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Archive for the ‘RNA interference (RNAi) therapeutic’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

RNA plays various roles in determining how the information in our genes drives cell behavior. One of its roles is to carry information encoded by our genes from the cell nucleus to the rest of the cell where it can be acted on by other cell components. Rresearchers have now defined how RNA also participates in transmitting information outside cells, known as extracellular RNA or exRNA. This new role of RNA in cell-to-cell communication has led to new discoveries of potential disease biomarkers and therapeutic targets. Cells using RNA to talk to each other is a significant shift in the general thought process about RNA biology.

 

Researchers explored basic exRNA biology, including how exRNA molecules and their transport packages (or carriers) were made, how they were expelled by producer cells and taken up by target cells, and what the exRNA molecules did when they got to their destination. They encountered surprising complexity both in the types of carriers that transport exRNA molecules between cells and in the different types of exRNA molecules associated with the carriers. The researchers had to be exceptionally creative in developing molecular and data-centric tools to begin making sense of the complexity, and found that the type of carrier affected how exRNA messages were sent and received.

 

As couriers of information between cells, exRNA molecules and their carriers give researchers an opportunity to intercept exRNA messages to see if they are associated with disease. If scientists could change or engineer designer exRNA messages, it may be a new way to treat disease. The researchers identified potential exRNA biomarkers for nearly 30 diseases including cardiovascular disease, diseases of the brain and central nervous system, pregnancy complications, glaucoma, diabetes, autoimmune diseases and multiple types of cancer.

 

As for example some researchers found that exRNA in urine showed promise as a biomarker of muscular dystrophy where current studies rely on markers obtained through painful muscle biopsies. Some other researchers laid the groundwork for exRNA as therapeutics with preliminary studies demonstrating how researchers might load exRNA molecules into suitable carriers and target carriers to intended recipient cells, and determining whether engineered carriers could have adverse side effects. Scientists engineered carriers with designer RNA messages to target lab-grown breast cancer cells displaying a certain protein on their surface. In an animal model of breast cancer with the cell surface protein, the researchers showed a reduction in tumor growth after engineered carriers deposited their RNA cargo.

 

Other than the above research work the scientists also created a catalog of exRNA molecules found in human biofluids like plasma, saliva and urine. They analyzed over 50,000 samples from over 2000 donors, generating exRNA profiles for 13 biofluids. This included over 1000 exRNA profiles from healthy volunteers. The researchers found that exRNA profiles varied greatly among healthy individuals depending on characteristics like age and environmental factors like exercise. This means that exRNA profiles can give important and detailed information about health and disease, but careful comparisons need to be made with exRNA data generated from people with similar characteristics.

 

Next the researchers will develop tools to efficiently and reproducibly isolate, identify and analyze different carrier types and their exRNA cargos and allow analysis of one carrier and its cargo at a time. These tools will be shared with the research community to fill gaps in knowledge generated till now and to continue to move this field forward.

 

References:

 

https://www.nih.gov/news-events/news-releases/scientists-explore-new-roles-rna

 

https://www.cell.com/consortium/exRNA

 

https://www.sciencedaily.com/releases/2016/06/160606120230.htm

 

https://www.pasteur.fr/en/multiple-roles-rnas

 

https://www.nature.com/scitable/topicpage/rna-functions-352

 

https://www.umassmed.edu/rti/biology/role-of-rna-in-biology/

 

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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

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 –

− 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

http://www.alnylam.com/our-science/intellectual-property/

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

http://investors.alnylam.com/news-releases/news-release-details/alnylam-announces-first-ever-fda-approval-rnai-therapeutic?elqTrackId=5b9b83df05514e548f022d8324583ba1&elq=e50414057f3841798651d20561bbe4db&elqaid=22818&elqat=1&elqCampaignId=10597

https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisir an-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/

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