– In Randomized, Double-Blind,
Placebo-Controlled Study, Givosiran Demonstrates Decreased
Annualized Attack Rate and Hemin Usage –
– Initial Results from Ongoing Open Label
Extension (OLE) Study Show Consistent Reductions in Porphyria
Attacks with Continued Givosiran Treatment –
– Givosiran Administration Generally Well
Tolerated with Treatment up to 12 Months –
– Company Plans to Initiate Phase 3 Clinical
Program in Late 2017 –
– Management to Discuss New Clinical Data in
Webcast Conference Call Today, Monday, June 26th at 8:00 a.m. ET
–
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading
RNAi therapeutics company, announced today new positive interim
results from Part C, cohorts 1-3, of its ongoing double-blind,
randomized, placebo-controlled Phase 1 study, in addition to
initial results from an open-label extension (OLE) study with
givosiran, an investigational RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute
hepatic porphyrias. These results were presented today in an oral
presentation at the 2017 International Congress on Porphyrins and
Porphyrias (ICPP), being held from June 25 – 28, 2017 in Bordeaux,
France. Results provide evidence that givosiran has the potential
to prevent porphyria attacks in patients with acute intermittent
porphyria (AIP) suffering with recurrent attacks. Based on initial
results from the OLE study, prolonged administration of givosiran
appears to be associated with consistent reductions in the
incidence of porphyria attacks. Givosiran administration was
generally well tolerated with up to 12 months of treatment. In
addition, the Company plans to present updated results from the
EXPLORE natural history study of patients with acute hepatic
porphyria who experience recurrent attacks.
“The acute hepatic porphyrias are a family of ultra-rare,
under-diagnosed diseases caused by mutations in the heme synthesis
pathway resulting in debilitating acute attacks and chronic
manifestations including severe pain, and changes in mental status
and weakness. There is significant unmet medical need for novel
therapies that could prevent acute attacks and improve chronic
disease manifestations,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President of R&D at Alnylam. “We believe these
new interim results continue to demonstrate the potential for
givosiran to achieve meaningful reductions in the frequency of
porphyria attacks, as well as demonstrate tolerability with
extended dosing. We look forward to further exploring givosiran’s
clinical activity and safety profile as we complete Part C of the
Phase 1 study, which is now fully enrolled, and continue dosing in
the OLE study.”
“We believe that a long acting therapeutic agent that has the
potential to prevent porphyria attacks and that can be administered
via a once monthly, low volume, subcutaneous injection could be a
potentially transformative treatment option for patients suffering
with this debilitating and potentially life-threatening disease,”
said Jeff Miller, General Manager of the givosiran program. “Based
on these encouraging interim results and with both Breakthrough
Therapy and PRIME designations granted, we will continue to work
with global regulatory authorities to rapidly advance givosiran
toward regulatory filings and, if approved, to patients. To that
end, we remain on track to initiate the givosiran Phase 3 program
in late 2017.”
New results presented at ICPP include all available data from
cohorts 1-3 in Part C of the Phase 1 trial (N=12) and cohorts 1 and
2 (N=8) of the OLE study as of the data cutoff date of April
21, 2017. Givosiran achieved potent silencing of the ALAS1 mRNA,
which resulted in robust and durable lowering of aminolevulinic
acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates
that mediate acute attacks and chronic porphyria symptoms. In the
first three unblinded treatment cohorts from Part C,
givosiran-treated patients (N=9) experienced a mean 63 percent
reduction in the annualized number of all porphyria attacks
relative to the run-in period attack rate, with consistent effects
observed across a wide range of baseline attack rates. Evaluating
only attacks that were treated at a healthcare facility or with
hemin, givosiran administration was associated with a mean 73
percent reduction in annualized attack rate relative to placebo
during the treatment period. In addition, a 73 percent mean
decrease in annualized hemin doses relative to the run-in period
was reported. Finally, in a new analysis, the observed reduction in
annualized attack rate was found to be associated with the degree
of ALA and PBG lowering.
Initial results from cohorts 1 and 2 (N=8) of the givosiran OLE
study were also presented; to date, all eligible patients have
rolled over from the Phase 1 study to the OLE study. Longer-term
treatment with givosiran was associated with consistent reductions
in the annualized porphyria attack rate. In addition, preliminary
evidence was obtained suggesting the potential for further
reductions in the attack rate with extended dosing. Specifically,
for the six OLE patients randomized to receive givosiran in Phase
1, the mean annualized attack rate during the Phase 1 treatment
period was nine and this was reduced further to five in the OLE
study with a mean follow up of 111 days. Further, in the two OLE
patients randomized to receive placebo in Phase 1, no attacks have
occurred as of the data cut-off date following givosiran
administration in the OLE study, with a mean follow up of 31 days.
