AVROBIO, Inc. Announces Updated Clinical Data from Ongoing Phase 1 and Phase 2 Studies for AVR-RD-01 Gene Therapy for Fabry Disease

  • All patients with reported data exhibit AGA enzyme activity above the
    diagnostic range for males with classic Fabry disease after receiving
    AVR-RD-01, including at 22 months for Patient 1 in the Phase 1 study
  • Impact of gene therapy on substrate and metabolite levels observed
    both in patients who have discontinued ERT and in ERT-naïve patients;
    85% reduction in lyso-Gb3 for first patient in Phase 2 study who is
    ERT-naïve; lyso-Gb3 levels of first patient in Phase 1 study were
    lower at 22 months while on AVR-RD-01 alone than while on ERT
  • AVR-RD-01 has been generally well tolerated in the Phase 1 and Phase 2
    studies to date
  • AVROBIO introduces plato™, a vector system and automated, closed, cell
    manufacturing solution designed to support worldwide commercialization
  • Analyst and Investor Event webcast today, February 6, 2019 at 5:30
    p.m. ET, in conjunction with WORLDSymposium

(Nasdaq: AVRO) (the “Company”), a Phase 2 clinical-stage
gene therapy company, today announced clinical trial updates from the
ongoing investigator-sponsored Phase 1 clinical study and the
AVROBIO-sponsored Phase 2 clinical trial of AVR-RD-01. AVR-RD-01 is an
investigational gene therapy candidate designed to treat Fabry disease
by inserting the GLA gene that encodes functional α-galactosidase A
(AGA, the enzyme that is deficient in patients with Fabry disease) with
the goal of enabling continuous endogenous AGA production and
distribution to tissues and organs.

“Today’s update shows a consistent readout across multiple surrogate
markers that support the potential of AVR-RD-01 to address the genetic
basis of Fabry disease,” said Birgitte Volck, MD, PhD, AVROBIO’s
President of Research and Development. We believe these results are
significant because the data reported show sustained AGA enzyme levels
with associated reductions in substrate and metabolite levels. This
suggests that our gene therapy exerts its effects as intended in
patients previously treated with ERT, as well as in treatment-naïve
patients. Taken together, these clinical data represent a growing body
of evidence of the therapeutic potential of AVR-RD-01 as a gene therapy
for patients with Fabry disease.”

The investigator-sponsored Phase 1 study is designed to assess the
safety of AVR-RD-01 in up to six patients with Fabry disease who have
been treated with standard of care enzyme replacement therapy (ERT) for
at least six months prior to receiving AVR-RD-01. The AVROBIO-sponsored
Phase 2 trial of AVR-RD-01 (the FAB-201 Study1) is an
open-label, single-arm clinical trial evaluating the efficacy and safety
of AVR-RD-01 in eight to twelve treatment-naïve patients who have not
received ERT.

To date, six patients have been dosed in the AVR-RD-01 studies – four
patients in the Phase 1 study and two patients in the Phase 2 study.
Across both studies, four patients have reached the point of three-month
data analysis or longer after receiving AVR-RD-01 – three patients in
the Phase 1 study and one patient in the Phase 2 study. Clinical data
for these four patients are detailed in this update.

AGA enzyme activity sustained in patients in Phase 1 and Phase 2

  • All patients with reported data after dosing with AVR-RD-01 exhibited
    AGA plasma enzyme activity (AGA) above the diagnostic range for males
    with classic Fabry disease (defined as less than 1 nmol/hr/ml), at all
    timepoints measured in the two studies. For the four patients assessed
    at three months or longer after dosing, AGA activity at the latest
    measure was as follows:
  • In the Phase 1 study: Patient 1 had AGA of 1.6 nmol/hr/ml at 22
    months; Patient 2 had AGA of 3.4 nmol/hr/ml at 12 months; and Patient
    3 had AGA of 5.4 nmol/hr/ml at six months.
  • In the Phase 2 study, Patient FAB-201-1 had AGA of 2.9 nmol/hr/ml at
    six months.
  • Two patients in the Phase 1 study have now discontinued ERT. Patient 1
    discontinued the prescribed bi-weekly treatment with ERT at the
    investigator’s discretion and patient consent after the 18-month
    follow-up visit, and he remains off of ERT. Patient 3 chose not to
    resume the prescribed bi-weekly treatment with ERT after receiving the
    AVR-RD-01 dose.

