Prothena Corporation plc
PRTA, a late-stage clinical biotechnology company focused on the
discovery, development and commercialization of novel antibodies for the
potential treatment of diseases that involve amyloid or cell adhesion, today
announced the initiation of the VITAL Amyloidosis Study, an international,
multi-center, registrational Phase 3 clinical trial, based on positive results
from an ongoing Phase 1/2 clinical study of NEOD001 in patients with AL
amyloidosis and persistent organ dysfunction.
"The results of our ongoing Phase 1/2 clinical study confirm and strengthen
data presented in April 2014 at the XIV International Symposium on Amyloidosis
and I'm pleased to report that as of September 30, 2014, we believe that the
primary and secondary endpoints of the trial have been met. Importantly, we
believe the robust 50.0% cardiac and 42.9% renal best response rates in
patients treated with NEOD001 compare favorably with historical data that
would have predicted 26.5% cardiac and approximately 24% renal response rates
in patients treated solely with off-label standard of care," said Gene Kinney,
PhD, Chief Scientific Officer and Head of Research and Development at
Prothena. "We look forward to further evaluation of NEOD001 in the expansion
portion of our Phase 1/2 study that is currently enrolling additional patients
with AL amyloidosis and selected persistent organ dysfunction for which we
expect to present initial results in 2015, and annually thereafter. Today,
following favorable conversations with the US and EU regulatory bodies, we are
excited to announce initiation of the VITAL study, our registrational Phase 3
trial in newly-diagnosed, treatment-naïve patients with AL amyloidosis."
Cardiac and Renal Biomarker Responses in Phase 1/2 Study
Seven of 14 cardiac-evaluable patients (50.0%) treated with NEOD001
demonstrated a cardiac response, defined as more than 30.0% and 300 pg/mL
decrease in levels of NT-proBNP (a validated cardiac biomarker associated with
mortality). Cardiac responders, on average, showed more NT-proBNP decline with
added monthly NEOD001 infusions. The 50.0% cardiac response rate compares
favorably with the expected results of a 26.5% cardiac response rate from
historical data in patients treated solely with off-label standard of care
(Comenzo, et al., Leukemia. 2012;26:2317-2325). As noted in numerous
peer-reviewed publications, increasing levels of NT-proBNP predicts higher
mortality rates in patients with AL amyloidosis. Conversely, decreasing levels
of NT-proBNP predicts lower mortality rates.
In a best response analysis of renal-evaluable patients treated with NEOD001,
six of 14 renal-evaluable patients (42.9%) demonstrated a response, defined as
a 30.0% decrease in proteinuria in the absence of estimated glomerular
filtration rate (eGFR) worsening. The 42.9% renal response rate compares
favorably with the expected results of an approximately 24% renal response
rate from historical data in patients treated solely with off-label standard
of care (Palladini, et al., Blood. 2014 124: 2325-2332). Increased levels of
proteinuria and decreased eGFR predicts faster progression to dialysis where
decreased levels of proteinuria and increased eGFR predicts delayed time to
dialysis.
"NEOD001 potentially holds significant promise for patients with AL
amyloidosis as we now see clinically meaningful decreases in both cardiac and
renal biomarkers with monthly NEOD001 infusions," said Raymond L. Comenzo, MD,
Professor of Medicine and Pathology at Tufts University School of Medicine.
"NEOD001 appears to be the first agent that works directly to address the
buildup of light-chain (AL) amyloid in organs. The results presented today
strongly support moving into a Phase 3 trial, which I believe is designed to
test whether or not NEOD001 provides meaningful clinical benefit for patients
with AL amyloidosis."
Mechanism of Action
The clinical results demonstrated to date expand on more than a decade of
amyloid research. NEOD001 elicits a rapid response initially, and a deepening
response with additional monthly infusions. The results are consistent with
the mechanism of action showing that NEOD001 functions in two ways:
neutralization of circulating soluble amyloid and clearance of deposited
insoluble amyloid within affected organs. The Phase 1/2 data supports that
NEOD001 acts as a disease-modifying agent in AL amyloidosis which is distinct
from current off-label standard of care therapies that attempt to solely
reduce production of immunoglobulin light chain and are associated with
adverse events.