The Company expects to continue enrollment and dosing of patients
in the OLE study, and plans on reporting results at least once
annually.
As of the data cutoff date, givosiran administration was
generally well tolerated in recurrent attack AIP patients in
cohorts 1-3 in Part C of the Phase 1 study and in cohorts 1 and 2
of the ongoing OLE study, with a mean of 169 and 111 days on study,
respectively, and up to 12 months on givosiran. In Part C there
were no drug-related serious adverse events (SAEs) or
discontinuations due to adverse events (AEs). Excluding porphyria
attacks, three patients had four SAEs; none were assessed as
related to study drug. As previously reported, one death occurred
in a patient in cohort 3 in the givosiran arm due to hemorrhagic
pancreatitis complicated by a pulmonary embolism and following a
recent hospitalization for bacteremia; the death was considered to
be unlikely related to study drug by the investigator and the
study's Safety Review Committee. During the Phase 1 treatment
period, all randomized patients reported at least one AE. The
majority of AEs were assessed as mild or moderate in severity.
Twenty-five percent of patients had severe AEs, assessed as
unrelated to study drug. AEs in three or more patients included:
abdominal pain, headache, nasopharyngitis, nausea and vomiting.
Four patients were assessed as having AEs possibly related to study
drug, including injection site reaction (mild and self-limiting),
hypersensitivity, myalgia, headache, moderate renal impairment (in
a patient with a history of moderate renal impairment) and
erythema. There were no other clinically significant changes in
vital signs, electrocardiograms, clinical laboratory parameters
(including liver function tests and lipase tests), or physical
examination. The overall safety experience in the ongoing OLE study
was consistent with results from the Phase 1 study. No SAEs
(excluding porphyria attacks) or discontinuations due to AEs have
been reported in the OLE study.
Data from the EXPLORE natural history study will also be
presented at the conference. EXPLORE is a prospective,
multinational, observational study characterizing the natural
history and clinical management of AHP patients with recurrent
attacks (3 or more attacks/year) or who receive hemin or
gonadotropin-releasing hormone analogue prophylaxis to prevent
attacks. A total of 112 patients with acute hepatic porphyria
(AHP), of which 104 have AIP, were enrolled from 13 countries.
Updated 12-month data from EXPLORE demonstrate that patients suffer
from both acute attacks and chronic symptoms (64 percent of
patients) in between attacks, that together result in a diminished
quality of life. The annualized attack rate on study was
approximately five attacks/person with a mean attack duration of
seven days. The majority of attacks (77 percent) required treatment
in the hospital, urgent healthcare facility or with hemin. An
analysis of costs associated with AHP and recurrent attacks – the
first analysis of its kind in AHP in the U.S. – revealed the
average estimated annual expenditure per patient ranges from
approximately $400,000 to $650,000. These analyses only incorporate
direct costs, and do not reflect indirect costs, such as the cost
associated with lost productivity for both patients and caregivers.
Updated EXPLORE data will be presented on Wednesday, June 28th and
the presentations will be posted to the Alnylam website in the
Capella section.
Conference Call Details
Management will discuss these results via conference call on
Monday, June 26, 2017 at 8:00 a.m. ET. A slide presentation will
also be available on the Investors page of the company's website,
www.alnylam.com, to accompany the conference call. To access the
call, please dial 877-312-7507 (domestic) or 631-813-4828
(international) five minutes prior to the start time and refer to
conference ID 42943196. A replay of the call will be available
beginning at 11:00 a.m. ET on June 26, 2017. To access the replay,
please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 42943196.
