Alnylam Reports Positive Phase II Data for Patisiran (ALN-TTR02), an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR), and Initiates Phase III Trial
Nov 10,2013
— New Results in ATTR Patients Show up to 96% Knockdown of TTR with Activity toward Both Wild-Type and Mutant TTR —
— Company Initiates APOLLO Phase III Trial, with Study Now Open for Enrollment; APOLLO to Evaluate Efficacy and Safety of Patisiran in ATTR Patients with Familial Amyloidotic Polyneuropathy (FAP) —
"These new data confirm what we have seen consistently with our
patisiran program, namely that we can achieve robust knockdown of
circulating wild-type and mutant TTR. Specifically, in this Phase II
study, we demonstrated up to 96% knockdown of TTR, the disease-causing
protein in ATTR, and established a dose and dose regimen for evaluation
in our Phase III trial. Knockdown of circulating TTR is expected to
result in improved clinical outcomes for patients with ATTR based on
data from FAP patients receiving liver transplants. Further, evidence
from other systemic amyloidotic diseases shows that as little as a 50%
reduction of the disease-causing protein can result in disease
improvement or stabilization," said
The Phase II study with patisiran in ATTR polyneuropathy patients (n=29)
was an open-label, multi-center, multi-dose, dose-escalation trial to
evaluate the safety and tolerability of two doses of patisiran and to
demonstrate clinical activity based on serial measurement of circulating
serum levels of wild-type and mutant TTR. Patients received two doses of
patisiran in 5 cohorts with doses ranging from 0.01 to 0.30 mg/kg, using
either a once-every-four-week or once-every-three-week dosing regimen.
The international study included 10 sites in
The new data from 28 patients enrolled and currently analyzed showed that multiple doses of patisiran resulted in rapid, dose-dependent, and durable knockdown of serum TTR levels. As compared with the lowest dose group of 0.01 mg/kg, there was a statistically significant knockdown of serum TTR at doses of 0.15 mg/kg (p < 0.05) and 0.30 mg/kg (p < 0.001). The study results support further evaluation of patisiran at the 0.30 mg/kg dose administered once every three weeks. With this dose and regimen, mean TTR knockdown at nadir of 83.8% and 86.7% was observed following the first and second doses, respectively, with maximum TTR knockdown of up to 96.0%. A more detailed summary of TTR knockdown data is provided in the table below.
|
Summary of Patisiran (ALN-TTR02) Clinical Activity Results |
|||||||||||||||
|
(mg/kg) |
N | Dose 1 | Dose 2 | ||||||||||||
|
Max TTR KD (%) |
TTR KD @ Nadir (Mean % ± SD) |
Max TTR KD (%) |
TTR KD @ Nadir (Mean % ± SD) |
||||||||||||
| 0.01 q4w | 4+ | 37.8 | 22.1 ± 12.5 | 34.4 | 32.9 ± 2.3 | ||||||||||
| 0.05 q4w | 3 | 58.0 | 48.4 ± 16.2 | 58.5 | 46.9 ± 15.0 | ||||||||||
| 0.15 q4w | 3 | 81.7 | 74.5 ± 6.8*** | 86.0 | 77.0 ± 7.8* | ||||||||||
| 0.30 q4w | 6^ | 87.5 | 82.6 ± 5.9*** | 90.8 | 84.8 ± 10.5*** | ||||||||||
| 0.30 q3w | 12 | 94.2 | 83.8 ± 5.1*** | 96.0 | 86.7 ± 7.0*** | ||||||||||
| *p < 0.05 vs. 0.01 mg/kg group |
| ***p < 0.001 vs. 0.01 mg/kg group |
| p values from ANCOVA models including baseline TTR and dose groups as factors |
| + Includes first dose data from additional patient prior to protocol amendment |
| ^ Excludes post-day 28 data from patient that experienced drug extravasation during second infusion |
A number of additional analyses were performed in this first-ever multi-dose study of patisiran in ATTR patients. First, a proprietary mass spectrometry method was used to measure serum levels of wild-type and mutant V30M proteins. These results showed 1:1 correspondence in knockdown of mutant and wild-type TTR (r2=0.95, p < 0.001), with essentially superimposable pharmacodynamic effects toward both protein species. Of interest, patients on TTR stabilizer therapy (specifically tafamidis or diflunisal) showed significantly increased baseline levels of serum TTR; regardless, patisiran administration resulted in a similar degree of TTR knockdown in these patients. These results confirm the absence of any interference by TTR stabilizer drugs with the pharmacologic activity of patisiran, and also demonstrate that RNAi-mediated knockdown of TTR is achieved independent of baseline TTR serum levels. Finally, and as expected, serum TTR knockdown was highly correlated with a reduction in circulating levels of retinol binding protein (RBP) (r2=0.89, p < 0.001) and vitamin A (r2=0.90, p < 0.001).
Multiple doses of patisiran were found to be generally safe and well tolerated in this study. The majority of the adverse events were mild or moderate. There were no abnormalities seen in liver function tests, renal function, or hematologic parameters. There were two serious adverse events. As previously reported, an episode of self-limiting cellulitis of the arm occurred as a result of drug extravasation at the infusion site in a patient with poor intravenous access. In addition, an episode of nausea and vomiting occurred in a patient with autonomic involvement due to disease; this patient discontinued the study after one dose. The most common adverse event reported was a mild or moderate infusion-related reaction (IRR) which occurred in 10.3% (3/29) of patients overall; this adverse event was managed with a prolonged intravenous infusion and was not associated with any patient discontinuations. Notably, no IRRs were reported among 12 patients who received 0.30 mg/kg once every three weeks, 9 of whom received their infusion with a proprietary micro-dosing regimen administered over 70 minutes.
