− Patisiran Global Open-Label Extension (OLE)
Study Demonstrates Maintained Reversal of Disease Progression and
Consistent Safety Profile, with Greater Than Four Years of Patient
Experience and Over 6,000 Doses Administered –
− APOLLO Patients Previously on Tafamidis
Benefited from Patisiran with Improvements in Neuropathy Impairment
and Quality of Life –
− Indirect Treatment Comparison Results Show
Favorable Treatment Effects of Patisiran Relative to Inotersen
Across All Endpoints Evaluated –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today new results from the Global
Open-Label Extension (OLE) study of ONPATTRO®
(patisiran), an RNAi therapeutic for the treatment of the
polyneuropathy of hereditary ATTR (hATTR) amyloidosis. Results were
presented at the 2019 Peripheral Nerve Society (PNS) Annual
Meeting, being held June 22-26, 2019 in Genoa, Italy. In addition,
the Company reported on new analyses from the APOLLO Phase 3 study
of patisiran and results of an indirect treatment comparison of
patisiran and inotersen.
“With over four years of patient experience with ONPATTRO and
more than 6,000 doses administered in our OLE study, we are pleased
to see that hATTR amyloidosis patients with polyneuropathy continue
to experience durable improvement, with ONPATTRO maintaining
reversal of neuropathy impairment and an encouraging safety
profile,” said Eric Green, Senior Vice President and General
Manager, TTR Program at Alnylam. “Additional analyses from APOLLO
showed that patients previously treated with tafamidis experienced
improvements in both neuropathy impairment and quality of life with
patisiran.”
“It’s encouraging to see durable evidence of improvement with
patisiran. Based on its unique mechanism of action with potent
knockdown of serum TTR and an encouraging tolerability profile,
these long-term data continue to highlight the potential for
meaningful clinical benefit with patisiran treatment,” said Michael
Polydefkis, M.D., MHS, Professor, Johns Hopkins Neurology. “In
addition, these results also highlight the need to avoid any delays
in treatment to prevent accumulation of greater disease burden in
hATTR amyloidosis patients with polyneuropathy.”
Results from Global OLE Study
12-month interim results were presented from the ongoing Global
OLE study of patisiran evaluating the drug’s long-term efficacy and
safety in eligible patients (N=211) who completed the Phase 2 OLE
(N=25) and Phase 3 APOLLO (N=186) studies. The data presented were
as of a September 24, 2018 data cutoff date. Serum transthyretin
(TTR) levels were reduced by approximately 80 percent at 6 months
in patients in the placebo arm of APOLLO who started treatment with
patisiran, and were durably maintained over time. Patients on
treatment for 30 to 36 months demonstrated sustained improvement in
neuropathy impairment and quality of life relative to corresponding
parent study baselines, as demonstrated by mean negative changes in
modified Neuropathy Impairment Score + 7 (mNIS+7) and Quality of
Life – Diabetic Neuropathy (QOL-DN) scores, respectively.
Furthermore, the rapid trajectory of disease progression among
APOLLO placebo patients was halted and, in a majority of patients
reversed, once patisiran treatment was initiated in the Global OLE.
Nevertheless, placebo patients did not return to their parent study
baseline, as measured by mNIS+7 or QOL-DN scores, due to the
disease worsening experienced while on placebo in APOLLO,
highlighting the important need for early treatment with
patisiran.
As of September 24, 2018, patients in the Global OLE received a
mean of 20.5 months (range: 1.3–39.0 months) of patisiran, with
over 6,000 doses administered. The safety of patisiran was
consistent with that observed and previously reported in APOLLO and
Phase 2 OLE studies, with an encouraging tolerability profile. Mild
or moderate infusion-related reactions (IRRs: 12 percent)
represented the most common drug-related adverse events (AEs). The
proportion of patients experiencing IRRs was higher in patients
newly treated with patisiran (APOLLO placebo) and decreased over
time, with no discontinuations attributed to IRRs.
Exposure-adjusted mortality occurred at a rate of 4.8 per 100
patient years, comparing favorably with disease natural history
(exposure-adjusted rates of mortality from 6.8-29 per 100
patient-years), and the observed mortality in placebo-treated
patients in APOLLO (18.9 per 100 patient-years). Mortality was
lowest (1.7 per 100 patient-years) among patients from the Phase 2
OLE group, who initiated patisiran treatment at an earlier stage of
disease compared with those in either of the APOLLO study arms.
APOLLO Results on Patients Previously Treated with
Tafamidis
In addition, results were also presented on the impact of
patisiran in patients who received tafamidis (a TTR tetramer
stabilizer) treatment prior to enrolling in APOLLO. Approximately
one-third of patients enrolled in APOLLO were previously treated
with tafamidis. Thirty-four percent of those patients discontinued
treatment with tafamidis due to disease progression; the majority
of other patients discontinued tafamidis to participate in the
APOLLO study for unspecified reasons. Patients with prior tafamidis
use who received patisiran treatment for 18 months in APOLLO
experienced significant improvement from baseline in polyneuropathy
and QOL compared with placebo, similar to that observed in the
overall APOLLO population. As with the overall study population,
improvements in neuropathy impairment were also observed as early
as nine months. These data suggest that patients who experience
disease progression on tafamidis, or who discontinue tafamidis, may
experience improvement in their polyneuropathy and QOL upon
initiating treatment with patisiran.
