Alnylam and Sanofi 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
– 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 –
– Alnylam to Host Conference Call Today at
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
Norfolk-Quality of Life-Diabetic Neuropathy ( NorfolkQOL-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.,
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
Phase 2 Open-Label Extension (OLE) Study Results Over 36 Months
Alnylam and Sanofi Genzyme also announced today 36 month results from patients originally on 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
- 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.
Conference Call Details
Alnylam management will discuss these results via conference call on November 2, 2017 at 12:30 p.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 2354344. A replay of the call will be available beginning at 3:30 p.m. ET on November 2, 2017. To access the replay, please dial (855) 859-2056 (domestic) or (404) 537-3406 (international), and refer to conference ID 2354344.
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. The primary endpoint of the study is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness (NIS-W); Rasch-built Overall Disability Scale (R-ODS); modified BMI (mBMI); timed 10-meter walk (10-MWT); and the COMPASS-31 autonomic symptom score. The trial enrolled 225 hATTR amyloidosis patients that were randomized 2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg once every three weeks for 18 months. The study was designed with 90 percent power to conservatively detect as little as a 37.5 percent difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate was derived from an Alnylam analysis of natural history data from 283 hATTR amyloidosis patients. All patients completing the APOLLO Phase 3 study are eligible to screen for the Global OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
Patisiran is an investigational intravenously administered RNAi
therapeutic targeting transthyretin (TTR) in development for the
treatment of hereditary ATTR amyloidosis with polyneuropathy. It is
designed to target and silence specific messenger RNA, potentially
blocking the production of TTR protein before it is made. This may help
to enable the clearance of TTR amyloid deposits in peripheral tissues
and potentially restore function to these tissues. The safety and
efficacy of patisiran have not been evaluated by the
About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an
inherited, progressively debilitating, and often fatal disease caused by
mutations in the TTR gene. TTR protein is primarily produced in the
liver and is normally a carrier of vitamin A. Mutations in TTR cause
abnormal amyloid proteins to accumulate and damage body organs and
tissue, such as the peripheral nerves and heart, resulting in
intractable peripheral sensory neuropathy, autonomic neuropathy, and/or
cardiomyopathy. hATTR amyloidosis represents a major unmet medical need
with significant morbidity and mortality, affecting approximately 50,000
people worldwide. hATTR amyloidosis patients have a life expectancy of
2.5 to 15 years from symptom onset, and the only approved treatment
options for early stage disease are liver transplantation and tafamidis
About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.
Alnylam - Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi Genzyme, the specialty care global
business unit of Sanofi, formed an alliance to accelerate the
advancement of RNAi therapeutics as a potential new class of innovative
medicines for patients around the world with rare genetic diseases. The
alliance enables Sanofi Genzyme to expand its rare disease pipeline with
Alnylam's novel RNAi technology and provides access to Alnylam's R&D
engine, while Alnylam benefits from Sanofi Genzyme's proven global
capabilities to advance late-stage development and, upon
commercialization, accelerate market access for these promising genetic
medicine products. In the case of patisiran, Alnylam will advance the
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, 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, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
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
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
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.
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
Alnylam Pharmaceuticals, Inc.
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