Prothena Presents Phase 1 Study Results of PRX004 in Oral
Presentation at AAN 2021
Prothena Corporation plc (NASDAQ:PRTA) today presented positive
results from the Phase 1 study of PRX004 as part of the Emerging
Science Session at the American Academy of Neurology (AAN) 2021
Virtual Annual Meeting. PRX004 showed favorable results as
demonstrated by slowing of neuropathy progression for all 7
evaluable patients at 9 months, including improvement in neuropathy
in 3 of the 7 patients, and improved cardiac systolic function for
all 7 patients. In this Phase 1 study, PRX004 was found to be
generally safe and well tolerated across all dose levels. The
positive results were presented by Dr. Ole Suhr, Senior Professor,
Department of Public Health and Clinical Medicine, Umeå University,
gastroenterologist and internist who was a principal investigator
in the study and were previously highlighted by Prothena on
December 9, 2020.
For all of the evaluable patients, slowing of
neuropathy progression was demonstrated by a mean change from
baseline in Neuropathy Impairment Score (NIS) of +1.29 points at 9
months. This compares favorably to a calculated mean change in NIS
of +9.2 points at 9 months in untreated and placebo-treated
patients with hereditary ATTR peripheral neuropathy (hATTR-PN)
based on analysis of published historical data. In addition, the
change in NIS for each of these evaluable patients was more
favorable than the published historical data. In this highly
progressive disease, it was encouraging to see 3 of 7 patients
demonstrate improvement in neuropathy with a mean change in NIS of
–3.33 points at 9 months. These positive results were observed in
patients with or without concomitant use of stabilizer therapy.
PRX004 also demonstrated improvement in cardiac systolic function
in each of the 7 evaluable patients, with a mean change in GLS of
–1.21% at 9 months (centrally read). For the 3 patients who
improved on NIS, GLS improvement was more pronounced, with a mean
change of –1.51% at 9 months. Taken together, these positive
clinical findings suggest PRX004’s depleter mechanism of action can
result in benefits in both neuropathy and cardiac function.
“I was pleased to see evidence of both a slowing
of disease progression as well as a rapid improvement in neuropathy
in some patients after only 9 months of treatment with PRX004.
Given the expected clinical progression in these patients, the more
favorable than expected change in NIS for all 7 patients is an
encouraging finding, as is PRX004’s favorable safety and
tolerability profile,” stated Ole Suhr, MD. “These results
demonstrate the potential of PRX004’s depleter mechanism to provide
a new treatment paradigm that is highly needed to treat patients at
high risk of early mortality due to amyloid deposition in vital
organs.”
Today’s presentation at AAN 2021 will be made
available on the Company’s website at www.prothena.com under the
Investors tab in the Events and Presentations section.
PRX004 Phase 1 Study
The Phase 1, open-label, multicenter
dose-escalation study (NCT03336580) enrolled 21 patients with
hereditary ATTR Amyloidosis (hATTR) to receive PRX004 intravenously
once every 28 days for up to 3 infusions in the dose escalation
phase of the study. Patients were enrolled into 1 of the following
6 PRX004 dose cohorts: 0.1, 0.3, 1, 3, 10, and 30 mg/kg, starting
with the lowest dose. Eligible patients who completed
dose-escalation were provided the opportunity to enroll in the
long-term extension (LTE) portion of the study. All 21 patients
enrolled in the Phase 1 study successfully completed
dose-escalation and 17 patients subsequently enrolled in the
LTE.
In order to inform dose selection, a
pharmacokinetic/pharmacodynamic (PK/PD) model was developed and
subsequently confirmed by observed reductions in free non-native
TTR (transthyretin) in plasma of patients following PRX004
administration. Based on this model, dose levels ≥3 mg/kg were
predicted to saturate (occupy ≥90%) amyloid deposits. Therefore,
cohorts 4, 5 and 6 were considered equivalent, and efficacy was
explored in these patients and pooled. Of the 12 patients in these
cohorts, 7 patients (n=3 in cohort 4, n=3 in cohort 5 and n=1 in
cohort 6) received all infusions through 9 months and were
therefore considered evaluable for efficacy. The remaining 5
patients did not meet these criteria due to COVID-19
pandemic-related disruptions.