Results of Indirect Treatment Comparison of Patisiran versus
Inotersen
Additional data presented at PNS included results from an
indirect treatment comparison analysis evaluating the efficacy of
patisiran versus inotersen from the Phase 3 APOLLO and NEURO-TTR
studies, respectively; there have been no head-to-head clinical
studies comparing patisiran with inotersen. An indirect treatment
comparison is a method widely accepted by regulators and payers for
deriving a comparative estimate between two treatments that have
not been compared in head-to-head trials, notwithstanding the
limitations of this approach, including differential durations of
the respective trials requiring interpolation of data, and the
degree of missing outcome data due to higher discontinuations in
the NEURO-TTR study. The indirect treatment comparison revealed
favorable treatment effects of patisiran relative to inotersen
across all endpoints evaluated, including mNIS+7Ionis, QOL, body
mass index, and polyneuropathy disability score, as calculated via
various statistical models and approaches. Specifically, at 15
months, mean differences in mNIS+7Ionis and QOL – key study
endpoints – ranged from -6.5 to -16.2 points and from -8.2 to -11.6
points, respectively, favoring patisiran.
To view the results presented by Alnylam at PNS 2019 Annual
Meeting, please visit www.alnylam.com/capella.
Important Safety Information
ONPATTRO is a medicine that treats the polyneuropathy caused by
an illness called hereditary transthyretin-mediated amyloidosis
(hATTR amyloidosis). ONPATTRO is used in adults only.
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients
treated with ONPATTRO. In a controlled clinical study, 19 percent
of ONPATTRO-treated patients experienced IRRs, compared to 9
percent of placebo-treated patients. The most common symptoms of
IRRs with ONPATTRO were flushing, back pain, nausea, abdominal
pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive
premedication with a corticosteroid, paracetamol, and
antihistamines (H1 and H2 blockers) at least 60 minutes prior to
ONPATTRO infusion. Monitor patients during the infusion for signs
and symptoms of IRRs. If an IRR occurs, consider slowing or
interrupting the infusion and instituting medical management as
clinically indicated. If the infusion is interrupted, consider
resuming at a slower infusion rate only if symptoms have resolved.
In the case of a serious or life-threatening IRR, the infusion
should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended
Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A
levels. Supplementation at the recommended daily allowance (RDA) of
vitamin A is advised for patients taking ONPATTRO. Higher doses
than the RDA should not be given to try to achieve normal serum
vitamin A levels during treatment with ONPATTRO, as serum levels do
not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they
develop ocular symptoms suggestive of vitamin A deficiency (e.g.
night blindness).
Adverse Reactions
The most common adverse reactions that occurred in patients
treated with ONPATTRO were respiratory tract infections (29
percent) and infusion-related reactions (19 percent).
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial was a randomized, double-blind,
placebo-controlled, global study designed to evaluate the efficacy
and safety of patisiran in hATTR amyloidosis patients with
polyneuropathy. The primary endpoint of the study was the change
from baseline in modified Neuropathy Impairment Score +7 (mNIS+7)
relative to placebo at 18 months. Secondary endpoints included: the
Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score;
NIS-weakness (NIS-W); Rasch-built Overall Disability Scale (R-ODS);
timed 10-meter walk (10-MWT); modified BMI (mBMI); and the
composite autonomic symptom score-31 (COMPASS-31). In addition,
exploratory cardiac assessments included measurement of N-terminal
pro-brain natriuretic peptide (NT-ProBNP) levels and
echocardiography. The trial enrolled 225 hATTR amyloidosis patients
from 19 countries with 39 genotypes who were randomized 2:1,
patisiran:placebo, with patisiran administered at 0.3 mg/kg once
every three weeks for 18 months. All patients who completed the
APOLLO Phase 3 study were eligible to screen for the Global OLE
study, in which they have the opportunity to receive patisiran on
an ongoing basis.
About ONPATTRO® (Patisiran)
ONPATTRO is an RNAi therapeutic that is approved by the U.S.
Food and Drug Administration (FDA) for the treatment of the
polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also
approved in the European Union for the treatment of hATTR
amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and
in Japan for the treatment of hATTR amyloidosis with polyneuropathy
by the Japanese Ministry of Health, Labour and Welfare (MHLW).
Based on Nobel Prize-winning science, ONPATTRO is an intravenously
administered RNAi therapeutic targeting transthyretin (TTR) for the
treatment of hereditary ATTR amyloidosis. It is designed to target
and silence TTR messenger RNA, thereby blocking the production of
TTR protein before it is made. ONPATTRO blocks the production of
TTR in the liver, reducing its accumulation in the body’s tissues
in order to halt or slow down the progression of the disease.
