Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Reporter: Aviva Lev-Ari, PhD, RN
− First and Only FDA-approved Treatment Available in the United States for this Indication –
− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with Reversal of Neuropathy Impairment Compared to Baseline in Majority of Patients –
− Improvement in Specified Measures of Quality of Life and Disease Burden Demonstrated Across Diverse, Global Patient Population –
− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −
CAMBRIDGE, Mass.–(BUSINESS WIRE)–Aug. 10, 2018– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the United States Food and Drug Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and only FDA-approved treatment for this indication. hATTR amyloidosis is a rare, inherited, rapidly progressive and life-threatening disease with a constellation of manifestations. In addition to polyneuropathy, hATTR amyloidosis can lead to other significant disabilities including decreased ambulation with the loss of the ability to walk unaided, a reduced quality of life, and a decline in cardiac functioning. In the largest controlled study of hATTR amyloidosis, ONPATTRO was shown to improve polyneuropathy – with reversal of neuropathy impairment in a majority of patients – and to improve a composite quality of life measure, reduce autonomic symptoms, and improve activities of daily living.
ONPATTRO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations. On July 27, patisiran received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy under accelerated assessment by the European Medicines Agency. The recommended Summary of Product Characteristics (SmPC) for the European Union (EU) includes data on secondary and exploratory endpoints. Expected in September, the European Commission will review the CHMP recommendation to make a final decision on marketing authorization, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Regulatory filings in other markets, including Japan, are planned beginning in mid-2018.
This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20180810005398/en/
INTELLECTUAL PROPERTY
Alnylam protects its Intellectual Property (IP) with fundamental, chemistry, delivery, and target patents and patent applications covering the development and commercialization of RNAi therapeutics as well as that afforded by the various trademark, copyright, and trade secret laws.
Alnylam’s patent estate includes a large number of issued patents and pending patent applications in the world’s major pharmaceutical markets—United States, European Union, and Japan, along with other countries throughout the world. This broad portfolio covers, for example, oligonucleotides, including synthetic RNA molecules, both modified and unmodified, optimized for a variety of delivery modalities, such as lipid- and conjugate-based systems, their synthesis and use, including use as therapeutics, diagnostics, and research reagents. We believe these patents and pending applications place Alnylam in the strongest possible position to not only build our company over the long term and accelerate our efforts to bring life-saving drugs to patients in need, but to enable other companies for advancement of RNAi therapeutics with licenses to our IP estate and associated know-how. This belief has been validated by the progress of Alnylam to date with multiple programs in pre-clinical and clinical development and with well over 30 distinct agreements entered into with leading pharmaceutical, biotechnology, and research reagent companies.
Alnylam has an extensive array of registered trademarks in the United States, European Union, Japan and other countries throughout the world as well as various copyrighted works. In addition to patent protection, Alnylam further safeguards its IP through the use of trade secret protection afforded by the relevant state and federal trade secret laws.
SOURCE
Post : Patisiran
URL : http://newdrugapprovals.org/2018/08/13/patisiran/
Posted : August 13, 2018 at 9:51 am
Author : DR ANTHONY MELVIN CRASTO Ph.D
Tags : 50FKX8CB2Y, 6024128, ALN-18328, ALN-TTR02, Alnylam
Pharmaceuticals, BREAKTHROUGH THERAPY, FAST TRACK, FDA 2018,
GENZ-438027, Onpattro, Orphan Drug Designation, patisiran, Priority
review, SAR-438037
Categories : 0rphan drug status, Breakthrough Therapy Designation,
FAST TRACK FDA, FDA 2018, Priority review
https://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/Patisiran.png/60
0px-Patisiran.png
Patisiran
Sense strand:
https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif
GUAACCAAGAGUAUUCCAUdTdT
https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif
Anti-sense strand:
https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif
AUGGAAUACUCUUGGUUACdTdT
RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex with RNA
(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1),
ALN-18328, 6024128 , ALN-TTR02 , GENZ-438027 , SAR-438037 ,
50FKX8CB2Y (UNII code)
for RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex
with RNA(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1)
Nucleic Acid Sequence
Sequence Length: 42, 21, 2112 a 7 c 7 g 4 t 12 umultistranded (2);
modified
CAS 1420706-45-1
Treatment of Amyloidosis,
SEE…..https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisi
ran-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/
Lipid-nanoparticle-encapsulated double-stranded siRNA targeting a 3
untranslated region of mutant and wild-type transthyretin mRNA
Patisiran (trade name Onpattro®) is a medication for the treatment of
polyneuropathy ( https://en.wikipedia.org/wiki/Polyneuropathy ) in
people with hereditary transthyretin-mediated amyloidosis (
https://en.wikipedia.org/wiki/Hereditary_transthyretin-mediated_amyloidosi
s
) . It is the first small interfering RNA (
https://en.wikipedia.org/wiki/Small_interfering_RNA ) -based drug
approved by the FDA ( https://en.wikipedia.org/wiki/FDA ) . Through
this mechanism, it is a gene silencing (
https://en.wikipedia.org/wiki/Gene_silencing ) drug that interferes
with the production of an abnormal form of transthyretin (
https://en.wikipedia.org/wiki/Transthyretin ) .
https://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/Patisiran.png/60
0px-Patisiran.png
( https://en.wikipedia.org/wiki/File:Patisiran.png )
Chemical structure of Patisiran.
