uniQure Announces Hemophilia B Gene Therapy Program To Enter Pivotal Study With FIX-Padua Variant in 2018
October 19 2017 - 7:00AM
~ AMT-060 with the FIX-Padua Modification
(AMT-061) Demonstrates Substantial Increase in FIX Activity in
Non-human Primates ~
uniQure N.V. (NASDAQ:QURE), a leading gene therapy company
advancing transformative therapies for patients with severe medical
needs, today announced that following multi-disciplinary meetings
with the U.S. Food and Drug Administration (FDA) and the European
Medicines Agency (EMA), the company plans to expeditiously advance
AMT-061, which combines an AAV5 vector with the FIX-Padua mutant,
into a pivotal study in 2018 for patients with severe and
moderately severe hemophilia B.
AMT-061 and AMT-060, the latter of which has
been tested in 10 patients in an ongoing Phase I/II clinical trial,
are identical in structure apart from two nucleotide substitutions
in the coding sequence for FIX. The gene variant, referred to
as FIX-Padua, expresses a protein with a single amino acid
substitution that has been reported in multiple preclinical and
nonclinical studies to provide an approximate 8 to 9-fold increase
in FIX activity compared to the wild-type FIX protein. All other
critical quality attributes of AMT-061 are expected to be
comparable to those of AMT-060, as AMT-061 utilizes the same AAV5
capsid and proprietary insect cell-based manufacturing
platform.
“Our mission in hemophilia B has always been to
develop the safest and most effective gene therapy with the
broadest application to patients. We believe AMT-061 moves us
closer to this goal, as it has the potential to provide optimized
clinical and tolerability benefits to nearly all severe and
moderately severe patients with hemophilia B,” stated Matthew
Kapusta, chief executive officer of uniQure. “We are
delighted to have received constructive guidance from both the FDA
and EMA, which we believe allows us to expeditiously advance
AMT-061 into a pivotal study next year, as previously planned. In
anticipation of this, we have begun GMP production of AMT-061 in
our Lexington facility and preparations for the pivotal study are
underway.”
“I believe AMT-061 has the potential to be an
important gene therapy for patients suffering with hemophilia B,”
stated Steven Pipe, M.D., professor of pediatrics and pathology and
pediatric medical director of the hemophilia and coagulation
disorders program at the University of Michigan. “Based on the data
generated to date, AMT-061 may be the first gene therapy to provide
durable, curative benefits to nearly all patients with hemophilia
B, without the complications associated with capsid-related immune
responses. I very much look forward to serving as an
investigator in this exciting Phase III program.”
Clinical and Regulatory Pathway for AMT-061
- The FDA has agreed that AMT-061 will be included under the
existing Breakthrough Therapy designation and Investigational New
Drug (IND) for AMT-060. The EMA also has agreed that AMT-061 will
be included under the current PRIME designation.
- The Company achieved general agreement with the FDA and EMA on
the proposed pivotal trial plan for AMT-061. The study is expected
to be an open-label, single-dose, multi-center, multi-national
trial investigating the efficacy and safety of AMT-061 administered
to adult patients with severe or moderately severe hemophilia B.
The primary objective of the trial is to evaluate AMT-061 for
prevention of bleedings. Secondary objectives include additional
efficacy and safety aspects. Patients will serve as their own
control, with a baseline established during a six-month
observational lead-in phase prior to treatment with AMT-061.
- Concurrent with the start of the six-month lead-in phase of the
pivotal study, a short dose-confirmation study is expected to begin
in the third quarter of 2018. Three patients will receive a single
intravenous (IV) dose of AMT-061 at 2 x 1013 gc/kg and will be
evaluated for a period of approximately six weeks to assess FIX
activity levels and confirm the dose. Each patient will
continue to be followed longer term, and no lead-in phase is
required for the dose confirmation study.
AMT-061 Nonclinical Data Demonstrate
Tolerability and Substantial Increases in FIX Activity
- A Good Laboratory Practices (GLP), nonclinical study of AMT-061
has been performed in non-human primates at four different dose
levels up to a dose of 9 x 1013 gc/kg. The purpose of this study
was to compare AMT-061 to AMT-060 with respect to liver
transduction, circulating FIX protein levels, circulating FIX
activity levels and toxicity, after a single intravenous dose with
13- or 26-week observation periods.
- Data from the study demonstrated a strong correlation between
dose and human FIX (hFIX) expression levels, as well as biological
activity of the expressed hFIX protein. At equal doses,
circulating vector DNA plasma levels, liver distribution, liver
cell transduction and hFIX protein expression were comparable for
both AMT-060 and AMT-061. Additionally, AMT-061 demonstrated
substantial increases in hFIX clotting activity compared to
AMT-060, consistent with those previously reported for
FIX-Padua.
- Based on a statistical analysis of the AMT-061 and AMT-060
non-human primate data, as well as the clinical data from the Phase
I/II trial of AMT-060, the Company believes that AMT-061
administered at a dose of 2 x 1013 gc/kg may lead to mean FIX
activity of approximately 30 to 50 percent of normal.
