Prothena Corporation plc (Nasdaq:PRTA), a late-stage clinical
biotechnology company focused on the discovery, development and
commercialization of novel protein immunotherapies, today
highlighted research from two new studies being presented at the
Heart Failure Society of America (HFSA) Annual Scientific Meeting
in Dallas, Texas that further supports the important role of the
cardiac biomarker NT-proBNP in both the biology and clinical
aspects of AL amyloidosis. Preclinical data presented in a
moderated poster talk and poster session at the conference
demonstrated the relationship between misfolded light chain
toxicity to heart cells and production of NT-proBNP. In addition, a
clinical outcomes study also presented by Prothena showed a
correlation between NT-proBNP response and quality of life measures
in patients who have AL amyloidosis with cardiac involvement.
NT-proBNP is a cardiac biomarker that has been shown in multiple
independent studies to predict survival in patients with AL
amyloidosis (Merlini, et. al, Leukemia, 2016).
“These results provide new insights into the
important role of NT-proBNP in AL amyloidosis, unique from other
forms of heart failure, and offer further support for the clinical
utility of NT-proBNP as a surrogate biomarker in AL amyloidosis
studies,” said Sarah Noonberg, MD, Ph.D., Chief Medical Officer of
Prothena. “Furthermore, data from our clinical outcomes research
demonstrate a clinically meaningful relationship between NT-proBNP
response and quality of life improvements that are highly relevant
to patients, and will be further evaluated in our two late-stage
studies of NEOD001.”
New preclinical research supports
relationship between lowering of NT-proBNP and improved survival in
patients with AL amyloidosis
New preclinical research presented at HFSA
provides mechanistic insight into how misfolded light chains induce
cardiotoxicity and increase NT-proBNP production. Prothena’s
research demonstrated that aggregated light chain induces oxidative
stress and leads to an increase in expression of the oxidative
response marker heme oxygenase-1 (Hmox-1) in cardiomyocytes. The
research further showed that NT-proBNP secretion is increased by
aggregated light chain, via a mechanism dependent on Hmox-1
catalytic activity. Aggregated light chain exhibited dose-dependent
binding to cardiomyocytes, suggesting that the observed effect is
driven by the direct interaction between aggregated light chains
and cardiomyocytes.
Taken together, these results support the
finding that aggregated light chain induces cardiomyocyte toxicity
and provides a direct link between the misfolded protein and
NT-proBNP elevation in AL amyloidosis.
Furthermore, these data indicate that the role
of NT-proBNP in AL amyloidosis is differentiated from other forms
of heart failure, and support the relationship that has been
reported between lowering of NT-proBNP and improved cardiac
function and survival in patients with AL amyloidosis.
Clinical outcomes research demonstrates
NT-proBNP response is associated with clinically meaningful
improvements in health-related quality of life in patients with AL
amyloidosis
New clinical outcomes research also presented by
Prothena at HFSA establishes for the first time a correlation
between NT-proBNP response and health-related quality of life
measures. In this study, data were extracted from a community-based
sample of 108 patients with AL amyloidosis and validated against
patient health records from an AL amyloidosis Center of Excellence
(COE) sample of 95 patients. All patients in both samples had AL
amyloidosis with cardiac involvement. Patients' health-related
quality of life was evaluated using the SF-36® Health Survey for
eight domains of functional health and well-being that provided two
summary scores, one physical and one mental. Patients in the
community-based sample were also evaluated by the Kansas City
Cardiomyopathy Questionnaire – Short Form (KCCQ-12), a validated
health-related quality of life measure that is specific to heart
failure.
In the community-based sample (n=108), cardiac
response was defined as a 30 percent or greater decrease in
NT-proBNP. Differences in SF-36 scores for patients with and
without a previous response in NT-proBNP were statistically
significant (p<0.05 for all domains and both summary scores) and
clinically meaningful. In addition, patients with a history of
cardiac response reported SF-36 scores that were significantly
better than existing congestive heart failure (CHF) benchmarks
across all SF-36 domains and both summary components.
Differences in burden of disease as measured by
KCCQ-12 scores for patients with and without previous NT-pro-BNP
response were also statistically significant (p < 0.05 for all
subscales). The average total KCCQ-12 score for patients with a
history of NT-proBNP response (n=75) was 66, which corresponds to
scores previously observed in patients with New York Heart
Association (NYHA) functional class II symptoms, indicating slight
limitation in physical activity. The average score for patients
with no history of NT-proBNP response (n=33) was 42, which
corresponds to scores previously observed in patients with NYHA
functional class III symptoms, indicating a marked limitation in
physical activity.
Results from the AL amyloidosis Center of
Excellence validation patient cohort (n=95) showed comparable
findings.
