Sanofi and Alnylam present positive complete results from APOLLO Phase 3 study of investigational patisiran in heredita...
02 Novembre 2017 - 3:46PM
Press ReleaseSource: Sanofi (EURONEXT: SAN)
(NYSE: SNY)
Sanofi and Alnylam present positive complete results from
APOLLO Phase 3 study of investigational patisiran in hereditary
ATTR (hATTR) amyloidosis patients with polyneuropathy
- Patisiran meets primary endpoint with a 34.0 point mean
difference relative to placebo and a negative 6.0 point mean change
(improvement) relative to baseline in modified neuropathy
impairment score (mNIS+7) at 18 months
- Patisiran meets all secondary endpoints, including a 21.1 point
mean difference relative to placebo and a negative 6.7 point mean
change (improvement) relative to baseline in Norfolk-Quality of
Life-Diabetic Neuropathy (QOL-DN) score at 18 months
- Significant effects observed on certain exploratory cardiac
biomarker and echocardiographic endpoints in pre-specified cardiac
subpopulation relative to placebo at 18 months
- Encouraging safety profile with up to 18 months of dosing
Paris, France and Cambridge, MA - November 2,
2017 - Sanofi Genzyme, the specialty care global business unit
of Sanofi, and Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the
leading RNAi therapeutics company, announced today positive
complete results from the APOLLO Phase 3 study of patisiran, an
investigational RNAi therapeutic being developed for patients with
hereditary ATTR (hATTR) amyloidosis with polyneuropathy.
These clinical data were presented today in an
oral presentation at the 1st European ATTR Amyloidosis Meeting for
Patients and Doctors being held November 2-3, 2017 in Paris,
France. Based on these results, Alnylam intends to file a new drug
application (NDA) in the United States for patisiran by end-2017
and a marketing authorization application (MAA) in the European
Union shortly thereafter.
The full APOLLO results showed improvement with
patisiran relative to placebo in the primary endpoint of modified
Neuropathy Impairment Score +7 (mNIS+7) and additional secondary
endpoints encompassing sensory, motor, and autonomic neuropathy
symptoms, as well as in exploratory cardiac endpoints, at 18
months. Patients exhibited improved quality of life,
activities of daily living, nutritional status, motor strength, and
ambulatory ability, with reduced disease symptoms and disability.
Favorable effects of patisiran relative to placebo were observed
across subgroups defined by demographic and baseline hATTR
amyloidosis disease characteristics. In a pre-specified cardiac
subpopulation, significant positive effects were observed for
patisiran on certain exploratory cardiac biomarker and
echocardiographic endpoints.
The most commonly reported adverse events (AEs)
that occurred more frequently in patisiran-treated patients were
generally mild to moderate and included peripheral edema and
infusion-related reactions (IRRs). The frequency of deaths and
serious adverse events (SAEs) was similar in the patisiran and
placebo groups. These data support the potential of patisiran to
stabilize and even improve the cardinal, multi-system disease
manifestations of hATTR amyloidosis, including improvement in
patients' quality of life.
"We are very pleased for patients and
families living with hATTR amyloidosis as we believe these results
from APOLLO offer new hope for the treatment of this devastating
disease. Indeed, patisiran holds the potential to halt or improve
neurological impairment and broader disease features in patients
with hATTR amyloidosis. We also view these results as a landmark
achievement for the field of RNAi therapeutics, as we believe they
demonstrate the transformational potential of this novel class of
innovative medicines," said Akshay Vaishnaw, M.D., Ph.D., Executive
Vice President of R&D at Alnylam. "Alnylam is indebted to all
the patients, investigators, and study staff who took part in the
APOLLO study, making this important and notable milestone possible.
We're also grateful to the caregivers and family members whose
support of APOLLO patients was such an important contribution. With
these promising APOLLO data in hand, we intend to start filing our
results with regulatory authorities in late 2017 with the goal of
achieving approval in mid-2018."
