To evaluate the efficacy and safety of patisiran in patients with wtATTR amyloidosis and symptomatic polyneuropathy by evaluating the effect on neurologic impairment and quality of life.

Start Date03 Aug 2022

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

NCT04201418 / CompletedNot Applicable

A Phase 4 Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of Hereditary Transthyretin-Mediated (ATTRv) Amyloidosis With a V122I or T60A Mutation

To evaluate the effectiveness of patisiran in patients with ATTRv amyloidosis with polyneuropathy who have a V122I or T60A mutation.

Start Date18 Dec 2019

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

NCT03997383 / Active, not recruitingPhase 3

APOLLO-B: A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Patisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

The purpose of this study is to evaluate the efficacy and safety of patisiran in participants with ATTR amyloidosis with cardiomyopathy.

Start Date04 Sep 2019

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

100 Clinical Results associated with Patisiran sodium

100 Translational Medicine associated with Patisiran sodium

100 Patents (Medical) associated with Patisiran sodium

240

Literatures (Medical) associated with Patisiran sodium

04 Sep 2024·Journal of the American Society for Mass Spectrometry

Separation and Characterization of Therapeutic Oligonucleotide Isomer Impurities by Cyclic Ion Mobility Mass Spectrometry

Article

Author: Inoue, Takao ; Obika, Satoshi ; Yamaguchi, Takao ; Kawase, Taiji ; Omuro, Shogo ; Yoshida, Tokuyuki ; Hirose, Kenji

Therapeutic oligonucleotides such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA) are among the most remarkable modalities in modern medicine. ASOs and siRNA are composed of single- or double-stranded 15-25 mer synthesized oligonucleotides, which can be used to modulate gene expression. Liquid chromatography-mass spectrometry (LC/MS) is a necessary technique for the quality control of therapeutic oligonucleotides; it is used to evaluate the quantities of target oligonucleotides and their impurities. The widely applied oligonucleotide therapeutic quantitation method uses both ultraviolet (UV) absorbance and the MS signal intensity. Peaks separated from the main peak, which contains full-length product, are generally quantitated by UV. However, coeluting impurities, such as n - 1 shortmers, abasic oligonucleotides, and PS → PO (phosphorothiate to phosphodiester) oligonucleotides, are quantitated by MS. These coeluting impurities can also be comprised of various isomers with the same modification, thus increasing the difficulty in their separation and relative quantitation by LC/MS. It is possible that a specific isomer with a certain structural form induces toxicities. Therefore, characterization of each isomer separation is in high demand. In this study, we separated and characterized oligonucleotide isomers by employing a cyclic ion mobility mass spectrometry (cyclic IMS) system, which allows the separation of ions with the same m/z ratio based on their structural differences. Patisiran antisense and sense strands and their n - 1 and abasic isomers were used as sample sequences, and their ratio characterization was achieved by cyclic IMS. In addition, we evaluated the PS → PO conversion isomers of the antisense strand of givosiran, which originally contained four PS modification sites. The PS → PO isomers exhibited specific and distinguishable mobiligram patterns. We believe that cyclic IMS is a promising method for evaluating therapeutic oligonucleotide isomers.

