Alnylam Pharmaceuticals, Inc. ALNY, the leading RNAi therapeutics company, announced today preliminary results from its ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, both investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of hereditary TTR-mediated amyloidosis (hATTR amyloidosis). These new clinical data are being presented at the XV International Symposium on Amyloidosis held July 3 – 7, 2016 in Uppsala, Sweden. Data from the patisiran Phase 2 OLE study provided evidence of improvement or no change in the mean neuropathy impairment score (mNIS+7) following 24 months of dosing in hATTR patients with polyneuropathy (hATTR-PN, also known as Familial Amyloidotic Polyneuropathy, or FAP). These results support the therapeutic hypothesis that TTR knockdown with patisiran can potentially halt or improve neuropathy progression in patients with hATTR-PN. The Company also presented baseline demographics from its APOLLO Phase 3 study of patisiran in hATTR-PN patients, showing, among other things, that the majority of patients have evidence of cardiac disease, which should allow the evaluation of patisiran's potential effects on cardiac manifestations of hATTR amyloidosis. In addition, initial 12-month data from the revusiran Phase 2 OLE study continued to show robust and sustained knockdown of serum TTR, and 6-minute walk distance (6-MWD) results were found to be generally stable in the majority of evaluable hATTR patients with cardiomyopathy (hATTR-CM, also known as Familial Amyloidotic Cardiomyopathy, or FAC). Alnylam also announced today that it expects to complete enrollment in the ENDEAVOUR Phase 3 study of revusiran this summer, ahead of schedule, with data readout now expected in early 2018.
"We believe that data from these ongoing Phase 2 OLE studies further support the potential of patisiran and revusiran as innovative investigational medicines for the treatment of hereditary ATTR amyloidosis. With patisiran, we believe the mean 6.7 point decrease in mNIS+7 seen over 24 months is a promising result in light of the rapid increase in neuropathy impairment scores that would have been anticipated based on analyses of other historical data sets. Moreover, we're encouraged to see that individual patient mNIS+7 responses show evidence for halting of or improvement in neuropathy progression in over 70 percent of patients," said Eric Green, Vice President, General Manager, TTR Program. "Accordingly, we look forward to reporting data from the APOLLO Phase 3 trial with patisiran in mid-2017, where, in addition to evaluating the effect on neuropathy progression, we also expect to evaluate patisiran's impact on other aspects of the disease, including cardiac manifestations, given the significant number of patients enrolled in the trial with cardiac involvement."
Patisiran Results Show Potential to Halt or Improve Neuropathy
Progression
In the patisiran single-arm Phase 2 OLE study, new
results for patients (N=24) who reached the 24-month endpoint as of a
data cutoff date of May 12, 2016, showed a mean decrease of 6.7 points
from baseline in mNIS+7 after 24 months of treatment. This compares
favorably to an estimated mean increase in mNIS+7 of 26 to 30 points at
24 months based upon analyses of historical data sets in untreated
hATTR-PN patients with similar baseline neurologic impairment (Adams et
al., Neurology, 2015;85:675-682; Berk et al., JAMA, 2013;310:2658-67).
Similar results were seen in patients with or without concomitant use of
TTR tetramer stabilizers. In a new analysis, over 70 percent of patients
showed either improvement or no change in mNIS+7 at 24 months. The
maximal improvement achieved was a robust 34.6 point decrease in mNIS+7.
In addition, patisiran administration was associated with statistically
significant mean improvements in nerve fiber density from sweat gland
biopsy samples from both the distal thigh and distal leg (p less than
0.01 for both), as read histologically in a blinded manner by a central
lab. Over the 24-month period, hATTR-PN patients with associated cardiac
involvement (N=11) showed stability in their cardiac biomarkers,
echocardiographic measures, and 10-meter walk test (i.e., gait speed).
Serum TTR levels were also measured throughout the OLE study, and showed
TTR knockdown of up to 97 percent, a mean maximal knockdown of 93
percent, and a mean knockdown of 84 percent at 24 months.
In addition, Alnylam also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, the degree of TTR knockdown on Day 17 after the first dose of patisiran was compared to changes in mNIS+7 at 6, 12, 18, and 24 months. There was a positive correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement; the strongest correlations were observed at 6 and 12 months (p less than 0.01), and a trend was observed at 18 and 24 months (p equal to 0.055 and 0.15, respectively). Over 24 months, patients with lesser degrees of initial TTR knockdown also had improvements in mNIS+7, suggesting that there may be an accrual of clinical benefit to even those patients with lesser degrees of TTR knockdown if treated over longer periods of time. Altogether the Company believes these data support the therapeutic hypothesis that reduction of mutant and wild-type TTR with patisiran has the potential to halt or improve neuropathy progression in patients with hATTR-PN.