Substrate and metabolite levels reduced in patients in Phase 1 and
Phase 2 studies

  • Of the three patients not on ERT treatment who were assessed for
    substrate (Gb3) and metabolite (lyso-Gb3) levels at three months or
    longer after dosing, one patient is in the Phase 2 study that
    evaluates ERT-naïve patients and two patients are in the Phase 1 study
    and have discontinued ERT treatment. AVROBIO believes that meaningful
    changes in substrate levels could be measured in evaluating the effect
    of AVR-RD-01 alone in these patients, in the absence of potential
    confounding effects from concurrent ERT. All three of these patients
    showed decreases in plasma lyso-Gb3 (lyso-Gb3):
  • In the Phase 2 study, Patient FAB-201-1, who was ERT-naïve, had a
    lyso-Gb3 measurement of 31 nmol/hr/ml at six months, as compared to a
    lyso-Gb3 measurement of 202 nmol/hr/ml at the start of the study,
    representing an 85% reduction in lyso-Gb3.
  • An additional measurement of substrate for Patient FAB-201-1 was
    evaluated via skin biopsy analysis, which showed a reduction in
    substrate inclusions in endothelial cells of the skin between baseline
    and at six months after treatment with AVR-RD-01. The skin biopsies
    were evaluated using a standard scoring system for Gb3 accumulation
    and clearance. The scoring system has a range of zero to 3, with a
    score of zero representing none or trace accumulation, and a score of
    3 representing severe accumulation. This patient scored a 3 at
    baseline and scored a 2 at six months after treatment with AVR-RD-01,
    as assessed by two independent blinded readers. This tissue-related
    data point is consistent with, and AVROBIO believes supports, the
    metabolite reduction observed with plasma lyso-Gb3.
  • For Patient 1 in the Phase 1 study, plasma lyso-Gb3 level was reduced
    below pre-gene therapy levels by 3 months and sustained up to 22
    months with AVR-RD-01 gene therapy alone, after discontinuation of
    enzyme replacement therapy (ERT) at month 18. For Patient 3, who chose
    not to resume ERT following treatment with AVR-RD-01, his initial
    lyso-Gb3 was 52 nmol/hr/ml, which decreased to 33 nmol/hr/ml at
    three months (while on gene therapy alone).

AVR-RD-01 remains generally well tolerated in clinical studies

  • Preliminary safety data for all patients dosed in the Phase 1 and
    Phase 2 studies indicate that AVR-RD-01 has been generally well
    tolerated; no serious adverse events (SAEs) assessed related to
    AVR-RD-01 were reported as of the safety data cut-off dates of January
    1, 2019 for the Phase 2 study and November 26, 2018 for the Phase 1
    study. Adverse events (AEs) were as expected for patients undergoing
    melphalan conditioning.

Vector Copy Number is as Expected

The overall vector copy number (VCN) trends for the Phase 1 and Phase 2
studies remain as expected. For Patient 1 in the Phase 1 study, the VCN
is stable between month 17 and month 22 at 0.1. VCN refers to the
average number of copies of the lentiviral-vector inserted gene that are
integrated into the genome of a cell.


