Alnylam Reports Positive Initial Clinical Results for ALN-AS1, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1 (ALAS1) for the Treatment of Acute Hepatic Porphyrias

– In Phase 1 Study of Asymptomatic High Excreter (ASHE) Patients with
Acute Intermittent Porphyria (AIP), ALN-AS1 Achieves up to 82% Lowering
of Aminolevulinic Acid (ALA) and up to 93% Lowering of Porphobilinogen
(PBG), the Toxic Heme Synthesis Intermediates that Mediate Porphyria
Attacks –

– Using Exosomal mRNA Preparations from Serum and Urine, ALN-AS1
Showed Potent, Dose-Dependent, and Durable Silencing of ALAS1 mRNA in
Liver –

– ALN-AS1 also Generally Well Tolerated with No Clinically
Significant Drug-Related Adverse Events to Date –

– Company has Now Transitioned to Part B of Phase 1 Study with
Monthly Subcutaneous Dosing and Plans to Start Part C in AIP Patients
Suffering from Recurrent Attacks in Early 2016 –

– Company to Host Conference Call Today, Tuesday, September 15, at
8:30 am ET to Discuss Results –

Pharmaceuticals, Inc.
(Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today initial
positive results
from its ongoing Phase 1 clinical trial with
ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic
acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias.
The Phase 1 study is being performed in asymptomatic “high excreter”
(ASHE) patients, who carry the genetic mutation of acute intermittent
porphyria (AIP) and have elevated levels of aminolevulinic acid (ALA)
and porphobilinogen (PBG), the toxic heme intermediates that mediate
porphyria attacks. Study results showed that single subcutaneous doses
of ALN-AS1 resulted in an up to 82% lowering of ALA and an up to 93%
lowering of PBG, providing human proof-of-concept for this
investigational RNAi therapeutic as a potential therapy for AIP and
other acute hepatic porphyrias. In addition, through analysis of
exosomal mRNA preparations from serum and urine, it was demonstrated
that ALN-AS1 treatment resulted in potent, dose-dependent, and durable
silencing of ALAS1 mRNA in liver. Further, ALN-AS1 was found to be
generally well tolerated with no clinically significant drug-related
adverse events to date. The company has now transitioned to Part B of
the Phase 1 study, in which subjects are receiving monthly subcutaneous
dosing, and the company expects to initiate Part C in AIP patients
suffering from recurrent attacks in early 2016. In addition, Alnylam
presented initial data from the EXPLORE trial, a multinational,
prospective observational study of patients with hepatic porphyrias
suffering from recurrent attacks.

“The acute hepatic porphyrias are caused by mutations in heme synthesis
enzymes that result in build up of ALA and PBG, the toxic intermediates
that mediate porphyria attacks. Accordingly, we’re very encouraged by
these initial Phase 1 data, showing up to 82% lowering of ALA and up to
93% lowering of PBG in ASHE patients with AIP. We are also impressed by
the durability of effect on these disease biomarkers following a single
subcutaneous injection, which we believe to be supportive of a monthly
or potentially once quarterly dosing regimen, and we’ve now transitioned
to the multi-dose cohorts in the Phase 1 study to explore this
potential. Importantly, ALN-AS1 has been generally well tolerated, with
no clinically significant drug-related adverse events reported to date.
We very much look forward to the continued advancement of ALN-AS1, which
we believe has the potential to be a transformative therapy for patients
with acute hepatic porphyrias, a group of ultra-rare orphan diseases
with enormous unmet medical need,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President of R&D and Chief Medical Officer at Alnylam.
“It’s also notable that this is now our fifth GalNAc-siRNA conjugate
program to demonstrate robust clinical activity and excellent
translation from non-human primate to human studies, providing further
support that we’ve achieved what we believe to be a reproducible and
modular platform for innovative medicines. Accordingly, our R&D efforts
continue to create what we believe to be a significant opportunity for
patient impact and value creation.”

“Patients with AIP and other hepatic porphryias often present with
acute, and at times recurrent attacks that are characterized by severe
abdominal pain, neuropathy, neuropsychiatric manifestations, and, in
very severe cases, cardiovascular instability, paralysis and respiratory
failure. Novel therapies are clearly needed for porphyria patients who
suffer from recurrent attacks, as these patients experience enormous
suffering and 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 these initial Phase 1 data with ALN-AS1,
which I believe support the potential for an RNAi therapeutic to reduce
disease burden in patients with AIP and other acute hepatic porphyrias.
If proven to be safe and effective in more advanced studies, I believe a
subcutaneously administered drug with an infrequent dosing regimen would
be a very welcome therapeutic option for these patients and their

ALN-AS1 is a subcutaneously administered, investigational RNAi
therapeutic that employs Alnylam’s ESC-GalNAc delivery technology. The
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 porphobilinogen deaminase (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 will
be a multi-dose study in up to eight AIP patients who experience
recurrent porphyria attacks, and will 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 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.

