Alnylam Reports Positive Interim Results from Ongoing Phase 1 Study of ALN-AS1, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyrias
Sep 07, 2016
- In Asymptomatic High Excreter (ASHE) Porphyria Subjects, Single and Multiple Doses of ALN-AS1 Achieve Rapid, Dose-Dependent, and Durable Lowering of Toxic Heme Synthesis Intermediates, with Effects Sustained for Over Ten Months After a Single Dose -
- ALN-AS1 Generally Well Tolerated Following Single and Multiple Doses -
- ALN-AS1 Granted Orphan Drug Designation for the Treatment of Acute
Hepatic Porphyrias by the
- Company to Discuss New Clinical Data during ALN-AS1 RNAi Roundtable
on
"The acute hepatic porphyrias are a group of ultra-rare orphan diseases
with enormous unmet medical need, where novel therapies are clearly
warranted. Accordingly, we're very encouraged by these interim Phase 1
data in ASHE subjects, showing robust lowering of the toxic heme
synthesis intermediates that mediate porphyria attacks," said
New results include all available data as of the data transfer date of June 28, 2016. In Part A (N=20), subjects were enrolled in five single ascending dose (SAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving ALN-AS1 at doses from 0.035 to 2.5 mg/kg. In Part B (N=8), subjects were enrolled in two multiple ascending dose (MAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving two monthly subcutaneous doses of ALN-AS1 at 0.35 or 1.0 mg/kg. In both Parts A and B, ALN-AS1 administration resulted in rapid, dose-dependent, and durable silencing of liver ALAS1 mRNA. In addition, ALN-AS1 resulted in rapid and dose-dependent lowering of ALA and PBG of up to 95%. Reductions in ALA and PBG were highly durable, with effects lasting for over ten months after a single dose.
As of the data transfer date, ALN-AS1 continued to be generally well tolerated in ASHE subjects following single and multiple doses. There were three serious adverse events (SAEs) that were all deemed to be unlikely related to study drug. A total of 78 adverse events (AEs) were reported in both the SAD and MAD cohorts, of which 62 were determined to be not related or unlikely related to ALN-AS1 administration. With the exception of one AE, not related to study drug, that was severe, all other AEs were mild or moderate in severity, and most commonly included abdominal pain, diarrhea, hypoesthesia, nasopharyngitis, pruritis, and rash. Two mild and transient injection site reactions (ISRs) were reported. There were no clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters, or physical examination.
To view the ALN-AS1 clinical data described in this press release, please visit www.alnylam.com/capella.
Alnylam also announced today that the
ALN-AS1 RNAi Roundtable Webinar Information
Alnylam will
review these new clinical data and discuss acute hepatic porphyrias and
plans for the further development of ALN-AS1 in an RNAi Roundtable
webinar next Tuesday, September 13, 2016 at 11:30 a.m. ET. Speakers
include:
-
John Maraganore , Ph.D., Chief Executive Officer -
William Querbes , Ph.D., Associate Director, Research -
Guest Speaker:
Herbert Bonkovsky , M.D., Professor of Gastroenterology atWake Forest Baptist Medical Center andScientific Advisory Board Member of the American Porphyria Foundation -
Guest Speaker:
Ariel Lager , living with Acute Intermittent Porphyria
To register for the webinar, please visit www.alnylam.com/roundtables. A replay of the webinar and downloadable PDF of the presentation will be available on that website shortly after the Roundtable.
About the ALN-AS1 Phase 1 Study
The ALN-AS1 Phase 1 trial is
being conducted in three parts. Parts A and B are 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. Per protocol, ASHE subjects in the study have a defined
mutation in the PBGD gene and elevated urinary levels of ALA and PBG,
but do not have a recent history of porphyria attacks or disease
activity. The primary objective of Parts A and 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.
Exploratory objectives include the impact of ALN-AS1 on liver ALAS1 mRNA
as measured from circulatory or excreted exosomal mRNA preparations in
serum or urine, respectively. Part C is a randomized (3:1,
drug:placebo), double-blind, multi-dose study in up to 12 AIP patients
who experience recurrent porphyria attacks, to assess safety,
tolerability, pharmacodynamics (i.e., lowering of serum and urine ALA
and PBG, as well as liver ALAS1 mRNA) and clinical activity of multiple
doses of ALN-AS1. In addition, this part of the study includes 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.
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.
ALN-AS1 is an investigational compound, currently in early stage
clinical development. The safety and efficacy of ALN-AS1 have not been
evaluated by the
About Acute Hepatic Porphyrias
The porphyrias are a family
of rare metabolic disorders with mostly autosomal dominant inheritance
predominately caused by a genetic mutation in one of the eight enzymes
responsible for heme biosynthesis. Acute hepatic porphyrias (AHP)
constitute a subset where the enzyme deficiency occurs within the liver,
and includes acute intermittent porphyria (AIP), hereditary
coproporphyria, and variegate porphyria. Exposure of AHP 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 neurotoxic heme
intermediates that precipitate disease symptoms. Patients with AHP 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 paralysis and 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. There are no approved therapeutics for
prophylactic use (i.e., the prevention of acute attacks), although
hematin is sometimes used in this manner in patients who experience
recurrent attacks. Chronic administration of hematin may result in renal
insufficiency, iron overload, systemic infections (due to the
requirement for central venous access) and, in some instances,
tachyphylaxis.
In January 2014, Alnylam and Sanofi
Genzyme, the specialty care global business unit of Sanofi, 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 Sanofi
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 (ROW) through the end of 2019, together with certain
broader co-development/co-commercialization rights and global product
rights for certain products, including ALN-AS1.
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 and durability, and a wide therapeutic index.
This delivery platform is being employed in nearly all of Alnylam's
pipeline 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 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 Ionis, Novartis, Roche, Takeda,
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 investigational therapeutics, including ALN-AS1,
its expectations regarding the timing of clinical studies and the
expected timing for the presentation of clinical data from these
studies, including from Part C of the ongoing Phase 1 study of 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 and future plans may differ materially from those
indicated by these forward-looking statements as a result of various
important risks, uncertainties and other 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 product 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 for a
specified indication or at all, actions or advice of regulatory
agencies, which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for additional
pre-clinical and/or clinical testing, delays, interruptions or failures
in the manufacture and supply of our product candidates, obtaining,
maintaining and protecting intellectual property, Alnylam's ability to
enforce its intellectual property rights against third parties and
defend its patent portfolio against challenges from third parties,
obtaining and maintaining regulatory approval, pricing and reimbursement
for products, progress in establishing a commercial and ex-
The scientific information discussed in this news release relating to
Alnylam's investigational therapeutic, ALN-AS1, is preliminary and
investigative. ALN-AS1has not been approved by the
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