During its development, patisiran was granted orphan drug status (
https://en.wikipedia.org/wiki/Orphan_drug_status ) , fast track
designation ( https://en.wikipedia.org/wiki/Fast_track_designation ) ,
priority review ( https://en.wikipedia.org/wiki/Priority_review ) and
breakthrough therapy designation (
https://en.wikipedia.org/wiki/Breakthrough_therapy_designation ) due
to its novel mechanism and the rarity of the condition it is designed
to treat.[1] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-1 )
[2] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-2 ) It was
approved by the FDA in August 2018 and is expected to cost around
$345,000 to $450,000 per year.[3] (
https://en.wikipedia.org/wiki/Patisiran#cite_note-3 )
Patisiran was granted orphan drug designation in the U.S. and Japan
for the treatment of familial amyloid polyneuropathy. Fast track
designation was also granted in the U.S. for this indication. In the
E.U., orphan drug designation was assigned to the compound for the
treatment of transthyretin-mediated amyloidosis (initially for the
treatment of familial amyloid polyneuropathy)
Hereditary transthyretin-mediated amyloidosis (
https://en.wikipedia.org/wiki/Hereditary_transthyretin-mediated_amyloidosi
s
) is a fatal rare disease (
https://en.wikipedia.org/wiki/Rare_disease ) that is estimated to
affect 50,000 people worldwide. Patisiran is the first drug approved
by the FDA to treat this condition.[4] (
https://en.wikipedia.org/wiki/Patisiran#cite_note-4 )
Patisiran is a second-generation siRNA therapy targeting mutant
transthyretin (TTR) developed by Alnylam for the treatment of familial
amyloid polyneuropathy. The product is delivered by means of Arbutus
Biopharma’s (formerly Tekmira Pharmaceuticals) lipid nanoparticle
technology
https://endpts.com/wp-content/uploads/2018/08/GettyImages-902989426.jpg
“A lot of people think it’s winter out there for RNAi. But I think
it’s springtime.” — Alnylam CEO John Maraganore, NYT, February 7,
2011.
Patisiran — designed to silence messenger RNA and block the production
of TTR protein before it is made — is number 6 on Clarivate’s list of
blockbusters (
https://endpts.com/12-blockbusters-the-surging-list-of-1b-plus-drugs-rolli
ng-out-on-the-market-this-year-might-surprise-you/
) set to launch this year, with a 2022 sales forecast of $1.22
billion. Some of the peak sales estimates range significantly higher
as analysts crunch the numbers on a disease that afflicts only about
30,000 people worldwide.
PATENT
WO 2016033326
https://patents.google.com/patent/WO2016033326A2
Transthyretin (TTR) is a tetrameric protein produced primarily in the
liver.
Mutations in the TTR gene destabilize the protein tetramer, leading to
misfolding of monomers and aggregation into TTR amyloid fibrils
(ATTR). Tissue deposition results in systemic ATTR amyloidosis
(Coutinho et al, Forty years of experience with type I amyloid
neuropathy. Review of 483 cases. In: Glenner et al, Amyloid and
Amyloidosis, Amsterdam: Excerpta Media, 1980 pg. 88-93; Hou et al.,
Transthyretin and familial amyloidotic polyneuropathy. Recent progress
in understanding the molecular mechanism of
neurodegeneration. FEBS J 2007, 274: 1637-1650; Westermark et al,
Fibril in senile systemic amyloidosis is derived from normal
transthyretin. Proc Natl Acad Sci USA 1990, 87: 2843-2845). Over 100
reported TTR mutations exhibit a spectrum of disease symptoms.
[0004] TTR amyloidosis manifests in various forms. When the peripheral
nervous system is affected more prominently, the disease is termed
familial amyloidotic
polyneuropathy (FAP). When the heart is primarily involved but the
nervous system is not, the disease is called familial amyloidotic
cardiomyopathy (FAC). A third major type of TTR amyloidosis is called
leptomeningeal/CNS (Central Nervous System) amyloidosis.