Overall Efficacy Results
Patisiran met the primary endpoint of mNIS+7
change from baseline at 18 months relative to placebo, and all
secondary study endpoints. Specifically:
- Patisiran treatment (N=148) resulted in a negative 6.0 point
mean change (improvement) in mNIS+7 score from baseline at 18
months as compared to a 28.0 point mean increase (worsening)
reported for the placebo group (N=77), resulting in a 34.0 point
mean difference relative to placebo (p=9.26 x 10-24).
- The results were found to be consistent across all
sub-components of the mNIS+7 scale.
- Improvement in mNIS+7 from patisiran treatment was also
consistently observed across all defined patient subgroups,
including age, sex, race, geographic region, baseline neuropathy
impairment, genotype, prior TTR stabilizer use, baseline familial
amyloid polyneuropathy (FAP) stage, and inclusion in the
pre-specified cardiac subpopulation.
- Patisiran treatment resulted in a negative 6.7 point mean
change (improvement) in Norfolk-Quality of Life-Diabetic Neuropathy
(Norfolk QOL-DN) score from baseline at 18 months as compared to a
14.4 point mean increase (worsening) reported for the placebo
group, resulting in a mean 21.1 point difference relative to
placebo (p=1.10 x 10-10).
- Improvements in mNIS+7 and Norfolk QOL-DN with patisiran were
also seen at nine months, the earliest time point for these
measurements in the study with a mean 16.0 and a mean 15.0 point
difference observed, respectively, relative to placebo.
- In a pre-specified binary analysis of neurological improvement,
56 percent (95 percent CI: 48.1, 64.1) of patisiran patients had an
improvement in mNIS+7 (less than 0 point change compared to
baseline at 18 months), while 4 percent (95 percent CI: 0.0, 8.2)
of placebo patients had an improvement (p=1.82 x 10-15).
- Similarly, 51 percent (95 percent CI: 43.3, 59.4) of patisiran
patients had an improvement in Norfolk QOL-DN (less than 0 point
change compared to baseline at 18 months), versus 10 percent (95
percent CI: 3.6, 17.2) for placebo (p=1.95 x 10-10).
- Patisiran also demonstrated statistically significant and
clinically meaningful improvements over placebo in all other
secondary endpoints at 18 months, including: NIS-W (p=1.40 x
10-13), the subdomain of mNIS+7 assessing muscle strength;
Rasch-built Overall Disability Scale (R-ODS) (p=4.07 x 10-16), a
patient reported outcome measure of daily living and disability;
timed ten-meter walk test (10-MWT) (p=1.88 x 10-12), assessing
ambulatory ability and gait speed; modified body mass index (mBMI)
(p=8.83 x 10-11), assessing nutritional status; and, COMPASS-31
(p=0.0008), a patient questionnaire assessing autonomic disease
symptoms.
Cardiac Subpopulation Results
Favorable and significant changes in several
exploratory cardiac measures, including N-terminal pro b-type
natriuretic peptide (NT-proBNP), certain echocardiographic
parameters, and 10-MWT were reported in patisiran-treated patients
in the pre-specified cardiac subpopulation*. Specifically:
- Patisiran treatment resulted in a median decrease (improvement)
of 49.9 pg/ml in NT-proBNP levels as compared to a median increase
(worsening) of 320 pg/ml reported for the placebo arm at 18 months
(nominal p=7.74 x 10-8, based on analysis of log-transformed
values).
- Regarding echocardiographic measures, patisiran treatment
resulted in a mean 0.93 mm reduction (improvement) in left
ventricular (LV) wall thickness (nominal p=0.0173) and a mean
absolute 1.37 percent improvement in longitudinal strain (nominal
p=0.0154) relative to placebo.
- Regarding functional measures in the cardiac subpopulation,
patisiran treatment resulted in a 0.35 m/sec increase (improvement)
in 10-MWT (nominal p=7.42 x 10-9) relative to placebo at 18
months.
- Changes relative to baseline were also measured for troponin-I,
LV mass, and LV ejection fraction but were not statistically
significant.