About hATTR amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is
an inherited, progressively debilitating, and often fatal disease
caused by mutations in the TTR gene. TTR protein is primarily
produced in the liver and is normally a carrier of vitamin A.
Mutations in the TTR gene cause abnormal amyloid proteins to
accumulate and damage body organs and tissue, such as the
peripheral nerves and heart, resulting in intractable peripheral
sensory-motor neuropathy, autonomic neuropathy, and/or
cardiomyopathy, as well as other disease manifestations. hATTR
amyloidosis represents a major unmet medical need with significant
morbidity and mortality, affecting approximately 50,000 people
worldwide. The median survival is 4.7 years following diagnosis,
with a reduced survival (3.4 years) for patients presenting with
cardiomyopathy.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene
silencing that represents one of the most promising and rapidly
advancing frontiers in biology and drug development today. Its
discovery has been heralded as “a major scientific breakthrough
that happens once every decade or so,” and was recognized with the
award of the 2006 Nobel Prize for Physiology or Medicine. By
harnessing the natural biological process of RNAi occurring in our
cells, a new class of medicines, known as RNAi therapeutics, is now
a reality. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam's RNAi therapeutic platform,
function upstream of today’s medicines by potently silencing
messenger RNA (mRNA) – the genetic precursors – that encode for
disease-causing proteins, thus preventing them from being made.
This is a revolutionary approach with the potential to transform
the care of patients with genetic and other diseases.
About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a new class of innovative medicines with
the potential to transform the lives of people afflicted with rare
genetic, cardio-metabolic, hepatic infectious, and central nervous
system/ocular diseases. Based on Nobel Prizewinning science, RNAi
therapeutics represent a powerful, clinically validated approach
for the treatment of diseases with high unmet need. ONPATTRO®
(patisiran) is the first-ever RNAi therapeutic approved by the U.S.
FDA for the treatment of the polyneuropathy of hereditary
transthyretin-mediated (hATTR) amyloidosis in adults and by the EMA
for the treatment of hATTR amyloidosis in adults with stage 1 or
stage 2 polyneuropathy. Alnylam has a deep pipeline of
investigational medicines, including five product candidates in
Phase 3 studies and one in registration. Looking forward, Alnylam
will continue to execute on its "Alnylam 2020" strategy of building
a multi-product, commercial-stage biopharmaceutical company with a
sustainable pipeline of RNAi-based medicines to address the needs
of patients who have limited or inadequate treatment options.
Headquartered in Cambridge, MA, Alnylam employs over 1,200 people
worldwide. For more information about our people, science and
pipeline, please visit www.alnylam.com and engage with us on
Twitter at @Alnylam or on LinkedIn.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including, without limitation,
Alnylam's views with respect to the potential benefits from
treatment with patisiran, and expectations regarding "Alnylam 2020"
guidance for the advancement and commercialization of RNAi
therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under The Private Securities
Litigation Reform Act of 1995. Actual results and future plans may
differ materially from those indicated by these forward-looking
statements as a result of various important risks, uncertainties
and other factors, including, without limitation, Alnylam's ability
to discover and develop novel drug candidates and delivery
approaches, successfully demonstrate the efficacy and safety of its
product candidates, the pre-clinical and clinical results for its
product candidates, which may not be replicated or continue to
occur in other subjects or in additional studies or otherwise
support further development of product candidates for a specified
indication or at all, actions or advice of regulatory agencies,
which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for
additional preclinical and/or clinical testing, delays,
interruptions or failures in the manufacture and supply of its
product candidates, obtaining, maintaining and protecting
intellectual property, Alnylam's ability to enforce its
intellectual property rights against third parties and defend its
patent portfolio against challenges from third parties, obtaining
and maintaining regulatory approval, pricing and reimbursement for
products, progress in establishing a commercial and ex-United
States infrastructure, successfully launching, marketing and
selling its approved products globally, Alnylam’s ability to
successfully expand the indication for ONPATTRO in the future,
competition from others using technology similar to Alnylam's and
others developing products for similar uses, Alnylam's ability to
manage its growth and operating expenses, obtain additional funding
to support its business activities, and establish and maintain
strategic business alliances and new business initiatives,
Alnylam's dependence on third parties for development, manufacture
and distribution of products, the outcome of litigation, the risk
of government investigations, and unexpected expenditures, as well
as those risks more fully discussed in the "Risk Factors" filed
with Alnylam's most recent Quarterly Report on Form 10-Q filed with
the Securities and Exchange Commission (SEC) and in other filings
that Alnylam makes with the SEC. In addition, any forward-looking
statements represent Alnylam's views only as of today and should
not be relied upon as representing its views as of any subsequent
date. Alnylam explicitly disclaims any obligation, except to the
extent required by law, to update any forward-looking
statements.
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version on businesswire.com: https://www.businesswire.com/news/home/20190624005273/en/
Christine Regan
Lindenboom (Investors and
Media) 617-682-4340
Josh Brodsky (Investors) 617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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