Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it is broadening its pipeline with
ALN-AGT, a subcutaneously administered RNAi therapeutic targeting
angiotensinogen (AGT) for the treatment of hypertensive disorders of
pregnancy (HDP), including preeclampsia, one of the most common
complications of pregnancy. Preeclampsia leads to increased risk of
maternal mortality, perinatal fetal mortality, fetal pre-maturity, or
even the need for late-term abortion to save the mother’s life. AGT,
which is primarily expressed in the liver, is the protein precursor for
angiotensin II, a peptide hormone that promotes vasoconstriction as part
of the renin-angiotensin system. Gain-of-function human mutations or
variants of AGT are associated with increased risk for hypertension and
preeclampsia in pregnant women. Small molecule inhibitors of the
renin-angiotensin system, such as angiotensin-converting enzyme (ACE)
inhibitors or angiotensin receptor blockers (ARBs) are known to cross
the placental barrier and are associated with fetal toxicity.
Accordingly, ACE inhibitors and ARBs are contraindicated for the
management of hypertension during pregnancy.
In a poster presented at the American Heart Association’s High Blood
Pressure Research 2014 Scientific Sessions, Alnylam and collaborators at
the Charité - Universitätsmedizin in Berlin presented results of an
ALN-AGT lead molecule in an established preeclamptic rodent model. The
study showed that administration of ALN-AGT resulted in knockdown of
maternal AGT in the liver without detectable evidence of fetal drug
exposure, significantly improved pregnancy-related hypertension,
ameliorated preeclamptic sequelae in the mother such as proteinuria, and
improved fetal outcomes.
“At Alnylam, we continue to pursue development of RNAi therapeutics
targeting genetically validated, liver-expressed genes involved in the
cause or pathway of human disease with high unmet medical need. ALN-AGT,
our new cardio-metabolic program targeting angiotensinogen, exemplifies
this strategy since human gain-of-function AGT variants are associated
with preeclampsia and also more broadly with hypertension. New therapies
are clearly needed to prevent or treat HDP, including preeclampsia,
since existing small molecule anti-hypertensive drugs readily cross the
placental barrier and can cause fetal toxicity,” said Rachel Meyers
Ph.D., Vice President of Research and RNAi Lead Development (RLD) at
Alnylam. “The new pre-clinical data demonstrate that an RNAi therapeutic
targeting AGT ameliorates the clinical sequelae of preeclampsia and
improves outcomes for the fetus in an established transgenic rat model.
This treatment approach has the potential for selective delivery to the
pregnant mother without fetal drug exposure, as our study has confirmed
undetectable siRNA levels in the fetus. We look forward to advancing
ALN-AGT as a highly innovative approach for the management of HDP and
preeclampsia.”
“HDP and preeclampsia represent areas of very high unmet medical need.
Today, well over half a million pregnancies in the U.S. and EU are
complicated by hypertension; preeclampsia occurs with an incidence of
over 250,000 cases per year, and accounts for 10-20% of maternal or
fetal perinatal deaths. Early delivery of infants from preeclamptic
mothers is associated with prematurity requiring neonatal intensive care
and accompanied risks of mortality and morbidity for the newly born
infant,” said S. Ananth Karumanchi, M.D., Associate Professor of
Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School.
“Unfortunately, few options exist for management of
hypertension-associated pregnancies, and, in the case of preeclampsia,
treatment can require early delivery or termination of pregnancy to save
the mother’s life. These pre-clinical data with ALN-AGT are promising,
since new treatment options are clearly needed for the management of
these patients.”
Alnylam and collaborators presented
results of a pre-clinical study entitled “RNAi Therapeutics
Targeting Human Angiotensinogen (hAGT) Ameliorate Preeclamptic Sequelae
in an Established Transgenic Rodent Model for Preeclampsia.” A
GalNAc-siRNA conjugate targeting human AGT was designed and synthesized
using Alnylam’s ESC-GalNAc-conjugate delivery platform, which enables
subcutaneous delivery of RNAi therapeutics with a wide therapeutic
index. In a transgenic rat model of preeclampsia, subcutaneous
administration of the lead ALN-AGT molecule resulted in silencing of
human AGT in maternal liver by over 90%, reduced mean arterial blood
pressure by approximately 20 mmHg, and attenuated proteinuria by greater
than 80%; elevated blood pressure and proteinuria are established
hallmarks of preeclampsia. ALN-AGT administration also reduced
additional manifestations of the preeclamptic phenotype in the mother,
including activity levels of agonistic angiotensin 1 receptor
autoantibodies and maternal kidney mRNA expression of soluble fms-like
tyrosine kinase-1 (sflt-1), which were reduced by approximately 90% and
75%, respectively. Preeclampsia is also known to be associated with
abnormal placentation - dysfunction in the interface between mother and
fetus - and reduced placental size associated with impaired fetal
growth. In the pre-clinical model, administration of ALN-AGT was
associated with improved uteroplacental unit weight, increased overall
fetal weight, and normalized fetal brain to liver ratio. In aggregate,
these results showed that ALN-AGT administration improved fetal
outcomes. Finally, quantitative measurements of ALN-AGT drug levels in
the maternal and fetal liver were performed. Results showed that while
significant levels (>20 μg/g liver) of ALN-AGT could be detected in the
maternal liver, levels of ALN-AGT in the fetal liver were below the
lower limit of quantitation for the assay (<0.0013 μg/g liver). These
results are consistent with published data for large macromolecules such
as siRNA, in addition to current company data showing that RNAi
therapeutics do not cross the placental barrier.
About Hypertensive Disorders of Pregnancy and Preeclampsia
Hypertensive
disorders of pregnancy (HDP) are associated with an increased risk of
preeclampsia, one of the most common complications of pregnancy in the
U.S. and one of the most common causes of maternal death in developed
countries. There are over half a million women in the U.S. and EU who
suffer from HDP. Preemclampsia occurs in over 200,000 pregnant women in
the U.S. and EU and is associated with increased risk of maternal
mortality, perinatal fetal mortality, infant prematurity, neonatal
intensive care, and infant morbidity. Presentation with severe
preeclampsia before the fetus is viable may necessitate termination of
the pregnancy, as delivery is the only known cure to save the mother’s
life. Hypertensive drugs such as angiotensin converting enzyme (ACE)
inhibitors and angiotensin receptor blockers (ARBs) are contraindicated
due to side effects to the fetus; patients are typically managed with
bed rest and careful monitoring.
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 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 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), 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 TTR cardiac amyloidosis, including
familial amyloidotic cardiomyopathy (FAC) and senile systemic
amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD);
ALN-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic
targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of
hepatic porphyrias including acute intermittent porphyria (AIP);
ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1
antitrypsin (AAT) for the treatment of AAT deficiency-associated liver
disease; ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus
(HBV) genome for the treatment of HBV infection; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi
therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment
of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic targeting
angiotensinogen (AGT) for the treatment of hypertensive disorders of
pregnancy (HDP), including preeclampsia; 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 North America and Europe, while
Genzyme will develop and commercialize products in the rest of world. In
addition, Alnylam and Genzyme will co-develop and co-commercialize
ALN-TTRsc in North America and Europe. In March 2014, Alnylam acquired
Sirna Therapeutics, a wholly owned subsidiary of Merck. 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, 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 ALN-AGT for the treatment
of hypertensive disorders of pregnancy, including preeclampsia, and its
expectations regarding its “Alnylam 5x15” product strategy, 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 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.
Copyright Business Wire 2014