We aim to halt or reverse disease throughout the body by

driving durable expression of functional protein, even in hard-to-reach tissues and organs including the brain, muscle and bone. Our clinical-stage programs include

Fabry disease, Gaucher disease and cystinosis and we also are advancing a program in Pompe disease. AVROBIO is powered by the plato gene therapy platform, our foundation designed to scale