Dec 01, 2014 Press Release for Alnylam
New Paper in Journal of the American Chemical Society Documents Pioneering Discovery of GalNAc-Conjugated siRNA by Alnylam Scientists
Dec 01, 2014
- GalNAc-siRNA Conjugates Enable Potent and Durable Knockdown of Hepatocyte-Expressed Disease Genes with Subcutaneous Dosing and Wide Therapeutic Index -
"This publication as a JACS ‘Communication' documents the
landmark discovery by Alnylam scientists of GalNAc-conjugates as a
potent and durable approach for subcutaneous administration of RNAi
therapeutics with a wide therapeutic index. Indeed, our scientists
championed the application of GalNAc-conjugates for delivery of RNA
therapeutics, including siRNAs, and we believe that this approach has
emerged as the optimal strategy across the entire industry for RNA
therapeutics targeting hepatocyte-expressed disease genes," said Muthiah
(
Alnylam's GalNAc-siRNA conjugate platform is a clinically validated delivery technology that is being employed in essentially all of Alnylam's RNAi therapeutic pipeline programs. Recently, the company presented positive initial Phase 2 data with revusiran (ALN-TTRsc), a GalNAc-conjugated RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR cardiac amyloidosis; revusiran is a first generation GalNAc-conjugate that utilizes Standard Template Chemistry (STC). In the Phase 2 multi-dose study, revusiran demonstrated clinical activity with an up to 98.2% knockdown of serum TTR - the disease-causing protein - and was found to be generally well tolerated in patients with TTR cardiac amyloidosis and advanced disease burden. The Phase 2 results support advancement of revusiran in a Phase 3 randomized, double-blind, placebo-controlled study in TTR cardiac amyloidosis, and the company expects to start the study before year's end.
Earlier this year, Alnylam reported positive
top-line clinical results with ALN-AT3, an investigational RNAi
therapeutic targeting antithrombin (AT) for the treatment of hemophilia
and rare bleeding disorders; ALN-AT3 employs a second generation
GalNAc-conjugate chemistry termed "Enhanced Stabilization Chemistry," or
"ESC." In the first part of a Phase 1 clinical study, where ALN-AT3 was
administered at low doses to healthy human volunteers, a single 0.03
mg/kg subcutaneous dose resulted in an up to 32% knockdown of serum AT
and increases in thrombin generation. These clinical results suggest
that ESC-GalNAc conjugates have a greater than 50-fold enhanced potency
in humans as compared with STC-GalNAc conjugates due to enhanced
stability in humans. Alnylam expects to present initial data
from the ALN-AT3 Phase 1 study, including results in human volunteers
and the first, lowest dose cohort of hemophilia subjects, at the
In addition, Alnylam has presented extensive non-human primate data with other ESC-GalNAc-siRNA conjugates, including ALN-PCSsc - an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia - and ALN-CC5 - an investigational RNAi therapeutic targeting complement C5 for the treatment of complement-mediated diseases. Recently, the company has filed and received approval for a Clinical Trial Application (CTA) to initiate a Phase 1 study of ALN-PCSsc in normal human volunteers with elevated LDL-C; the company expects to start the Phase 1 study by the end of 2014 and plans to report initial clinical data in mid-2015. In the case of ALN-CC5, Alnylam remains on track to file a CTA by the end of 2014, and expects to report initial clinical data in mid-2015.
In addition to data on siRNA conjugates, additional proof-of-concept for GalNAc-conjugates as a potent delivery platform for RNA therapeutics was recently reported by Regulus Therapeutics with positive interim clinical data with RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C virus (HCV) infection. As reported by Regulus, interim results from an ongoing clinical study demonstrated that treatment with a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy resulted in significant and sustained reductions in HCV RNA, as well as a mean viral load reduction of 4.1 log10 at day 29; RG-101 was reported to be well tolerated in the study. Regulus has a license to Alnylam's GalNAc-conjugate technology in the field of microRNA therapeutics through the companies' 2007 license agreement. Further, Isis Pharmaceuticals has reported successful adoption of GalNAc-conjugated antisense oligonucleotides (ASOs) in pre-clinical studies. Isis has obtained a license to Alnylam's GalNAc-conjugate technology in the field of single-stranded oligonucleotide therapeutics, including ASOs, through the companies' 2004 license agreement.
Alnylam has obtained broad intellectual property protection for its GalNAc-conjugate delivery platform for RNA therapeutics. Amongst other issued and granted patents, the Manoharan et al. patent (US 8,828,956) includes claims directed to compositions including those comprising a modified RNA agent linked to a biantennary or triantennary ligand. Specifically, the patent includes claims that broadly cover single-stranded or double-stranded chemically modified RNA therapeutics conjugated with an N-acetylgalactosamine (GalNAc) ligand, independent of length, sequence, or disease target.
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 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, durability, and a wide therapeutic index, and is being employed in several of Alnylam's genetic medicine programs, including programs in clinical development.
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 as genetic medicines, including programs as
part of the company's "Alnylam 5x15™" product strategy. Alnylam's
genetic medicine programs are RNAi therapeutics directed 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) targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR)
in patients with familial amyloidotic polyneuropathy (FAP); revusiran
(ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR
cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC)
and senile systemic amyloidosis (SSA); ALN-AT3 targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD);
ALN-CC5 targeting complement component C5 for the treatment of
complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid
synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including
acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the
treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin
(AAT) for the treatment of AAT deficiency-associated liver disease;
ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment
of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders; ALN-ANG targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting
apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia;
ALN-AGT targeting angiotensinogen (AGT) for the treatment of
hypertensive disorders of pregnancy (HDP), including preeclampsia;
ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary
hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus
(HDV) genome for the treatment of HDV infection; ALN-PDL targeting
programmed death ligand 1 (PD-L1) for the treatment of chronic liver
infections; and other programs yet to be disclosed. As part of its
"Alnylam 5x15" strategy, as updated in early 2014, the company expects
to have six to seven genetic medicine product candidates in clinical
development - including at least two programs in Phase 3 and five to six
programs with human proof of concept - by the end of 2015. The company's
demonstrated commitment to RNAi therapeutics has enabled it to form
major alliances with leading companies including Merck, Medtronic,
Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early
2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product
geographic alliance on Alnylam's genetic medicine programs in the rare
disease field. Specifically, Alnylam will lead development and
commercialization of programs in
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 revusiran (ALN-TTRsc) for the treatment of TTR cardiac
amyloidosis, ALN-AT3 for the treatment of hemophilia and rare bleeding
disorders, ALN-PCSsc for the treatment of hypercholesterolemia, and
ALN-CC5 for the treatment of complement-mediated diseases, the timing of
submitting regulatory filings, beginning clinical studies, and reporting
data, its expectations regarding the potency and therapeutic index of
GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry
(ESC)-GalNAc conjugates, its expectations regarding its "Alnylam 5x15"
product 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 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
Vice
President, Investor Relations and Corporate Communications
or
Spectrum
Source:
News Provided by Acquire Media
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Christine Akinc
Chief Corporate Communications Officer media@alnylam.com 617-682-4340
For Investor Inquiries, please contact:
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VP, Investor Relations & Corporate Communications investors@alnylam.com 617-551-8276
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