01 Sep 2024·Current Opinion in Cardiology

Treatment of transthyretin cardiac amyloidosis

Review

Author: Maurer, Mathew S ; Wardhere, Abdirahman ; Bampatsias, Dimitrios

Purpose of reviewTafamidis is currently the only approved disease-modifying treatment for ATTR-CM. However, there have been important developments in the treatment of ATTR-CM, as the results of two phase 3 trials were published and several other trials are in their final stages. In this review, we summarize current and future therapies for ATTR-CM.Recent findingsRecently, acoramidis, a TTR stabilizer has been proven to be effective in reducing mortality and morbidity compared to placebo in the ATTRibute-CM trial. Additionally, patisiran, an RNA silencer, preserved functional capacity and quality of life compared to placebo in the APOLLO-B trial. However, the FDA declined to approve patisiran for ATTR-CM. The results of phase 1 trial of ALXN2220, an antiamyloid antibody raise hope for reversal of myocardial damage by amyloid depletion. Phase 3 trials evaluating the efficacy of different RNA silencers, gene editing with CRISPR-Cas9, and other anti-amyloid antibodies are ongoing.SummaryTherapies targeting different mechanism in the pathophysiology of ATTR-CM provide new alternatives for treating patients with ATTR-CM. Future research should focus on comparing their effectiveness, the potential of combined treatment with agents from different classes and on identifying the patients who will benefit most from each class of medication.

01 Sep 2024·Neurological Sciences

Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy

Article

Author: Gagliardi, Christian ; Fabrizi, Gian Maria ; Mazzeo, Anna ; Obici, Laura ; Romano, Angela ; Leonardi, Luca ; Manganelli, Fiore ; Lozza, Alessandro ; Mussinelli, Roberta ; Casagrande, Silvia ; Fenu, Silvia ; Salvalaggio, Alessandro ; Occhipinti, Giuseppe ; Tagliapietra, Matteo ; Tozza, Stefano ; Briani, Chiara ; Forcina, Francesca ; Luigetti, Marco ; Gemelli, Chiara ; Gentile, Luca ; De Luca, Marcella ; My, Filomena ; Guglielmino, Valeria ; Palladini, Giovanni ; Grandis, Marina ; Iabichella, Giacomo ; Russo, Massimo

AbstractBackgroundHereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP.MethodsThis was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life–Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed.ResultsForty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged.ConclusionsPatisiran largely stabilised disease in patients with ATTRv amyloidosis.

209

News (Medical) associated with Patisiran sodium

30 Aug 2024

·www.fiercepharma.com

Alnylam's Amvuttra turns in 'grand slam' showing in ATTR-CM, but leaves a window open for rivals