[0005] The most common mutations associated with familial amyloid
polyneuropathy (FAP) and ATTR-associated cardiomyopathy, respectively, are Val30Met
(Coelho et al, Tafamidis for transthyretin familial amyloid
polyneuropathy: a randomized, controlled trial. Neurology 2012, 79:
785-792) and Vall22Ile (Connors et al, Cardiac amyloidosis in African
Americans: comparison of clinical and laboratory features of
transthyretin VI 221 amyloidosis and immunoglobulin light chain
amyloidosis. Am Heart J 2009, 158: 607-614). [0006] Current treatment
options for FAP focus on stabilizing or decreasing the amount of
circulating amyloidogenic protein. Orthotopic liver transplantation
reduces mutant TTR levels (Holmgren et al, Biochemical effect of liver
transplantation in two Swedish patients with familial amyloidotic
polyneuropathy (FAP-met30). Clin Genet 1991, 40: 242-246), with
improved survival reported in patients with early-stage FAP, although
deposition of wild-type TTR may continue (Yazaki et al, Progressive
wild-type transthyretin deposition after liver transplantation
preferentially occurs into myocardium in FAP patients. Am J Transplant
2007, 7:235-242; Adams et al, Rapid progression of familial amyloid
polyneuropathy: a multinational natural history study Neurology 2015
Aug 25; 85(8) 675-82; Yamashita et al, Long-term survival after liver
transplantation in patients with familial amyloid polyneuropathy.
Neurology 2012, 78: 637-643; Okamoto et al., Liver
transplantation for familial amyloidotic polyneuropathy: impact on
Swedish patients’ survival. Liver Transpl 2009, 15: 1229-1235; Stangou
et al, Progressive cardiac amyloidosis following liver transplantation
for familial amyloid polyneuropathy: implications for amyloid
fibrillogenesis. Transplantation 1998, 66:229-233; Fosby et al, Liver
transplantation in the Nordic countries – An intention to treat and
post-transplant analysis from The Nordic Liver Transplant Registry
1982-2013. Scand J Gastroenterol. 2015 Jun; 50(6):797-808.
Transplantation, in press).
[0007] Tafamidis and diflunisal stabilize circulating TTR tetramers,
which can slow the rate of disease progression (Berk et al,
Repurposing diflunisal for familial amyloid polyneuropathy: a
randomized clinical trial. JAMA 2013, 310: 2658-2667; Coelho et al.,
2012; Coelho et al, Long-term effects of tafamidis for the treatment
of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260:
2802-2814; Lozeron et al, Effect on disability and safety of Tafamidis
in late onset of Met30 transthyretin familial amyloid polyneuropathy.
Eur J Neurol 2013, 20: 1539-1545). However, symptoms continue to
worsen on treatment in a large proportion of patients, highlighting
the need for new, disease-modifying treatment options for FAP.
[0008] Description of dsRNA targeting TTR can be found in, for example,
International patent application no. PCT/US2009/061381 (WO2010/048228) and
International patent application no. PCT/US2010/05531 1 (WO201
1/056883).
Summary
[0009] Described herein are methods for reducing or arresting an increase
in a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a
human subject by administering an effective amount of a transthyretin
(TTR)-inhibiting composition, wherein the effective amount reduces a
concentration of TTR protein in serum of the human subject to below 50
μg/ml or by at least 80%. Also described herein are methods for
adjusting a dosage of a TTR- inhibiting composition for treatment of
increasing NIS or Familial Amyloidotic Polyneuropathy (FAP) by
administering the TTR- inhibiting composition to a subject having the
increasing NIS or FAP, and determining a level of TTR protein in the
subject having the increasing NIS or FAP. In some embodiments, the
amount of the TTR- inhibiting composition subsequently administered to
the subject is increased if the level of TTR protein is greater than
50 μg/ml, and the amount of the TTR- inhibiting composition
subsequently administered to the subject is decreased if the level of
TTR protein is below 50 μg/ml. Also described herein are formulated
versions of a TTR inhibiting siRNA.
http://www.alnylam.com/wp-content/uploads/2017/03/Acting_Upstream_of_Today
_s_Medicines.jpg
PATENT
WO 2016203402
PAPERS
Annals of Medicine (Abingdon, United Kingdom) (2015), 47(8), 625-638.
Pharmaceutical Research (2017), 34(7), 1339-1363
Annual Review of Pharmacology and Toxicology (2017), 57, 81-105
CLIP
https://www.thepharmaletter.com/media/image/alnylam-large.jpg
Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic,
ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of
Hereditary Transthyretin-Mediated Amyloidosis in Adults
Aug 10,2018
− First and Only FDA-approved Treatment Available in the United States
for this Indication –
− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with
Reversal of Neuropathy Impairment Compared to Baseline in Majority of
Patients –
− Improvement in Specified Measures of Quality of Life and Disease
Burden Demonstrated Across Diverse, Global Patient Population –
SOURCE
2012pharmaceutical
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