About Givosiran Phase 1 Study
The ongoing portion of the Phase 1 study of givosiran (Part C)
is being conducted as a randomized, double-blind,
placebo-controlled study in up to 24 patients with AIP who
experience recurrent porphyria attacks. Patients are initially
followed in a 3-month run-in phase, where the number and frequency
of porphyria attacks and levels of ALA and PBG are measured
prospectively. Patients who experience at least one porphyria
attack during the run-in phase are then eligible to enter the
6-month treatment phase of the study, where they are randomized to
receive 2 once-quarterly doses or 4 once-monthly doses of placebo
or givosiran at doses of 2.5 or 5.0 mg/kg. During the treatment
phase, the effects of placebo or givosiran on the number and
frequency of porphyria attacks, as well as on the levels of ALA and
PBG, are measured prospectively in a blinded manner and then
compared to run-in phase results. Additional measures include
safety, tolerability, hospitalizations, use of hemin, levels of
ALAS1 mRNA, and givosiran pharmacokinetics. Hemin is
an FDA-approved agent used to treat porphyria attacks when
they occur. Following the treatment phase, all patients are
eligible to receive givosiran in an open-label extension study.
About Givosiran
Alnylam is developing givosiran (formerly known as ALN-AS1), a
subcutaneously administered, investigational RNAi therapeutic
targeting ALAS1 for the treatment of AHP, including AIP. AIP is the
most common of the porphyrias, 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
ALA and PBG. Givosiran 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. Givosiran has the potential to be a
novel treatment approach for the prevention of recurrent attacks.
Givosiran has previously been granted PRIME designation which was
established by the European Medicines Agency (EMA) to bring
treatments to patients faster by enhancing the EMA’s support for
the development of medicines for diseases where there is an unmet
medical need and where early clinical data show potential to
benefit patients. Givosiran also received Breakthrough Designation
by the U.S. Food and Drug Administration (FDA). Breakthrough
Therapy designation is granted to expedite the development and
review of new drugs that treat serious or life-threatening diseases
where preliminary clinical evidence exists in support of
substantial benefit over available therapies. The designation is
aimed to help ensure that patients with unmet medical needs receive
access to new therapies through FDA approval as soon as possible.
In addition, Givosiran has been granted Orphan Drug Designations in
both the E.U. and the U.S. for the treatment of acute
hepatic porphyrias.
The safety and efficacy of givosiran have not been evaluated by
the FDA, the EMA or any other health authority.
About Acute Hepatic Porphyrias
The porphyrias are a family of rare metabolic disorders with
mostly autosomal dominant inheritance predominantly 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
(HCP), and variegate porphyria (VP) and ALAD-deficiency porphyria
(ADP). 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. There are no approved treatments for the prevention of
attacks; the only approved treatment for acute attacks is hemin for
injection (Panhematin® or Normosang®), a preparation of heme
derived from human blood. Hemin requires administration through a
large vein or a central intravenous line and is associated with a
number of complications including thrombophlebitis or coagulation
abnormalities. Chronic administration of hemin may 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 (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of patients who have
limited or inadequate treatment options. Based on Nobel
Prize-winning science, RNAi therapeutics represent a powerful,
clinically validated approach for the treatment of a wide range of
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust discovery platform and deep pipeline of investigational
medicines, including three product candidates that are in
late-stage development or will be in 2017. Looking forward, Alnylam
will continue to execute on its “Alnylam 2020” strategy of building
a multi-product, commercial-stage biopharmaceutical company with a
sustainable pipeline of RNAi-based medicines. For more information
about our people, science and pipeline, please visit
www.alnylam.com and engage with us on Twitter at @Alnylam.
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 givosiran, its expectations regarding the
timing of clinical studies, including the initiation of a Phase 3
trial for givosiran following interactions with regulatory
authorities, its expectations regarding scientific and regulatory
support for givosiran from the FDA and EMA and collaborating with
these agencies on the accelerated assessment of givosiran, its
expectations regarding the potential impact givosiran may have on
reducing the economic burden of AHP for patients and their
caregivers, its expectations regarding its “Alnylam 2020” guidance
for the advancement and 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-United
States infrastructure, competition from others using technology
similar to Alnylam's and others developing products for similar
uses, Alnylam's ability to manage its growth and operating
expenses, 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 and distribution of products, the
outcome of litigation, the risk of government investigations, 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, except to the
extent required by law, to update any forward-looking
statements.
The scientific information referenced in this news release
relating to givosiran is preliminary and investigative. Givosiran
has not been approved by the U.S. Food and Drug Administration,
European Medicines Agency, or any other regulatory authority and no
conclusions can or should be drawn regarding its safety or
effectiveness.
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version on businesswire.com: http://www.businesswire.com/news/home/20170626005482/en/
Alnylam Pharmaceuticals, Inc.Investors and MediaChristine
Regan Lindenboom, 617-682-4340orInvestorsJosh Brodsky,
617-551-8276
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