PRX004 demonstrated a PK profile consistent with
an lgG1 monoclonal antibody and exposures increased proportionally
with dose.
Monthly intravenous (IV) infusions of PRX004
were generally safe and well tolerated at all dose levels tested,
with 233 separate infusions and up to 17 infusions per patient in
the study. No drug-related serious adverse events (SAEs),
drug-related ≥ grade 3 adverse events, deaths or dose-limiting
toxicities were reported. The most frequent treatment-emergent AEs
(≥10%) were fall, anemia, upper respiratory tract infection, back
pain, constipation, diarrhea and insomnia. No clinically relevant
anti-drug antibodies were observed. Consistent with the proposed
mechanism of action, PRX004 administration did not impact levels of
native, normal tetrameric TTR.
About ATTR Amyloidosis
Transthyretin amyloidosis (ATTR amyloidosis) is
a rare, progressive and fatal disease characterized by deposition
of abnormal, non-native forms of TTR protein (amyloid) in vital
organs. ATTR amyloidosis can be hereditary (hATTR) when caused by a
mutation in the TTR gene, or wild-type (wtATTR) when it occurs
sporadically. Patients can experience a spectrum of clinical
manifestations due to deposition of amyloid that can affect
multiple organs, most commonly the heart and/or nervous system. It
is estimated that between 400,000 to 1.4 million patients suffer
from ATTR-cardiomyopathy (ATTR-CM). Within this population, between
130,000 to 490,000 patients are estimated to be
moderate-to-advanced and categorized as New York Heart Association
Class III and IV. TTR protein is produced primarily in the liver,
pancreas and choroid plexus and in its native tetrameric form
serves as a carrier for thyroxin and retinol binding protein (a
transporter for vitamin A) and has been proposed to have
neuroprotective effects.
About PRX004 and Depleter Mechanism of
Action
PRX004 is an investigational humanized
monoclonal antibody designed to deplete amyloid associated with
disease pathology that underlies hereditary and wild type ATTR
amyloidosis (hATTR and wtATTR, respectively), without affecting the
native, normal tetrameric form of the protein.
It is generally accepted that at the time of
diagnosis, affected organs in ATTR patients contain extracellular
amyloid deposits. These deposits, together with prefibrillar
species, are believed to cause organ dysfunction. PRX004 has been
shown in preclinical studies to promote clearance of insoluble
amyloid fibrils through antibody-mediated phagocytosis and inhibit
amyloid formation. This depleter mechanism of action has the
potential to provide benefit for ATTR patients at high risk for
early mortality due to amyloid deposition in vital organs.
About Prothena
Prothena Corporation plc is a late-stage
clinical company with expertise in protein dysregulation and a
pipeline of novel investigational therapeutics with the potential
to change the course of devastating rare peripheral amyloid and
neurodegenerative diseases. Fueled by its deep scientific expertise
built over decades of research, Prothena is advancing a pipeline of
therapeutic candidates for a number of indications and novel
targets for which its ability to integrate scientific insights
around neurological dysfunction and the biology of misfolded
proteins can be leveraged. Prothena’s pipeline includes both
wholly-owned and partnered programs being developed for the
potential treatment of diseases including AL amyloidosis, ATTR
amyloidosis, Alzheimer’s disease, Parkinson’s disease and a number
of other neurodegenerative diseases. For more information, please
visit the Company’s website at www.prothena.com and follow the
Company on Twitter @ProthenaCorp.
Forward-looking Statements
This press release contains forward-looking
statements. These statements relate to, among other things, the
treatment potential, design and proposed mechanism of action of
PRX004; and the design and capabilities of our misTTR assay for
hereditary ATTR. 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 effects on our business of the
worldwide COVID-19 pandemic and 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 26, 2021, as well as discussions of
potential risks, uncertainties, and other important factors in our
subsequent filings with the SEC. We undertake 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 our expectations.
Contacts:
Media:Ellen Rose, Head of
Communications650-922-2405, ellen.rose@prothena.com
Investors:Jennifer Zibuda,
Director, Investor Relations & Communications650-837-8535,
jennifer.zibuda@prothena.com
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