This study demonstrates the relationship between
the cardiac biomarker NT-proBNP with health-related quality of life
using multiple data sources and different analytic approaches. The
data further support that NT-proBNP may be a useful surrogate
measure for health-related quality of life and burden of disease
classification of patients.
About NEOD001
NEOD001 is an investigational first-in-class
antibody that specifically targets disease-causing misfolded light
chain aggregates in AL amyloidosis. There are two ongoing global
clinical studies for NEOD001. The PRONTO study, a global, Phase 2b,
double-blind, placebo-controlled, registration-directed study, will
evaluate NEOD001 vs. placebo in previously-treated patients with AL
amyloidosis and persistent cardiac dysfunction, and will assess
best response over 12 months of the cardiac biomarker NT-proBNP,
defined by the consensus criteria of NT-proBNP change, in addition
to other biomarker, quality of life and functional endpoints.
The VITAL Amyloidosis Study, a global, Phase 3, double-blind,
placebo-controlled, registrational study, is evaluating NEOD001 vs.
placebo in newly-diagnosed, treatment-naïve patients with AL
amyloidosis and cardiac dysfunction, with both arms of the study
receiving standard of care. The VITAL study will assess a composite
endpoint of all-cause mortality or cardiac hospitalizations in
addition to biomarker, quality of life and functional endpoints.
More information on the PRONTO study and The VITAL Amyloidosis
Study is available at www.clinicaltrials.gov, by searching NCT
#02632786 for PRONTO, and NCT #02312206 for VITAL or
www.clinicaltrialsregister.eu, by searching
EudraCT #2015-004318-14 for PRONTO, and EudraCT
#2014-003865-11 for VITAL.
About AL Amyloidosis
Systemic amyloidoses are a complex group of
diseases caused by tissue deposition of misfolded proteins that
result in progressive organ damage. AL amyloidosis, the most common
type, is a rare, progressive, and typically fatal disease caused by
extracellular deposition of misfolded immunoglobulin light chains.
An excess of light chains prone to misfolding are produced by
clonal plasma cells. Soluble toxic aggregates and deposited
fibrils (amyloid) lead to progressive failure of vital organs
including the heart, kidneys and nervous system, causing
significant morbidity and mortality. It is estimated that
approximately 30,000 – 45,000 patients in the U.S. and Europe
suffer from this disease. There are no approved treatments for AL
amyloidosis, although patients may be treated with off-label
therapies directed at the plasma cell dyscrasia. There is a large
unmet need for therapies that specifically target soluble toxic
aggregates and deposited fibrils, thereby improving vital organ
function. For more information on AL amyloidosis, please visit the
websites of the Amyloidosis Support Groups, The Amyloidosis
Research Consortium, and the Amyloidosis Foundation.
About Prothena
Prothena Corporation plc is a global, late-stage
clinical biotechnology company establishing fully-integrated
research, development and commercial capabilities. Fueled by its
deep scientific understanding built over decades of research in
protein misfolding and cell adhesion — the root causes of many
serious or currently untreatable amyloid and inflammatory diseases
— Prothena seeks to fundamentally change the course of progressive
diseases associated with this biology. The Company’s pipeline of
antibody therapeutic candidates targets a number of indications
including AL amyloidosis (NEOD001), Parkinson’s disease and other
related synucleinopathies (PRX002/RG7935), inflammatory diseases,
including psoriasis and psoriatic arthritis (PRX003), and ATTR
amyloidosis (PRX004). The Company continues discovery of additional
novel therapeutic candidates where its deep scientific
understanding of disease pathology can be leveraged. For more
information, please visit the Company’s website
at www.prothena.com.
Forward-looking Statements
This press release contains forward-looking
statements. These statements relate to, among other things, the
relationship between misfolded light chain toxicity and NT-proBNP
production; the correlation between NT-proBNP response and
health-related quality of life; whether aggregated light chain
induces cardiomyocyte toxicity; the clinical utility of NT-proBNP
as a surrogate biomarker in AL amyloidosis; and the correlation
between lowering of NT-proBNP and improved cardiac function and
survival in patients with AL amyloidosis. These statements are
based on estimates, projections and assumptions that may prove not
to be accurate, and actual results could differ materially from
those anticipated due to known and unknown risks, uncertainties and
other factors, including but not limited to the risks,
uncertainties and other factors described in the “Risk Factors”
sections of our Annual Report on Form 10-K filed with the
Securities and Exchange Commission (SEC) on February 27, 2017 and
our subsequent Quarterly Reports on Form 10-Q filed with the SEC.
Prothena undertakes no obligation to update publicly any
forward-looking statements contained in this press release as a
result of new information, future events or changes in Prothena's
expectations.
Media & Investor
Contact:
Ellen Rose, Head of Communications 650-922-2405,
ellen.rose@prothena.com
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