Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, and collaborators from the American Porphyria Consortium and
The European Porphyria Network have initiated the EXPLORE trial, a
prospective observational study of patients with hepatic porphyrias,
including Acute Intermittent Porphyria (AIP), Variegate Porphyria, and
Hereditary Coproporphyria, suffering from recurrent attacks. With this
study, Alnylam and clinical investigators aim to learn more about the
clinical course, management, and disease burden of patients with hepatic
porphyrias that suffer from recurrent attacks. Alnylam is currently
advancing ALN-AS1, a subcutaneously administered investigational RNAi
therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the
treatment of hepatic porphyrias, and expects to file an IND or IND
equivalent in late 2014 or early 2015.
“We believe ALN-AS1 has the potential to be a transformative therapy for
patients with hepatic porphyrias, a group of ultra-rare genetic
diseases, including AIP, where there is enormous unmet medical need.
With the initiation of EXPLORE, we aim to learn more about the clinical
course, management, and overall disease burden through patient and
physician assessments, in addition to a number of laboratory analyses,
for patients with hepatic porphyrias. We believe that these results
could give us critical insights in the disease course and management of
porphyria, improving our ability to better design trials for our ALN-AS1
investigational therapy,” said Amy Simon, M.D., Senior Director of
Clinical Development at Alnylam. “To date, we have generated encouraging
pre-clinical data showing that ALN-AS1 can achieve potent, rapid, and
durable suppression of the toxic heme biosynthesis intermediates that
cause the symptoms and disease pathology of AIP. We’re pleased to report
that we remain on track to file an IND or IND equivalent for ALN-AS1
later this year or early next year.”
“Patients with AIP present with acute, and at times recurrent attacks
that are characterized by severe abdominal pain, peripheral and
autonomic neuropathy, neuropsychiatric manifestations, and in very
severe cases paralysis and respiratory failure. Patients with these
frequent attacks can spend a significant number of days in the hospital
and many have a very poor quality of life,” said Robert J. Desnick,
M.D., Ph.D., Dean for Genetic and Genomic Medicine and Professor and
Chair Emeritus of the Department of Genetics and Genomic Sciences at the
Icahn School of Medicine at Mount Sinai in New York City. “Our lab’s
pre-clinical studies with ALN-AS1 support the potential for an RNAi
therapeutic as a new investigational medicine for patients with hepatic
porphyrias, and I am pleased with Alnylam’s efforts and commitment to
advance this program to the clinic. EXPLORE is an important component of
this overall effort, since this study should help us more fully
understand the clinical manifestations and treatment of AIP patients
suffering from recurrent attacks.”
EXPLORE is a prospective, multi-center observational study designed to
enroll up to 100 patients with hepatic porphyrias and a history of
recurrent attacks. The study’s primary objective is to characterize the
natural history, clinical management, and disease burden of patients
with hepatic porphyrias. The study’s secondary objectives are to further
characterize a number of disease features of hepatic porphyrias,
including: (i) signs and symptoms of porphyria during acute attacks;
(ii) levels of plasma and urinary aminolevulinic acid (ALA) and
porphobilinogen (PBG), the toxic intermediates of the heme biosynthesis
pathway that cause the symptoms and disease pathology of the acute
hepatic porphyrias; (iii) expression levels of aminolevulinic acid
synthase-1 (ALAS-1) during acute attacks; and (iv) medical and family
history of hepatic porphyria patients. Data obtained from EXPLORE are
expected to further the understanding of hepatic porphyrias and to
assist the design of clinical trials with ALN-AS1.
Hepatic porphyrias are a set of ultra-rare orphan diseases caused by
loss-of-function mutations in enzymes involved in heme biosynthesis,
leading to accumulation of toxic heme intermediate precursors. In the
case of AIP, there are approximately 5,000 patients in the U.S. and
Europe that suffer acute, life-threatening porphyria attacks every year;
there are approximately 500 patients afflicted with recurrent
debilitating attacks, that can occur as frequently as once per month or
more. Treatment options for AIP patients suffering from an attack are
limited, and include the administration of intravenous heme, which can
have a slow therapeutic onset, limited efficacy with repeat
administration and side effects including phlebitis, iron overload, and
infections related to the need for central venous access in some
patients. Currently, there are no approved drugs available to prevent
attacks from occurring. Alnylam’s approach is to knock down ALAS-1, the
first enzyme in the heme biosynthesis pathway that is upstream of other
enzymes defective in the hepatic porphyrias. RNAi-mediated silencing of
ALAS-1 in hepatocytes could reduce the abnormal production of the toxic
heme intermediates, specifically aminolevulinic acid (ALA) and
porphobilinogen (PBG), which mediate the symptoms and disease pathology
in multiple acute hepatic porphyrias. Alnylam believes that a
subcutaneously administered RNAi therapeutic targeting ALAS-1 has the
potential to be used as a prophylactic approach to prevent attacks, and
also as a therapy for acute attacks.
“The hepatic porphyrias represent an enormous unmet medical need, and
patients afflicted with these diseases are in need of new treatment
options. These diseases are often misdiagnosed, since symptoms can be
similar in appearance to more common conditions,” said Desiree Lyon
Howe, Executive Director of the American Porphyria Foundation. “I
applaud the efforts of Alnylam, the American Porphyria Consortium, and
The European Porphyria Network to better understand the disease burden
and clinical management of porphyria patients with recurrent attacks. I
believe that the data obtained from EXPLORE will be important in the
development of novel therapies for patients with hepatic porphyrias.”
Alnylam is advancing ALN-AS1 for the treatment of hepatic porphyrias. In pre-clinical
studies and as published in the Proceedings
of the National Academy of Sciences, silencing of ALAS-1 with
either prophylaxis or acute treatment dosing regimens resulted in
complete inhibition of ALA and PBG production in rodent models of AIP.
ALN-AS1 utilizes the company’s proprietary Enhanced Stabilization
Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous
dosing with increased potency and durability, and a wide therapeutic
index.
About Hepatic Porphyrias
The porphyrias are a family of rare
metabolic disorders with autosomal dominant inheritance predominately
caused by a genetic mutation in one of the eight enzymes responsible for
heme biosynthesis. Hepatic porphyrias constitute a subset where the
enzyme deficiency occurs in each case within the liver, and includes
acute intermittent porphyria (AIP), hereditary coproporphyria, and
variegate porphyria. Exposure of hepatic porphyria patients to certain
drugs, dieting, or hormonal changes can trigger strong induction of
aminolevulinic acid synthase-1 (ALAS-1), another enzyme in the heme
biosynthesis pathway, which can lead to accumulation of heme
intermediates that precipitate disease symptoms. Patients with hepatic
porphyrias can suffer from a range of symptoms that, depending on the
specific type, can include acute and/or recurrent life-threatening
attacks with severe abdominal pain, peripheral and autonomic neuropathy,
neuropsychiatric manifestations, cutaneous lesions and possibly death if
left untreated.
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 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 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-AS1 for the treatment
of hepatic porphyrias, its expectations regarding the EXPLORE trial, the
timing of regulatory filings for ALN-AS1, and the potential therapeutic
opportunities for ALN-AS1, as well as its expectations regarding its
“Alnylam 5x15” product strategy, and its plans regarding
commercialization of RNAi therapeutics, including ALN-AS1, 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