Phase 1 study results
were presented in an oral presentation at the
2015 International Congress of Porphyrins and Porphyrias (ICPP) held
September 14 – 16 in Dusseldorf, Germany. All results are based on data
in the database as of September 2, 2015. A total of 16 ASHE patients
were enrolled in four single ascending dose (SAD) cohorts (N=4 per
group), with subjects receiving 0.035, 0.1, 0.35, or 1.0 mg/kg doses of
ALN-AS1. In all dose cohorts, the volume of injection was less than 1.0
mL. The 0.035 mg/kg cohort was added to explore a lower dose after
initial results were obtained from the 0.1 and 0.35 mg/kg cohorts. The
multi-dose Part B of the study has now been initiated with monthly
subcutaneous doses of 0.35 mg/kg. Alnylam expects to report initial data
from this part of the study in 2016.

Measurement of ALAS1 mRNA levels employed a method
previously described by Alnylam scientists
known as circulating
extracellular mRNA detection (cERD) (Sehgal et al., RNA, 20:1-7(2014)),
and was performed using serial serum and urine samples. At baseline,
ASHE patients enrolled in the study were found to have substantially
higher levels of liver ALAS1 mRNA detected in serum and urine relative
to normal healthy volunteers. Specifically, there was an approximate
3-fold increase in liver ALAS1 mRNA (p less than 0.001, unpaired t test)
relative to levels observed in healthy subjects. ALN-AS1 administration
resulted in potent, dose-dependent, and durable silencing of liver ALAS1
mRNA. An up to 59% maximal and 44 ± 8% mean maximum (p less than 0.01,
relative to placebo) silencing of liver ALAS1 mRNA was observed in the
0.35 mg/kg dose cohort; as of the data cut-off date, mRNA silencing data
are pending for the top 1.0 mg/kg dose. Nadir silencing was achieved at
approximately day 21, and effects were highly durable lasting over 42
days after a single dose. While it has been speculated that ASHE
patients have increased liver ALAS1 mRNA levels compared to that of
healthy subjects, these data represent the first definitive evidence
that this is in fact the case in humans. In addition, to the company’s
knowledge, these mRNA silencing and time course data are the first to
ever be presented from any human study with RNAi therapeutics, marking
another milestone in Alnylam’s efforts to advance this potential new
class of medicines to patients.

In AIP, loss-of-function mutations in PBGD can result in excessive
accumulation of ALA and PBG, the toxic heme synthesis intermediates that
mediate porphyria attacks. ASHE patients are asymptomatic, but have
increased ALA and PBG levels that, while lower than those seen in AIP
patients during an acute attack, are still significantly higher than
normal reference values. In the Phase 1 ASHE patient study, mean
baseline urinary levels of ALA and PBG were 11.0 and 21.7 mmol/mol
creatinine, respectively. Compared to normal, these levels were elevated
by approximately 3-fold for ALA and 14-fold for PBG. A single
subcutaneous dose of ALN-AS1 resulted in potent, dose-dependent, and
highly durable lowering of ALA of up to 82% and PBG of up to 93%. An up
to 77 ± 7% and 73 ± 6% mean maximum lowering of urinary ALA and PBG,
respectively, was achieved in the 0.35 mg/kg cohort (p less than 0.01
for ALA and p equal to 0.06 for PBG, both relative to placebo). A
greater mean maximum lowering of ALA and PBG is expected to be achieved
at the 1.0 mg/kg dose, but current data are limited to 2 subjects
through day 14. Even at the lowest dose of 0.035 mg/kg, an approximately
33% lowering of ALA and PBG was observed. As with ALAS1 mRNA silencing,
nadir effects on ALA and PBG were observed on day 21. Further,
reductions in ALA and PBG were highly durable, with effects lasting over
42 days after a single dose. The durability of ALN-AS1 clinical activity
is supportive of a once monthly and possibly a once quarterly, low
volume subcutaneous dose regimen. There was a close correlation of liver
ALAS1 mRNA silencing with ALA and PBG lowering (r2=0.82, p
less than 10-15 for both ALA and PBG). Of note, a higher
degree of ALA and PBG reduction was achieved at relatively lower levels
of ALAS1 mRNA silencing, consistent with similar observations from
pre-clinical studies. These data suggest that a substantial reduction in
heme synthesis intermediate accumulation can be achieved with moderate
levels of ALAS1 mRNA silencing, essentially where mRNA levels are more
comparable to those seen in normal individuals. The initial clinical
activity results are summarized in the table below.