"Patients with hATTR amyloidosis are
afflicted with an aggressive, rapidly progressing, debilitating and
fatal disease, and have a profound need for effective and safe
treatment options," said David Adams, M.D., Ph.D., Department of
Neurology, Bicetre hospital, Greater Paris University Hospitals,
AP-HP and Principal Investigator for the APOLLO trial. "The
exciting APOLLO data that were released today demonstrate the
potential of patisiran to alleviate the multiple neurological,
cardiac, and autonomic manifestations of the disease. If approved,
I believe that patisiran could have a tremendous impact for
patients and physicians in the amyloidosis community. As a
clinician, it has been deeply rewarding to see the potential impact
patisiran may have on the lives of hATTR patients."
Safety and Tolerability
Patisiran showed an encouraging safety and
tolerability profile relative to placebo with up to 18 months of
dosing. Specifically:
- The most commonly reported AEs that occurred more frequently in
patisiran patients were peripheral edema (29.7 percent versus 22.1
percent in placebo) and IRRs (18.9 percent versus 9.1 percent in
placebo). These were generally mild to moderate in severity and
only one patient discontinued due to an IRR (0.7 percent).
- Compared to placebo, patisiran treatment was associated with
fewer treatment discontinuations (4.7 versus 14.3 percent) and
fewer study withdrawals (4.7 versus 11.7 percent) due to AEs.
- The incidence of SAEs across the patisiran (36.5 percent) and
placebo (40.3 percent) groups was similar.
- SAEs reported in 2 or more patients in the patisiran group
included: diarrhea (5.4 percent), cardiac failure, congestive
cardiac failure, orthostatic hypotension, pneumonia, and
atrioventricular block complete (2 percent each). These were all
considered unrelated to patisiran, except for one SAE of diarrhea.
SAEs occurred with similar frequency in the placebo group, except
for diarrhea (1.3 percent in placebo group).
- Deaths were recorded with a similar incidence across the
patisiran (4.7 percent) and placebo (7.8 percent) treatment groups.
- No deaths were considered related to study drug.
- There were no safety signals with regard to hepatic or renal
function, or evidence of thrombocytopenia, due to patisiran.
- Patisiran also showed an encouraging tolerability profile in
the pre-specified cardiac subpopulation, with a similar frequency
of AEs in the patisiran and placebo arms and a numerically lower
incidence of SAEs (34.4 percent for patisiran versus 50.0 percent
for placebo). The frequency of deaths was 5.6 percent for patisiran
versus 11.1 percent for placebo.
"The APOLLO data presented in Paris
provide robust evidence supporting the potential of RNAi as a novel
therapeutic approach for patients with hATTR amyloidosis," said
Elias Zerhouni, M.D., President, Global R&D, Sanofi. "In this
study, patisiran's effect in helping to alleviate neurological
impairment and improve the quality of life for people living with
this debilitating rare disease is a remarkable accomplishment.
Sanofi looks forward to coordinating global regulatory submissions
with Alnylam on an expedited basis."
Phase 2 Open-Label Extension (OLE) Study
Results Over 36 Months
Sanofi Genzyme and Alnylam also announced today
36 month results from patients originally in the patisiran Phase 2
OLE study. Specifically:
- Nearly all patients who were originally treated in the Phase 2
OLE study have continued to receive patisiran in the Global OLE
study.
- 25 patients who received 24 months of treatment in the Phase 2
OLE were followed for an additional mean 16.2 months in the Global
OLE study.
- There were no new safety concerns with additional dosing.
- The majority of AEs were mild or moderate in severity.
- Related AEs in two or more patients were IRRs (8.0
percent).
- For the 24 patients who have completed 36 months of treatment,
the clinical activity of patisiran was maintained, with a
negative 4.1 point mean change (improvement) in the mNIS+7 score
relative to baseline.
To view the results presented by Alnylam at the
1st European ATTR Amyloidosis Meeting, please visit
www.alnylam.com/capella.