Safety, Tolerability, Pharmacokinetics and Immunogenicity
Data from the Phase 1/2 study continued to demonstrate that chronic monthly
infusions of NEOD001 are safe and well-tolerated in patients with AL
amyloidosis and persistent organ dysfunction. A database analysis as of
September 30, 2014 showed a total of 27 patients in seven dosing cohorts
received 209 infusions, with each patient treated on average for approximately
eight months. No hypersensitivity reactions or drug-related serious adverse
events were reported and no anti-NEOD001 antibodies were detected. NEOD001
demonstrated excellent pharmacokinetic properties, supporting a dose level of
24 mg/kg on a 28 day cycle. The most frequently reported adverse events (more
than 10% of subjects) were fatigue, cough, dyspnea, diarrhea, upper
respiratory infection, anemia, headache, hyponatremia, nausea and edema. All
adverse events were mild to moderate and no dose limiting toxicities have been
observed. As of September 30, 2014, 19 patients continue on therapy (eight
patients discontinued). No patient discontinued due to drug-related adverse
events. Following selection of 24 mg/kg as the Phase 3 recommended dose, in
consultation with their treating physician, 13 out of 14 eligible patients
continuing in the dose escalation portion of the Phase 1/2 study have chosen
to escalate to 24 mg/kg.
Expansion Portion of Phase 1/2 Study
Prothena is now enrolling up to an additional 25 patients, with AL amyloidosis
and selected persistent organ dysfunction, in an open-label expansion portion
of the Phase 1/2 study. The company plans to enroll 10 patients with cardiac
dysfunction, 10 patients with renal dysfunction and five patients with
peripheral neuropathy, all of whom will receive 24 mg/kg intravenously every
28 days. The expansion phase will continue to evaluate safety, tolerability,
pharmacokinetics and immunogenicity of NEOD001 as well as the specific
clinical activity against cardiac, renal and neuropathy biomarkers. The
company expects to present results from the NEOD001 expansion portion of the
Phase 1/2 study at least once annually at appropriate medical conferences,
beginning in 2015.
VITAL Phase 3 Registrational Trial Design
The multi-center, randomized, double-blind, placebo-controlled Phase 3 study
continues Prothena's commitment to provide disease-modifying therapeutic
alternatives for patients suffering from AL amyloidosis. The trial is designed
to support global regulatory approvals and to enroll approximately 230
newly-diagnosed, treatment-naïve patients with cardiac dysfunction. Patients
will be randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo
via infusion every 28 days, with both arms receiving concurrent standard of
care therapy.
The composite primary endpoint is event-based, with all-cause mortality or
cardiac hospitalizations as qualifying events. Secondary endpoints of the
study include evaluation of the cardiac biomarker NT-proBNP, renal biomarker
proteinuria, six-minute walk test, and multiple quality of life evaluations
including SF-36 and the Kansas City Cardiomyopathy Questionnaire. Prothena
designed the study with 90% power to detect as little as 30% change in the
event rate between the treatment and placebo groups with a two-sided alpha of
0.05. The trial allows for an interim analysis to assess the primary endpoint
for efficacy and futility.
"Based on the encouraging results from our ongoing NEOD001 Phase 1/2 clinical
study, which confirms safety, tolerability and pharmacokinetic properties, and
noteworthy responses in patients with organ dysfunction, we are pleased to
initiate the VITAL study, our global Phase 3 trial for newly-diagnosed,
treatment-naïve patients with AL amyloidosis," said Dale Schenk, PhD,
President and Chief Executive Officer of Prothena. "We believe the responses
in multiple organs of NEOD001-treated patients compare favorably to historic
data in AL amyloidosis, and support and inform the initiation of the VITAL
study, our global Phase 3 registrational trial."
"This is an important event for the AL amyloidosis community, who is in
desperate need of new safe and well tolerated therapeutic alternatives for
this deadly, progressive disease. It is also a significant corporate milestone
for Prothena, as it marks the first Phase 3 program to evaluate a
disease-modifying agent targeting toxic amyloid in AL amyloidosis," continued
Dr. Schenk.
Conference Call Details
Prothena management will discuss these new Phase 1/2 study results with
NEOD001 for the treatment of AL amyloidosis in addition to the Phase 3 study
design for NEOD001, in a live audio webcast and conference call today,
Tuesday, December 2, 2014 at 4:30 p.m. ET. The webcast and slide presentation
will be made available on the company's website at www.prothena.com under the
Investors tab in the Events and Presentations section. Following the live
audio webcast, a replay of the webcast will be available on the Company's
website for 90 days.
To access the call via dial-in, please dial (877) 887-5215 (U.S. toll free) or
(315) 625-3069 (international) five minutes prior to the start time and refer
to conference ID number 42271521. The webcast will be available at
http://ir.prothena.com. A replay of the call will be available until December
9, 2014 via dial-in at (855) 859-2056 (U.S. toll free) or (404) 537-3406
(international), Conference ID Number 42271521.
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