Phase 1 Study of AVR-RD-01: Vector Copy Number (VCN)

Drug Product VCN     Patient 1


    Patient 2


    Patient 3


Peripheral Blood VCN     Patient 1     Patient 2     Patient 3
1 Month     0.4     0.8     0.2
3 Months     0.6     1.1     0.8
6 Months     0.4     0.4     0.5
9 Months     0.3          
12 Months     0.2     0.4      
17 Months     0.1            
22 Months     0.1            

Phase 2 Study of AVR-RD-01 (FAB-201): Vector Copy Number (VCN)

Drug Product VCN     Patient



Peripheral Blood VCN     Patient 1
1 Month     0.2
2 Months     0.2
3 Months     0.5
6 Months     0.2

Introduction of plato™, AVROBIO’s vector system and automated,
closed, cell manufacturing solution

Based on over three years of development, plato™ is AVROBIO’s vector
system and automated, closed, cell manufacturing solution for CD34+
cell-based therapies developed to enable worldwide commercialization of
the Company’s gene therapies. Components of plato were also designed to
safely enhance long-term gene therapy efficacy and durability and can
potentially address the CNS manifestations that accompany certain
lysosomal storage diseases. AVROBIO intends to utilize the plato
platform in its gene therapy programs, starting in 2019 with the ongoing
Phase 2 clinical program for AVR-RD-01 for Fabry disease and its planned
AVR-RD-02 clinical program for Gaucher disease.

“AVROBIO enters 2019 with strong momentum across multiple fronts. We are
extremely pleased with today’s AVR-RD-01 data and look forward to
presenting additional data from our Fabry studies over the course of the
year. Today’s news, along with the promise of our product pipeline and
plato platform, give us great confidence for the year ahead,” said Geoff
MacKay, AVROBIO’s Chief Executive Officer.

Other information

  • Data from the Phase 1 study of AVR-RD-01 will be highlighted in a
    platform presentation today at the WORLDSymposium by Jeffrey A.
    Medin, Ph.D., Vice Chair of Research Innovation and MACC Fund Chair of
    Pediatrics and Biochemistry, Medical College of Wisconsin. Dr. Medin
    is the principal investigator of the FACTs team (Fabry disease
    Clinical research and Therapeutics) in Canada that is conducting the
    Phase 1 study.
  • Enrollment in the Phase 1 and Phase 2 studies of AVR-RD-01 is ongoing.
    Further details of the ongoing AVROBIO-sponsored Phase 2 FAB-201 Study
    of AVR-RD 01 in Fabry disease are available on clinicaltrials.gov.2

Analyst and Investor Event and Webcast Information

AVROBIO will host an Analyst and Investor Event today, Wednesday,
February 6, 2019, in conjunction with the WORLDSymposium, an
annual conference dedicated to lysosomal diseases, in Orlando, FL. The
presentation at the event will be webcast beginning at 5:30 p.m. ET. At
the event, the Company will provide additional updated clinical data for
patients in the Phase 1 and Phase 2 studies evaluating AVR RD-01 in
Fabry disease, including additional substrate and metabolite levels in
plasma and urine, and safety and tolerability endpoints; will highlight
AVROBIO’s progress with the Phase 1 study and Phase 2 FAB-201 Study1 for
its lead clinical program in Fabry disease; will further discuss the
Company’s plato platform; and will provide updates on its other gene
therapy pipeline programs in Gaucher, cystinosis and Pompe.

For the Analyst and Investor Event, a live webcast of the presentation
and accompanying slides will be available under “Events
and Presentations
” in the Investors 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 days.