*Pre-specified cardiac subpopulation: patients
with evidence of pre-existing cardiac amyloid involvement and
without confounding medical conditions, i.e., patients with
baseline left ventricular wall thickness greater than or equal to
1.3 cm and no aortic valve disease or hypertension in medical
history.
About Sanofi Sanofi is dedicated to supporting
people through their health challenges. We are a global
biopharmaceutical company focused on human health. We prevent
illness with vaccines, provide innovative treatments to fight pain
and ease suffering. We stand by the few who suffer from rare
diseases and the millions with long-term chronic conditions. With
more than 100,000 people in 100 countries, Sanofi is transforming
scientific innovation into healthcare solutions around the globe.
Sanofi, Empowering Life Sanofi Genzyme focuses on developing
specialty treatments for debilitating diseases that are often
difficult to diagnose and treat, providing hope to patients and
their families. Learn more at www.sanofigenzyme.com. 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
people afflicted with rare genetic, cardio-metabolic, and hepatic
infectious diseases. Based on Nobel Prize-winning science, RNAi
therapeutics represent a powerful, clinically validated approach
for the treatment of a wide range of severe and 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 four product candidates that are in late-stage
development. 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 to address the needs of patients
who have limited or inadequate treatment options. Alnylam employs
over 600 people in the U.S. and Europe and is headquartered in
Cambridge, MA. For more information about our people, science and
pipeline, please visit www.alnylam.com and engage with us on
Twitter at @Alnylam or on LinkedIn. |
Sanofi Contacts Media Relations Ashleigh Koss Tel. : +1
(908) 981-8745 Mobile: +1 (908) 205-2572 mr@sanofi.com Alnylam
Contacts Investor and Media Relations Christine Regan
Lindenboom Tel. : +1 (617) 682-4340 |
Investor Relations George Grofik Tel.: +33 (0)1 53 77 45 45
ir@sanofi.com Investor Relations Josh Brodsky Tel.: +1 (617)
551-8276 |
Sanofi Forward-Looking Statements This press
release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, as amended.
Forward-looking statements are statements that are not historical
facts. These statements include projections and estimates regarding
the clinical development of and potential marketing approvals for
the product. Forward-looking statements are generally identified by
the words "expects", "anticipates", "believes", "intends",
"estimates", "plans", "would be" and similar expressions. Although
Sanofi's management believes that the expectations reflected in
such forward-looking statements are reasonable, investors are
cautioned that forward-looking information and statements are
subject to various risks and uncertainties, many of which are
difficult to predict and generally beyond the control of Sanofi,
that could cause actual results and developments to differ
materially from those expressed in, or implied or projected by, the
forward-looking information and statements. These risks and
uncertainties include among other things, the uncertainties
inherent in research and development of the product, future
clinical data and analysis, including post marketing, decisions by
regulatory authorities, such as the FDA or the EMA, regarding
whether and when to approve the product or biological application
that may be filed for the product as well as their decisions
regarding labeling and other matters that could affect the
availability or commercial potential of the product, the absence of
guarantee that the product if approved will be commercially
successful, risks associated with intellectual property, future
litigation, the future approval and commercial success of
therapeutic alternatives, and volatile economic conditions, as well
as those risks discussed or identified in the public filings with
the SEC and the AMF made by Sanofi, including those listed under
"Risk Factors" and "Cautionary Statement Regarding Forward-Looking
Statements" in Sanofi's annual report on Form 20-F for the year
ended December 31, 2016. Other than as required by applicable law,
Sanofi does not undertake any obligation to update or revise any
forward-looking information or statements. 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
complete results from its APOLLO Phase 3 clinical trial for
patisiran and the potential implications of such results for
patients, its plans for and the expected timing of regulatory
filings seeking approval for patisiran from regulatory authorities
in the United States, Europe and ROW countries, its expectations
regarding the potential for patisiran to improve the lives of hATTR
amyloidosis patients with polyneuropathy and their families, its
plans for the commercialization of patisiran if approved by
regulatory authorities, and 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 its
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.
Patisiran 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 the safety or effectiveness of this investigational
therapeutic. |
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