Alnylam
Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today that it has initiated a Phase 1 clinical trial
with ALN-AS1, a subcutaneously administered investigational RNAi
therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the
treatment of acute hepatic porphyrias, including acute intermittent
porphyria (AIP). The Phase 1 trial of ALN-AS1 will be conducted
initially in AIP patients who are asymptomatic “high excreters” (ASHE).
These ASHE subjects have a defined mutation in the porphobilinogen
deaminase (PBGD) gene and elevated urinary levels of aminolevulinic acid
(ALA) and porphobilinogen (PBG), but do not have a current history of
porphyria attacks or disease activity. Subsequently, the trial is
designed to enroll AIP patients who experience recurrent porphyria
attacks. The company expects to present initial clinical data from this
trial in early 2016.
“We believe ALN-AS1 has the potential to be a transformative therapy for
patients with acute hepatic porphyrias, a group of ultra-rare monogenic
diseases with enormous unmet medical need, and we’re excited to now
advance this innovative investigational medicine to the clinic. Our
Phase 1 study aims to obtain data on safety and tolerability in addition
to potential clinical activity in ASHE subjects and AIP patients with
recurrent attacks,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President of R&D and Chief Medical Officer of Alnylam. “We’re encouraged
by the potential for ALN-AS1 to make a difference in the lives of people
afflicted with acute hepatic porphyrias. In pre-clinical studies
performed in rodent models of AIP, we have shown that subcutaneous
administration of ALN-AS1 results in complete suppression of the toxic
heme biosynthesis intermediates that cause disease symptoms and
pathology. We very much look forward to the advancement of ALN-AS1 in
the clinic and expect to share initial data from the Phase 1 trial in
early 2016.”
“Patients with AIP often present with acute, and at times recurrent
attacks that are characterized by severe abdominal pain, neuropathy,
neuropsychiatric manifestations, and, in very severe cases, paralysis
and respiratory failure. Novel therapies are needed for porphyria
patients who suffer from recurrent attacks. These patients can spend a
significant number of days in the hospital every month and have a very
poor quality of life,” said Eliane Sardh, M.D., Ph.D., Senior Physician
at the Porphyria Centre Sweden and the Centre for Inherited Metabolic
Diseases and Department of Endocrinology, Metabolism and Diabetes at
Karolinska University Hospital in Stockholm, Sweden. “I am encouraged
with the pre-clinical data to date with ALN-AS1, which I believe support
the potential for an RNAi therapeutic as a novel therapeutic option for
patients with AIP and other acute hepatic porphyrias.”
ALN-AS1 is a subcutaneously administered, investigational RNAi
therapeutic that employs Alnylam’s ESC-GalNAc delivery technology.
ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of
RNAi therapeutic to hepatocytes through uptake by the asialoglycoprotein
receptor, and enable subcutaneous dosing with increased potency and
durability and a wide therapeutic index. In pre-clinical
studies, multi-dose administration of ALN-AS1 led to rapid,
dose-dependent, and long-lasting knockdown of the ALAS1 mRNA in the
liver of non-human primates, with an ED50 of approximately
1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at
doses as low as 2.5 mg/kg resulted in a complete blunting of
phenobarbital-induced production of ALA and PBG, the toxic heme
intermediates in AIP. Pre-clinical studies with RNAi therapeutics
targeting ALAS1 have been published
by Alnylam and collaborators previously (Yasuda et al., Proc Natl
Acad Sci USA 2014;111(21):7777-7782).
As per the filed CTA, the Phase 1 trial of ALN-AS1 will be conducted in
three parts. Parts A and B will be randomized (3:1, drug:placebo),
single-blind, single-dose (Part A) and multi-dose (Part B),
dose-escalation studies, designed to enroll up to a total of 40 ASHE
subjects. The primary objective of Part A and Part B is to evaluate
safety and tolerability of single and multiple subcutaneous doses of
ALN-AS1. Secondary objectives include evaluation of clinical activity
for ALN-AS1 as measured by reduction in plasma and urinary levels of ALA
and PBG. Part C will be an open-label, multi-dose study in up to eight
AIP patients who experience recurrent porphyria attacks, and will assess
safety, tolerability, PK/PD, and clinical activity of multiple doses of
ALN-AS1. In addition, this part of the study will include an exploratory
evaluation of the effects of ALN-AS1 on the number and severity of
attacks and other disease symptoms, use of hematin and pain medications,
number and duration of hospitalizations, and quality of life.