Initial ALN-AS1 Phase 1 Clinical Activity Results


SAD Cohort
















  3.4   1.1 ± 1.1   13.4   8.5 ± 3.1   25.6   11.7 ± 6.8

0.035 mg/kg

  23.4   15.9 ± 4.2   59.1   44.4 ± 7.5   62.5   45.3 ± 12.1

0.1 mg/kg

  42.2   33.7 ± 5.8**   78.8   65.5 ± 12.5*   89.3   70.5 ± 11.9*

0.35 mg/kg

  59.2   44.5 ± 8.2**   89.5   77.1 ± 6.9**   81.0   72.6 ± 5.5~

1.0 mg/kg

  Pending   Pending   81.7   Pending   93.0   Pending

#For mean maximum silencing/lowering relative to baseline, p values from
pairwise comparisons vs. placebo using ANCOVA model
^For 1.0 mg/kg
group, all ALAS-1 mRNA data are pending; for ALA and PBG data, N=2 at
day 14 and N=1 for days 21 and 28
~ p equal to 0.06
*p less
than 0.05
**p less than 0.01

In the ongoing study, ALN-AS1 was found to be generally well tolerated
with no clinically significant drug-related adverse events to date.
There was one serious adverse event (SAE) of acute abdominal pain, which
was deemed to be unlikely related to study drug. There were no study
discontinuations. An additional 28 mild to moderate adverse events (AEs)
were reported, of which 26 were determined to be not related or unlikely
related to ALN-AS1 administration; these occurred with similar incidence
in placebo and ALN-AS1 patients, with no dose-dependent trends. One
patient in the 1.0 mg/kg cohort experienced a mild, localized injection
site reaction (ISR), consisting of transient erythema. There were no
other clinically significant, drug-related abnormalities in any
laboratory or hematologic assessment, vital signs, electrocardiograms,
or physical examinations.

“Patients afflicted with acute hepatic porphyrias, such as AIP, can
suffer from severe and recurrent attacks resulting in a markedly
decreased ability to lead a normal functioning life,” said Desiree Lyon,
Co-Founder and Executive Director of the American Porphyria Foundation.
“I am encouraged by the initial clinical data emerging from Alnylam’s
investigational porphyria program, as they suggest the potential for
ALN-AS1 to have an impact on the cause of painful disease symptoms.
Moreover, I am grateful for Alnylam’s commitment and care for our
community, and believe that their efforts could make a meaningful
difference in the lives of our patients.”

Also in an oral presentation at the ICPP, Alnylam presented initial
results (from data in the database as of August 14, 2015) from the EXPLORE
, a multinational, prospective observational study of patients
with hepatic porphyrias suffering from recurrent attacks. This study
aims to provide enhanced understanding of the natural history of hepatic
porphyrias in patients with recurrent attacks, as well as to obtain
information about the burden of disease, current management and unmet
need. Initial data presented at ICPP were from 68 patients, who had a
mean of 10.6 ± 11.0 attacks for the 12 months prior to study entry. In
baseline questionnaires, the most common symptoms associated with past
porphyria attacks were abdominal and back pain, tiredness, nausea,
weakness, and change in urine color. Also, it was found that
approximately 50% of patients experience chronic porphyria symptoms even
when not having an acute attack. In their baseline evaluation, the
patients reported a diminished quality of life, with an EQ-5D Index of
0.74, even while not in the midst of an acute attack. After enrollment
in the study, a total of 101 porphyria attacks were documented, with
41/68 (60%) patients reporting at least one attack; the mean duration of
attacks was 7.9 days. The majority of attacks were treated in the
hospital setting with hematin and/or pain management. At baseline, liver
ALAS1 mRNA was elevated by over 4-fold compared to healthy subjects, and
this was found to significantly increase further during an acute attack
(p less than 0.0001, repeated measures model). Similarly, in a group of
patients (n=16) with paired samples from both asymptomatic and attack
periods, urinary ALA and PBG levels increased above asymptomatic levels
by 6.3- and 2.5-fold, respectively, during the acute attack period.
These data suggest that elevated levels of ALAS1 mRNA, ALA, and PBG are
associated with acute attacks in patients with acute hepatic porphyria,
and that they may be useful biomarkers for disease activity. The EXPLORE
study is ongoing, and the company plans to report additional data from
this study in 2016.

Genzyme Alliance
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.

Conference Call Information
Alnylam management will discuss
these new Phase 1 results with ALN-AS1 in a webcast conference call on
Tuesday, September 15 at 8:30 a.m. ET. A slide presentation will also be
available on the Investors page of the company’s website,,
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 36798385. A replay of
the call will be available beginning at 11:30 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 36798385.

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

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,

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 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.


Alnylam Pharmaceuticals, Inc.
Michael Mason, 617-551-8327
President, Finance and Treasurer
Liz Bryan
(Media), 202-955-6222 x2526

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