Patisiran administration was also found to be generally well tolerated in hATTR-PN patients out to 25 months, with no drug-related serious adverse events (SAEs) reported through the data transfer date. The most common drug-related or possibly drug-related adverse events (AEs) were flushing (22.2 percent) and infusion-related reactions (18.5 percent), all of which were mild in severity and did not result in any discontinuations. There were nine reports of SAEs in six patients, all of which were unrelated to study drug, including two deaths as previously reported. There were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelet counts.
APOLLO Phase 3 Study with Patisiran is Largest Controlled Study of
Patients with hATTR-PN to Date and Represents Global Patient Population
Alnylam
also presented baseline demographics from the APOLLO Phase 3 study of
patisiran. A total of 225 patients with hATTR-PN were enrolled at 44
sites in 19 countries around the world between December 2013 and January
2016. Ninety-five patients (42 percent) have the Val30Met TTR mutation,
the most prevalent genotype known to be associated with hATTR-PN; the
remaining 130 patients (58 percent) span 57 other mutations. In terms of
disease severity, 104 patients (46 percent) were FAP Stage 1 at
baseline, and 119 (53 percent) patients were Stage 2; only 2 patients (1
percent) were Stage 3. The mean baseline mNIS+7 score was 78.8 (range
8.0 – 165.0). Additionally, baseline mNIS+7 and quality of life (QOL)
scores were found to correlate with FAP Stage and polyneuropathy
disability (PND) score, underscoring the clinical relevance of specific
endpoints in the APOLLO Phase 3 study. A significant number of patients
(N=122, 54 percent) had cardiac involvement at baseline. The Company
believes this patient subset should allow for a controlled evaluation of
effects of patisiran on cardiac parameters, including cardiac biomarkers
NT-proBNP and troponin, left ventricular wall thickness, ejection
fraction, and 10-meter walk test, all included as secondary or
exploratory endpoints in the Phase 3 study protocol. Alnylam expects to
report data from the APOLLO trial in mid-2017.
12-Month Data with Revusiran Show Generally Stable 6-Minute Walk
Distance Results in Majority of Evaluable Patients with hATTR-CM
"With
revusiran, we are pleased to see the robust and durable knockdown of TTR
for up to eighteen months, representing our longest human dosing
experience with a GalNAc-siRNA conjugate. We're also encouraged to see
generally stable 6-minute walk distance results in the majority of
evaluable hATTR-CM patients," said Eric Green. "Nevertheless, given the
highly advanced patient population in the revusiran Phase 2 OLE study,
we continue to believe that further assessment of clinical activity in
hATTR-CM will need to await placebo-controlled results from the cardiac
subgroup in APOLLO and from ENDEAVOUR. To this end, we are pleased to
announce today that we expect to complete enrollment in the ENDEAVOUR
Phase 3 study of revusiran later this summer, ahead of schedule, which
should position us to report out data from this study in early 2018."
Preliminary results were presented for patients (N=16) who reached the 12-month endpoint as of a data cutoff of May 26, 2016. At 12 months, the majority of hATTR-CM patients evaluable for 6-MWD (5 of 9) showed generally stable results, with a mean change of -14 ± 8 meters in those patients. On average, all evaluable patients with hATTR-CM (N=9) exhibited a mean change of -73 ± 26 meters, and those with wild-type ATTR amyloidosis (wtATTR, also known as Senile Systemic Amyloidosis, or SSA) (N=6) exhibited a mean change of -152 ± 36 meters over 12 months. These results are generally in line with natural history data at 12 months. Finally, repeat dosing with revusiran achieved robust and sustained TTR knockdown out to 18 months, with an up to 98 percent maximal and 88 percent mean maximal knockdown of TTR.
Baseline demographics for patients in the revusiran Phase 2 OLE revealed a study population with advanced disease, with a mean time from diagnosis to first dose of 35 months. This compares with a nearly three-times shorter, 13-month mean time from diagnosis to first dose for hATTR-CM patients (N=139) enrolled in the ongoing ENDEAVOUR trial to date. All safety data from the revusiran Phase 2 OLE are through the data transfer date of May 26, 2016. Fourteen patients (56 percent) in the Phase 2 OLE presented with SAEs. One event, a case of lactic acidosis, was deemed possibly related to study drug. There were a total of seven deaths, all of which were unrelated to study drug. Time from ATTR diagnosis to first dose in the Phase 2 OLE study was found to be significantly correlated with death or disease progression, where patients who died or experienced disease progression (N=8) had a mean time of 48 months compared with patients (N=11) who remained on study who had a mean time of 25 months (p less than 0.05). The majority of AEs were mild or moderate in severity, and included injection site reactions (ISRs) in 12 patients (48 percent); the majority of reported ISRs were mild in severity. Beyond the three cases previously reported, there were no further discontinuations due to ISRs. There were no other notable changes in liver function tests, renal function or hematologic parameters, including platelets.