About Fabry Disease

Fabry disease is a rare lysosomal storage disease associated with
significant morbidity and early mortality. It is caused by a gene defect
that causes a deficiency in functional enzyme α-galactosidase A (AGA),
which breaks down a particular type of fat in the body’s cells known as
globotriaosylceramide, or Gb3. As Gb3 and other related substrates
increase in patients with Fabry disease, Gb3 and its metabolites
(principally lyso-Gb3) becomes toxic to the patient’s cells. Gb3 and
other glycosphingolipids accumulate and result in damage to multiple
tissues and organs, especially the kidneys, heart and brain.
Accumulation of Gb3 in tissues such as the heart and the vascular system
can lead to life threatening vascular blockages and thus to stroke and
heart attacks. In addition, high levels of Gb3 substrate accumulation in
the kidney can cause kidney failure. Gb3 can also accumulate in other
tissues, such as the nervous system, where it leads to debilitating
pain. Due to end-stage renal disease and other life-threatening
complications associated with Fabry disease, the average life expectancy
in affected males is approximately 58 years of age. Most patients with
Fabry disease begin experiencing chronic pain in childhood but are often
not diagnosed with Fabry disease until their twenties, due to a broad
variation in patient symptoms. Over 1,000 gene mutations associated with
Fabry disease have been identified. It is estimated that Fabry disease
is diagnosed in approximately one in 40,000 males and one in 118,000
females in the United States, but studies have suggested that a larger
number of patients may be undiagnosed.

About AVR-RD-01

is an ex vivo lentiviral gene therapy being investigated as a
single-dose therapy with the potential to provide durable and life-long
potential therapeutic benefit for patients with Fabry
. AVR-RD-01 is designed to employ a state-of-the-art
lentiviral vector system that is an efficient gene transfer technology
for the permanent integration of functional copies of the gene into the
patient’s own stem cells. In patients with Fabry disease, hematopoietic
stem cells are collected from the patient, and then transduced with
lentiviral vector carrying a functional version of the GLA gene that
encodes active α-galactosidase A (AGA) – the enzyme that is deficient in
Fabry disease – to create AVR-RD-01 gene therapy. AVR-RD-01 is then
infused back into the patient with the goal of restoring normal GLA gene
expression such that functional AGA enzyme is sufficiently produced by
the patient’s own body.

About AVROBIO, Inc.

., is a Phase 2 clinical-stage gene therapy company developing
gene therapies to potentially cure rare diseases with a single dose.
AVROBIO’s lentiviral-based
gene therapies
employ hematopoietic stem cells that are
collected from the patient and then modified with a lentiviral vector to
insert functional copies of the gene that is defective in the target
disease. AVROBIO is focused on the development of its gene therapy,
AVR-RD-01, in Fabry
, as well as additional gene therapy programs in other lysosomal
storage disorders
including Gaucher
, cystinosis
and Pompe
disease. The Company’s plato™ platform is a vector system and automated,
closed, cell manufacturing solution designed to support worldwide
commercialization. AVROBIO is headquartered in Cambridge, MA and has
offices in Toronto, ON. For additional information, visit www.avrobio.com.

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 such as “aims,” “anticipates,” “believes,” “could,”
“estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,”
“possible,” “potential,” “seeks,” “will,” and variations of these words
or similar expressions that are intended to identify forward-looking
statements. These forward-looking statements include, without
limitation, statements regarding our business strategy, prospective
products and goals, the therapeutic potential of our product candidates,
the design, enrollment and timing of ongoing or planned clinical trials,
clinical trial results, product approvals and regulatory pathways,
potential regulatory approvals and the timing thereof, anticipated
benefits of our gene therapy platform, timing and likelihood of success,
plans and objectives of management for future operations, future results
of anticipated products, and the market opportunity for our product
candidates. 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 realize the intended
benefits of our gene therapy 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, 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 Quarterly Report on Form 10-Q for the quarter ended September
30, 2018, 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.

Note regarding trademarks: PLATO is a trademark of AVROBIO. Other
trademarks referenced in this presentation are the property of their
respective owners.

1 The official name of the ’FAB-201 Study’ is AVRO-RD-01-201,
which is a Phase 2 trial of AVROBIO’s investigational gene therapy,
AVR-RD-01, in Fabry disease.

2 FAB-201 Study on clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03454893


Investor Contact:
Christopher F. Brinzey


Kathryn Morris
The Yates Network

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