“Patients afflicted with acute hepatic porphyrias, such as AIP, can
suffer from severe and recurrent attacks that are potentially
life-threatening and that can result in a markedly decreased ability to
lead a normal functioning life. Current treatment options are limited,
especially for patients with recurrent attacks that often require
monthly hospitalizations for administration of hematin and pain
management,” said Desiree Lyon, Co-Founder and Executive Director of the
American Porphyria Foundation. “Today is an important step forward for
our patient community, as ALN-AS1, a promising investigational medicine
for the treatment of acute hepatic porphyrias, has entered clinical
testing. I am so pleased with Alnylam’s commitment to make a difference
in the lives of our patients.”
In addition to the Phase 1 trial, Alnylam and clinicians from the
American Porphyria Consortium and The European Porphyria Network are
currently enrolling patients in the EXPLORE trial, a prospective
observational study of patients with acute hepatic porphyrias –
including 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 acute hepatic porphyrias that suffer
from recurrent attacks.
In January 2014, Alnylam and Genzyme, a Sanofi company, 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
Genzyme obtained the right to access certain programs in Alnylam's
current and future Genetic Medicines pipeline, including ALN-AS1, in the
rest of the world. In certain defined instances, Genzyme has
co-development/co-commercialization and/or global product rights.
Genzyme’s rights are structured as an opt-in that is triggered upon
achievement of human proof-of-principle.
About ALN-AS1
Alnylam is developing ALN-AS1, a subcutaneously administered,
investigational RNAi therapeutic targeting aminolevulinic acid synthase
1 (ALAS1) for the treatment of acute hepatic porphyrias, including acute
intermittent porphyria (AIP). AIP is an ultra-rare autosomal dominant
disease caused by loss of function mutations in porphobilinogen
deaminase (PBGD), an enzyme in the heme biosynthesis pathway that can
result in accumulation of toxic heme intermediates, including
aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP
can suffer from acute and/or recurrent life-threatening attacks
characterized by severe abdominal pain, neuropathy (affecting the
central, peripheral or autonomic nervous system), and neuropsychiatric
manifestations. ALN-AS1 is an ESC-GalNAc-siRNA conjugate targeting
ALAS1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the
heme biosynthesis pathway. Inhibition of ALAS1 is known to reduce the
accumulation of heme intermediates that cause the clinical
manifestations of AIP. ALN-AS1 has the potential to be a prophylactic
approach for the prevention of recurrent attacks, as well as for the
treatment of acute porphyria attacks.
About Acute 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. Acute hepatic
porphyrias constitute a subset where the enzyme deficiency occurs within
the liver, and includes acute intermittent porphyria (AIP), hereditary
coproporphyria, and variegate porphyria. Exposure of acute hepatic
porphyria patients to certain drugs, dieting, or hormonal changes can
trigger strong induction of aminolevulinic acid synthase 1 (ALAS1),
another enzyme in the heme biosynthesis pathway, which can lead to
accumulation of heme intermediates that precipitate disease symptoms.
Patients with one of the acute 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 untreated or if
there are delays in treatment. The only approved treatment for acute
attacks is hematin (Panhematin® or Normosang®), a preparation of heme
derived from human blood. Hematin requires administration through a
large vein or a central intravenous line and is associated with a number
of complications including thrombophlebitis or coagulation
abnormalities. While hematin is not approved for prophylactic use (i.e.,
the prevention of acute attacks), it is often used in this manner in
patients who experience recurrent attacks. Chronic administration of
hematin has been found to result in renal insufficiency, iron overload,
systemic infections (due to the requirement for central venous access)
and, in some instances, tachyphylaxis.
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 Merck, Medtronic, Novartis, Biogen, Roche, Takeda,
Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The
Medicines Company, and Genzyme, a Sanofi company. 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 ALN-AS1 for the treatment of acute hepatic porphyrias, its
expectations regarding the reporting of data from its ALN-AS1 clinical
studies, its expectations regarding the potential market opportunity for
ALN-AS1, 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.
View source version on businesswire.com: http://www.businesswire.com/news/home/20150526005413/en/
Copyright Business Wire 2015