To view all the results presented by Alnylam at the ISA meeting, please visit www.alnylam.com/capella.
Conference Call Information
Alnylam management will discuss
these data in a webcast conference call on Friday, July 1 at 8:30 a.m.
ET. A slide presentation will also be available on the Investors page of
the company's website, www.alnylam.com,
to accompany the conference call. To access the call, please dial
877-312-7507 (domestic) or 631-813-4828 (international) five minutes
prior to the start time and refer to conference ID 36431889. A replay of
the call will be available beginning at 10:30 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 36431889.
About the Patisiran Phase 2 OLE Study
The ongoing patisiran
OLE study is an open-label, multi-center trial designed to evaluate the
long-term safety and tolerability of patisiran administration in
patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)
that were previously enrolled in a Phase 2 study. Patisiran is being
administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous
infusion. The study is measuring a number of clinical endpoints every
six months, including mNIS+7, which is an evaluation of muscle weakness,
sensory and autonomic function, and nerve conductance, where neuropathy
progression leads to an increased score over time. The change in the
mNIS+7 measurement from baseline to 18 months is the primary endpoint in
the Company's APOLLO Phase 3 trial of patisiran in patients with
hATTR-PN.
About the Revusiran Phase 2 OLE Study
The ongoing revusiran
OLE study is an open-label, multi-center trial designed to evaluate the
long-term safety and tolerability of revusiran administration in TTR
cardiac amyloidosis patients that were previously enrolled in a Phase 2
study. Patients receive a fixed subcutaneous dose of 500 mg of revusiran
once daily for five days, followed by once-weekly dosing. The study is
measuring a number of clinical endpoints every six months, including
effects on serum TTR and on mortality, hospitalization, and 6-minute
walk distance (6-MWD). The changes in 6-MWD and serum TTR from baseline
to 18 months are the co-primary endpoints in the Company's ENDEAVOUR
Phase 3 trial of revusiran in patients with hereditary ATTR amyloidosis
with cardiomyopathy (hATTR-CM).
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial is a
randomized, double-blind, placebo-controlled, global study designed to
evaluate the efficacy and safety of patisiran in patients with hATTR-PN.
The primary endpoint of the study is the difference in the change in
mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints
include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score;
NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31
autonomic symptom score. The trial enrolled 225 hATTR-PN patients that
were randomized 2:1, patisiran:placebo, with patisiran administered at
0.3 mg/kg once every three weeks for 18 months. The study was designed
with 90% power to conservatively detect as little as a 37.5% difference
in change in mNIS+7 between treatment groups, with a two-sided alpha of
0.05. The placebo mNIS+7 progression rate was derived from an Alnylam
analysis of natural history data from 283 hATTR-PN patients. All
patients completing the APOLLO Phase 3 study are eligible to screen for
the APOLLO-OLE study, in which they have the opportunity to receive
patisiran on an ongoing basis.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi
Genzyme, the specialty care global business unit of Sanofi, formed an
alliance to accelerate and expand the development and commercialization
of RNAi therapeutics across the world. The alliance is structured as a
multi-product geographic alliance in the field of rare diseases. Alnylam
retains product rights in North America and Western Europe, while Sanofi
Genzyme obtained the right to access certain programs in Alnylam's
current and future Genetic Medicines pipeline in the rest of the world
(ROW) through the end of 2019, together with certain broader
co-development/co-commercialization rights and global rights for certain
products. In the case of patisiran, Alnylam will advance the product
in North America and Western Europe, while Sanofi Genzyme will advance
the product in the ROW. In the case of revusiran, Alnylam and Sanofi
Genzyme will co-develop/co-commercialize the product in North America
and Western Europe, while Sanofi Genzyme will advance the product in the
ROW.
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 produced primarily in the liver and is normally a
carrier of vitamin A. Mutations in TTR cause abnormal amyloid proteins
to accumulate and damage body organs and tissue, such as the peripheral
nerves and heart, resulting in intractable peripheral sensory
neuropathy, autonomic neuropathy, and/or cardiomyopathy. hATTR
represents a major unmet medical need with significant morbidity and
mortality; hATTR with polyneuropathy (hATTR-PN) – also known as familial
amyloidotic polyneuropathy (FAP) – affects approximately 10,000 people
worldwide and hATTR with cardiomyopathy (hATTR-CM) – also known as
familial amyloidotic cardiomyopathy (FAC) – is estimated to affect at
least 40,000 people worldwide. hATTR-PN patients have a life expectancy
of 5 to 15 years from symptom onset, and the only approved treatment
options for early stage disease are liver transplantation and tafamidis
(approved in Europe, Japan, and certain countries in Latin America).
hATTR-CM is fatal within 2.5 to 5 years of diagnosis and treatment is
currently limited to supportive care. Wild-type amyloidosis (wtATTR) –
also called senile systemic amyloidosis (SSA) – is a non-hereditary form
of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type
TTR; its prevalence is generally unknown, but is associated with
advanced age. There is a significant need for novel therapeutics to
treat patients with hATTR.
