uniQure Announces Findings from Reported Case of Hepatocellular
Carcinoma (HCC) in Hemophilia B Gene Therapy Program
uniQure N.V. (NASDAQ: QURE), a leading gene therapy company
advancing transformative therapies for patients with severe medical
needs, announced today the results of a comprehensive investigation
into the case of hepatocellular carcinoma (HCC) diagnosed in one
patient in the HOPE-B pivotal trial of etranacogene dezaparvovec.
The results of the investigation found that it is highly unlikely
the HCC was caused by etranacogene dezaparvovec.
Multiple analyses conducted by an independent
laboratory and reviewed by leading external experts in the field
show that AAV vector integration in the patient’s tissue sample was
extremely rare and accounted for 0.027% of the cells in the sample.
The integration events were distributed randomly across the genome,
and there was no evidence of clonal expansion or any dominant
integration event. Additionally, whole genome sequencing of the
tumor confirmed that the patient had several genetic mutations that
are characteristic of HCC and are independent of vector
integration. Finally, gene expression analysis of the tumor and
adjacent tissue suggested a precancerous state in the liver
consistent with several risk factors that predispose this patient
to HCC.
“This investigation has employed several
complementary genomic approaches to evaluate the involvement of the
AAV vector in the development of the liver cell cancer in this
patient,” stated David Lillicrap, M.D., FRCPC, Professor of the
Department of Pathology and Molecular Medicine, Queen’s University,
Kingston, Canada. “The investigations that have been
performed have shown no evidence to suggest that the AAV vector
delivered in the HOPE-B study has played a pathogenic role in the
hepatocellular cancer that has now been diagnosed in the
patient.”
“The external lab analyzed more than 220,000
cells from the tissue sample and identified 60 cells with random
integration events that have no known association with the
development of HCC,” stated Ricardo Dolmetsch, president of
research and development at uniQure. “Moreover, whole genome
sequencing of the tumor showed that this patient had large
abnormalities on chromosomes 1 and 8 that are commonly associated
with HCC, as well as mutation of TP53 and several other potentially
oncogenic genes.”
“Taken together, the findings from this
investigation strongly suggest that etranacogene dezaparvovec did
not contribute to this case of HCC,” he added. “We have now shared
these data with the FDA and are prepared to have further
communications regarding the status of the clinical hold in the
second quarter of 2021. We also expect to submit the data for
presentation at an upcoming industry conference yet to be
determined.”
The FDA placed a clinical hold on uniQure’s
hemophilia B program following the submission of a safety report in
mid-December 2020 of a possibly related serious adverse event
associated with a preliminary diagnosis of HCC in one patient in
the HOPE-B trial. The patient has multiple risk factors associated
with HCC, including a twenty-five-year history of hepatitis C
(HCV), history of hepatitis B (HBV), evidence of non-alcoholic
fatty liver disease, history of smoking, familial history of cancer
and advanced age. Chronic infections with hepatitis B and C have
been associated with approximately 80% of HCC cases.1
The liver lesion was detected during a routine
abdominal ultrasound conducted as part of the required study
assessments in patients at one-year post dosing. A surgical
resection was conducted along with a small biopsy of adjacent liver
tissue and analyzed to determine whether etranacogene dezaparvovec
was integrated into the tumor and whether the integration caused
malignancy. Polymerase chain reaction analysis of the integration
sites and whole genome sequencing also were performed.
All patients in uniQure’s hemophilia B gene
therapy program, including the 54 patients in HOPE-B, have now had
abdominal ultrasounds performed one year after dosing, and each
will continue to be monitored by their care teams. No other cases
of HCC have been reported in uniQure clinical trials conducted in
more than 100 patients in hemophilia B and other indications, with
some patients dosed more than 10 years ago.
“Based on the results from this very thorough
investigation involving an independent lab and several expert
reviews, we believe it is very unlikely that etranacogene
dezaparvovec is related to the HCC event in the HOPE-B study,”
stated Matt Kapusta, chief executive officer of uniQure. “Patient
safety will always be our top priority, and we are prepared to
discuss with the FDA the recently submitted analyses and the status
of the clinical hold as expeditiously as possible. As stated
previously, we do not anticipate any impact to the HOPE-B pivotal
study or our regulatory submission timeline as a result of the
clinical hold.”
About Etranacogene
Dezaparvovec
Etranacogene dezaparvovec consists of an AAV5
viral vector carrying a gene cassette with the patent-protected
Padua variant of Factor IX (FIX-Padua). uniQure holds multiple
issued patents in the United States and Canada broadly covering
methods of treating bleeding disorders, including hemophilia B,
using AAV gene therapy with the FIX-Padua variant. Etranacogene
dezaparvovec has been granted Breakthrough Therapy Designation by
the United States Food and Drug Administration and access to
Priority Medicine (PRIME) regulatory initiative by the European
Medicines Agency. In June 2020, the Company and CSL Behring entered
into a licensing agreement providing CSL Behring with exclusive
global rights to etranacogene dezaparvovec. This licensing
agreement has cleared antitrust regulatory review in Australia and
the United Kingdom and is subject to ongoing review in the United
States.
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 gene therapies to treat
patients with hemophilia B, Huntington's disease, Fabry disease,
spinocerebellar ataxia Type 3 and other
diseases. www.uniQure.com
uniQure Forward-Looking
StatementsThis press release contains forward-looking
statements. All statements other than statements of historical fact
are forward-looking statements, which are often indicated by terms
such as "anticipate," "believe," "could," "estimate," "expect,"
"goal," "intend," "look forward to", "may," "plan," "potential,"
"predict," "project," "should," "will," "would" and similar
expressions. Forward-looking statements are based on management's
beliefs and assumptions and on information available to management
only as of the date of this press release. These forward-looking
statements include, but are not limited to, whether there will be
any impact to our regulatory submission timeline for the hemophilia
B program as a result of this clinical hold. Our actual results
could differ materially from those anticipated in these
forward-looking statements for many reasons, including, without
limitation, the risk that the Company has not and may not be able
to definitively determine whether etranacogene dezaparvovec caused
the reported case of hepatocellular carcinoma (HCC) in a timely
manner, or at all; the risk that additional cases of HCC will be
discovered or reported in patients treated with etranadez
dezaparvovec over time; the risk that regulatory authorities may
not agree with the Company’s findings from the HCC investigation or
remove the clinical hold from our clinical trials of etranacogene
dezaparvovec or may impose a clinical hold on additional programs;
the risk that we may not be able to address regulatory authorities’
concerns quickly or at all; and the risk that our vector platform
across our development programs may be implicated, affecting the
development and potential approval of other products in
development, as well as the risks, uncertainties and other factors
described under the heading "Risk Factors" in uniQure’s Quarterly
Report on Form 10-K filed on March 1, 2021. 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: |
|
FOR MEDIA: |
|
|
|
Maria E. Cantor |
Chiara Russo |
Tom Malone |
Direct: 339-970-7536 |
Direct: 617-306-9137 |
Direct: 339-970-7558 |
Mobile: 617-680-9452 |
Mobile: 617-306-9137 |
Mobile:339-223-8541 |
m.cantor@uniQure.com |
c.russo@uniQure.com |
t.malone@uniQure.com |
_____________________________1 El-Serag HB. Epidemiology of
viral hepatitis and hepatocellular carcinoma. Gastroenterology.
2012 May;142(6):1264-1273.e1. doi: 10.1053/j.gastro.2011.12.061.
PMID: 22537432; PMCID: PMC3338949.
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