- The study also examined toxicology of AMT-061, including liver
enzyme activity, coagulation biomarkers and other safety
parameters. Data from the study demonstrated that AMT-061 was
well-tolerated with no evidence of any significant toxicological
findings. There was no increased thrombin generation or
increased fibrin formation or degradation detected during the six
months of follow-up. No increase in
immunogenicity is expected with AMT-061, as there are no changes in
the AAV5 capsid.
AMT-061 Continues to Leverage AAV5’s Favorable
Tolerability and Immunogenicity Results
- AAV5-based gene therapies have been demonstrated to be
generally safe and well-tolerated in a multitude of clinical
trials, including three uniQure trials conducted in 22 patients in
hemophilia B and other indications.
- In contrast to data reported using other AAV capsids delivered
systemically via IV infusion, no patient treated in clinical trials
with the Company’s AAV5 gene therapies has experienced any
confirmed, T-cell-mediated immune response to the capsid or
material loss of FIX activity.
- An independent clinical trial has demonstrated that AAV5 has
the lowest prevalence of preexisting neutralizing antibodies (NAb)
compared to other AAV vectors. Data from the Phase I/II study
of AMT-060 also demonstrated clinical proof-of-concept in the
presence of preexisting NAb to AAV5, suggesting that all, or nearly
all hemophilia B patients may be eligible for treatment with
AMT-061.
Commercial-scale, GMP Manufacturing of AMT-061
Clinical Material Underway
- uniQure has initiated production of multiple clinical-grade
batches of AMT-061 in its state-of-the-art Lexington, MA
manufacturing facility. Material is being produced at commercial
scale and utilizing current Good Manufacturing Practices
(cGMP). uniQure expects to begin releasing product for the
pivotal trial by the first quarter of 2018. The manufacturing
process, controls and methods utilized for AMT-061 are consistent
to those previously used for AMT-060.
- The Company has achieved alignment with the FDA and EMA on its
plan to establish comparability between AMT-061 and AMT-060.
uniQure expects to complete its ongoing comparability analysis and
plans to submit the data to the agencies for review in the first
quarter of 2018. Data reviewed to date support comparability
between AMT-061 and AMT-060.
Exclusive Patent Covers the Use of Padua in Gene Therapy for
Hemophilia B
- In a separate press release, uniQure today announced that it
has acquired a patent family that broadly covers the FIX-Padua
variant and its use in gene therapy for the treatment of
coagulopathies, including hemophilia B. This family includes a
patent issued in the U.S., as well as pending patent applications
in Europe and Canada. uniQure recently filed divisional
patent applications that would further strengthen its intellectual
property position related to the FIX-Padua variant.
- The patent family was acquired from Professor Paolo Simioni, a
renowned hemophilia expert at the University of Padua, Italy, who
is widely recognized as the first to identify the mutation.
Professor Simioni is serving as an advisor and consultant
exclusively to uniQure for the development of gene therapy products
using his invention. He is expected to assist the Company in
its discussions with regulators, investigators and key opinion
leaders throughout the clinical development of AMT-061.
Conference Call Information
uniQure will host a conference call today,
October 19, 2017 at 8:30 a.m. ET to discuss this
announcement. To access the live call by phone, dial (877)
280-2296 (United States) or +44 (0)20 3427 1900 (international);
the conference ID is 2516119. The call may also be accessed
through the Investors section of the Company’s website at
www.uniQure.com. Following the live webcast, a replay of the
call will be available at the same location through November 2,
2017.
About uniQure uniQure is
delivering on the promise of gene therapy – single treatments with
potentially curative results. We are leveraging our modular and
validated technology platform to rapidly advance a pipeline of
proprietary and partnered gene therapies to treat patients with
hemophilia, Huntington’s disease and cardiovascular diseases.
www.uniQure.com
uniQure Forward-Looking
Statements
This press release contains forward-looking statements. All
statements other than statements of historical fact are
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Forward-looking statements are based on management's beliefs and
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the date of this press release. These forward-looking statements
include, but are not limited to, the development of our gene
therapy product candidates, the success of our collaborations and
the risk of cessation, delay or lack of success of any of our
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reasons, including, without limitation, risks associated with our
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collaboration arrangements, corporate reorganizations and strategic
shifts, regulatory oversight, product commercialization and
intellectual property claims, as well as the risks, uncertainties
and other factors described under the heading "Risk Factors" in
uniQure’s Quarterly Report on Form 10-Q filed on August 8, 2017.
Given these risks, uncertainties and other factors, you should not
place undue reliance on these forward-looking statements, and we
assume no obligation to update these forward-looking statements,
even if new information becomes available in the future.
uniQure Contacts
For Investors:
Maria E. CantorDirect:
339-970-7536Mobile: 617-680-9452m.cantor@uniQure.com
Eva M.
Mulder
Direct: +31 20 240 6103 Mobile: +31 6 52 33 15
79e.mulder@uniQure.com
For Media:
Tom MaloneDirect: 339-970-7558Mobile:
339-223-8541t.malone@uniQure.com
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