About LNP Technology
Alnylam has licenses to Arbutus
Biopharma LNP intellectual property for use in RNAi therapeutic products
using LNP technology.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a
proprietary Alnylam delivery platform and are designed to achieve
targeted delivery of RNAi therapeutics to hepatocytes through uptake by
the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization
Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing
with increased potency and durability and a wide therapeutic index. This
delivery platform is being employed in nearly all of Alnylam's pipeline
programs, including programs in clinical development.
About RNAi
RNAi (RNA interference) is a revolution in
biology, representing a breakthrough in understanding how genes are
turned on and off in cells, and a completely new approach to drug
discovery and development. Its discovery has been heralded as "a major
scientific breakthrough that happens once every decade or so," and
represents one of the most promising and rapidly advancing frontiers in
biology and drug discovery today which was awarded the 2006 Nobel Prize
for Physiology or Medicine. RNAi is a natural process of gene silencing
that occurs in organisms ranging from plants to mammals. By harnessing
the natural biological process of RNAi occurring in our cells, the
creation of a major new class of medicines, known as RNAi therapeutics,
is on the horizon. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target
the cause of diseases by potently silencing specific mRNAs, thereby
preventing disease-causing proteins from being made. RNAi therapeutics
have the potential to treat disease and help patients in a fundamentally
new way.
About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical
company developing novel therapeutics based on RNA interference, or
RNAi. The company is leading the translation of RNAi as a new class of
innovative medicines. Alnylam's pipeline of investigational RNAi
therapeutics is focused in 3 Strategic Therapeutic Areas (STArs):
Genetic Medicines, with a broad pipeline of RNAi therapeutics for the
treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of
RNAi therapeutics toward genetically validated, liver-expressed disease
targets for unmet needs in cardiovascular and metabolic diseases; and
Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that
address the major global health challenges of hepatic infectious
diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance
for the advancement and commercialization of RNAi therapeutics as a
whole new class of innovative medicines. Specifically, by the end of
2020, Alnylam expects to achieve a company profile with 3 marketed
products, 10 RNAi therapeutic clinical programs – including 4 in late
stages of development – across its 3 STArs. The company's demonstrated
commitment to RNAi therapeutics has enabled it to form major alliances
with leading companies including Ionis, Novartis, Roche, Takeda, Merck,
Monsanto, The Medicines Company, and Sanofi Genzyme. In addition,
Alnylam holds an equity position in Regulus Therapeutics Inc., a company
focused on discovery, development, and commercialization of microRNA
therapeutics. Alnylam scientists and collaborators have published their
research on RNAi therapeutics in over 200 peer-reviewed papers,
including many in the world's top scientific journals such as Nature,
Nature Medicine, Nature Biotechnology, Cell, New England Journal of
Medicine, and The Lancet. Founded in 2002, Alnylam maintains
headquarters in Cambridge, Massachusetts. For more information about
Alnylam's pipeline of investigational RNAi therapeutics, please visit www.alnylam.com.
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 for RNAi therapeutics, including patisiran and revusiran,
the potential implications of reported results from its ongoing Phase 2
OLE studies of patisiran and revusiran, its expectations regarding the
timing of clinical studies and presentation of clinical data, including
for the APOLLO Phase 3 trial of patisiran and the ENDEAVOUR Phase 3
trial of revusiran, its expectations regarding its STAr pipeline growth
strategy, and its plans regarding 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 may differ materially from those
indicated by these forward-looking statements as a result of various
important 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 drug 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, actions of regulatory agencies, which may affect the
initiation, timing and progress of clinical trials, obtaining,
maintaining and protecting intellectual property, Alnylam's ability to
enforce its patents against infringers and defend its patent portfolio
against challenges from third parties, obtaining regulatory approval for
products, competition from others using technology similar to Alnylam's
and others developing products for similar uses, Alnylam's ability to
manage operating expenses, Alnylam's ability to 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, marketing,
sales and distribution of products, the outcome of litigation, 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 to update
any forward-looking statements.
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Alnylam Pharmaceuticals, Inc.
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