"I am very encouraged by these clinical activity and safety data with
patisiran, an RNAi therapeutic for the treatment of ATTR. In particular,
the potent, rapid, and durable knockdown of both mutant and wild-type
TTR achieved by patisiran is important since TTR protein reduction in
patients with ATTR has the potential to delay or even reverse disease
progression with associated clinical benefit," said
Alnylam is currently enrolling patients in a Phase II open-label extension (OLE) study with patisiran. Eligible patients treated in the Phase II study can enroll in the OLE study, where they will receive patisiran at a dose of 0.30 mg/kg every three weeks for up to two years. The primary objective of this study is to evaluate the long-term safety and tolerability of patisiran administration. In addition, the study will measure a number of clinical endpoints every six months. This includes measurement of a modified composite Neuropathy Impairment Score, termed "mNIS+7," which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance across a 304-point scale, where neuropathy progression leads to an increased score over time. A number of additional clinical endpoints will be assessed, including: quality of life; timed 10-meter walk test to evaluate mobility; modified body mass index as a measure of nutritional status; level of disability; and nerve fiber density in skin biopsies. In addition, serum TTR levels will be measured. Initial data from the OLE study are expected to be presented in 2014, with periodic updates thereafter approximately once a year.
Alnylam also announced today that it has initiated the APOLLO Phase III
study of patisiran. The APOLLO Phase III trial is a randomized,
double-blind, placebo-controlled, global study designed to evaluate the
efficacy and safety of patisiran in ATTR patients with FAP. 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 is designed to enroll up to 200 FAP
patients with a baseline NIS in the range of 10 to 100, which represents
patients with Stage 1 or Stage 2 disease. Patients will be randomized
2:1, patisiran:placebo, with patisiran administered at 0.30 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 FAP patients. Alnylam has obtained
protocol assistance for the patisiran Phase III study from the
"We are very pleased to be announcing today that we have initiated our
APOLLO Phase III trial, which is now open for enrollment. As the
company's first ever Phase III study, this is a very significant
milestone in our history and also for the entire field of RNAi
therapeutics. Further, initiation of our Phase III trial with patisiran
highlights continued execution on our ‘Alnylam 5x15' product development
and commercialization strategy, which is focused on advancing RNAi
therapeutics toward genetically defined targets for the treatment of
diseases with high unmet medical need," said
In 2012, Alnylam entered into an exclusive alliance with Genzyme, a
Sanofi company, to develop and commercialize RNAi therapeutics,
including patisiran and ALN-TTRsc, for the treatment of ATTR in
About Transthyretin-Mediated Amyloidosis
Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited,
progressively debilitating, and fatal disease caused by mutations in the
TTR gene. TTR protein is produced primarily in the liver and is normally
a carrier for retinol binding protein. 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. ATTR
represents a major unmet medical need with significant morbidity and
mortality; familial amyloidotic polyneuropathy (FAP) affects
approximately 10,000 people worldwide and familial amyloidotic
cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP
patients have a life expectancy of five to 15 years from symptom onset,
and the only treatment options for early stage disease are liver
transplantation and tafamidis (approved in
About LNP Technology
Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.
About RNA Interference (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 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 with a core
focus on RNAi therapeutics toward genetically defined targets for the
treatment of serious, life-threatening diseases with limited treatment
options for patients and their caregivers. These include: patisiran
(ALN-TTR02), an intravenously delivered RNAi therapeutic targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR)
in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a
subcutaneously delivered RNAi therapeutic targeting TTR for the
treatment of ATTR in patients with familial amyloidotic cardiomyopathy
(FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the
treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an
RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the
treatment of porphyria including acute intermittent porphyria (AIP);
ALN-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic
targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an
RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia
and iron-overload disorders; and, ALN-AAT, an RNAi therapeutic targeting
alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver
disease, amongst other programs. As part of its "Alnylam 5x15" strategy,
the company expects to have five RNAi therapeutic products for
genetically defined diseases in clinical development, including programs
in advanced stages, on its own or with a partner by the end of 2015.
Alnylam has additional partnered programs in clinical or development
stages, including ALN-RSV01 for the treatment of respiratory syncytial
virus (RSV) infection and ALN-VSP for the treatment of liver cancers.
The company's leadership position on RNAi therapeutics and intellectual
property have enabled it to form major alliances with leading companies
including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa
Hakko Kirin, Cubist, Ascletis, Monsanto, Genzyme, and The Medicines
Company. In addition, Alnylam holds an equity position in Regulus
Therapeutics Inc., a company focused on discovery, development, and
commercialization of microRNA therapeutics. Alnylam has also formed
Alnylam Biotherapeutics, a division of the company focused on the
development of RNAi technologies for applications in biologics
manufacturing, including recombinant proteins and monoclonal antibodies.
Alnylam's VaxiRNA™ platform applies RNAi technology to improve the
manufacturing processes for vaccines; GlaxoSmithKline is a collaborator
in this effort. Alnylam scientists and collaborators have published
their research on RNAi therapeutics in over 100 peer-reviewed papers,
including many in the world's top scientific journals such as Nature,
Nature Medicine, Nature Biotechnology, Cell, the
About "Alnylam 5x15™"
The "Alnylam 5x15" strategy, launched in
Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's expectations regarding its "Alnylam 5x15" product strategy,
Alnylam's views with respect to the potential for RNAi therapeutics,
including patisiran (ALN-TTR02), its expectations with respect to the
timing, execution, and success of its clinical trials for ALN-TTR02 and
its expectations regarding the use of a single, global Phase III study
of ALN-TTR02 for marketing authorization, and its expectations regarding
the potential market opportunity for ALN-TTR02, 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 manage operating
expenses, 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 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 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
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