After releasing pivotal trial data for Amvuttra in transthyretin amyloid cardiomyopy (ATTR-CM), Alnylam is ready to pursue a label expansion and play ball with Pfizer in a market showdown. Alnylam is circling the bases after walloping—in the words of chief medical officer Pushkal Garg M.D.—a “grand slam” with data that position its RNA silencer Amvuttra (vutrisiran) to potentially become a standard-of-care treatment for the rare heart disease transthyretin amyloid cardiomyopathy (ATTR-CM).Alnylam on Friday provided detailed results from the phase 3 HELIOS-B study, which met all 10 of its primary and secondary endpoints in both its overall and monotherapy populations, bolstering the company's claim that Amvuttra will challenge Pfizer’s Vyndaqel (tafamidis) franchise. Alnylam shared the results at the European Society of Cardiology conference in London.While Alnylam hailed the results, some analysts and investors took issue with the study findings. Mid-morning Friday, the company's shares were down about 7% as the results apparently failed to live up to expectations."Objectively this data appears to be short of the aforementioned investor bar," wrote Myles Minter, Ph.D., an analyst with William Blair.In June, Alnylam made waves when it released top-line data from the trial. On Friday, the company filled in the blanks with mortality and cardiovascular hospitalization endpoint curves, additional data on subgroups, as well as complete results from a 6-minute walk test. Also presented were findings from the patient-reported Kansas City Cardiomyopathy Questionnaire (KCCQ), plus the New York Heart Association (NYHA) heart failure classification survey.In the overall study group of 654 patients, including those who were on Pfizer's tafamadis, Amvuttra reduced the risk of death or recurrent cardiovascular events by 28% versus placebo. Of those in the monotherapy group—which comprised 60% of the patients in the trial—Amvuttra reduced the risk of death or recurrent cardiovascular events by 33% compared to placebo.In one crucial dataset that analysts have been waiting for, Amvuttra reduced the risk of death or recurrent cardiovascular events by 22% in patients who were taking tafamidis at the start of the study. The siRNA therapy also led to a 41% reduction in all-cause mortality among tafamadis takers through 42 months versus placebo."It suggests that, while not head-to-head, that you're seeing very compelling efficacy from this agent," Garg said in an interview earlier this week."With the level of benefit, we think vutrisiran is well positioned both as monotherapy as well as add on to tafamidis, boding well for market uptake after generic tafamidis entry in 2028," analysts at Evercore ISI wrote in a note to clients.Amvuttra started to show a survival benefit—as the all-cause mortality curves separated—in the overall study population at 18 months, which was in line with Pfizer's ATTR-ACT trial for tafamidis. For the group of patients in HELIOS-B who were using tafamidis at baseline, the curves separated at 24 months.The study was statistically powered to measure Amvuttra as a monotherapy and in the overall trial population, but not specifically on the subgroup of patients who received both tafamidis and the Alnylam drug. Later this year, Alnylam is kicking off a phase 3 study designed to show the value of Amvuttra and tafamidis as a combination treatment.Still, the company believes that the results are overwhelming evidence that Amvuttra is transformative in the indication.“We think this represents the potential for this drug to become the new standard of care for this disease, something that can be used front line in patients but also in those who are not optimally managed with current medicines as a switch therapy or even as an add-on over time,” Garg added.Subgroup analyses also showed all-cause mortality reductions of up to 65% in newly diagnosed patients.“We see disproportionate benefits in patients with earlier disease—those who are younger or have (less severe forms of the disease)—which really highlights the importance of getting the most effective treatment as early as possible,” Garg added. In an additional endpoint, which was revealed in June, in the overall patient population there was a 36% reduction in the risk of death up to month 42, while in the Amvuttra monotherapy group, there was a 35% reduction in the risk of death over the same period.In addition to the 40% of patients on tafamidis at the baseline of HELIOS-B, 22% more of the participants began taking Pfizer’s drug during the course of the trial. On top of that, 30% of the patients were on an SGLT2 inhibitor.“This was a pretty heady gauntlet for this drug to have to show a benefit on top of,” Garg said. “It really showed a remarkable benefit across the full spectrum of patients on some very, very hard endpoints.”Alnylam plans to file for FDA approval of Amvuttra in ATTR-CM later this year and will use a priority review voucher, which will slice by four months the regulator’s standard 10-month appraisal period.Amvuttra was approved in June of 2022 for ATTR-polyneuropathy, a condition which has roughly one-tenth the population size of ATTR-CM. Amvuttra generated sales of $558 million in 2023.Meanwhile, Pfizer’s group of tafamidis drugs—which include Vydaqel, Vyndamax and Vynmac (outside the U.S.)—rang up (PDF) sales of $3.3 billion in 2023, which were up 36% in their fourth full year on the market.As an RNA interference drug, Amvuttra may have a mechanism of action edge on tafamidis. While it reduces the circulating levels of the transthyretin (TTR) protein and hence the amyloid clumps in the heart, tafamidis works by stabilizing the TTR. Alnylam contends that Amvuttra’s treatment effects may expand over time."What we do is work upstream transthyretin and turn off production in the liver," Garg said. "We're stopping the disease-causing protein from being formed in the first place." Still, challenging Pfizer’s entrenched, first-of-its-kind treatment will not be easy, according to a note two months ago from analysts at Leerink Partners, who cited the “ease of use, pristine safety and accumulated real-world data,” of tafamidis.As for the ease of use, while vutrisiran is administered once every three months by way of injection, tafamidis is a daily pill.Among other companies pursuing the emerging class of RNA interference drugs, Intellia and Ionis have what analysts viewed as one of the most promising investigative treatments. Alnylam’s first RNA silencer, Onpattro (patirisan), was approved for ATTR-polyneuropathy in 2018 but the FDA rejected it last year for ATTR-CM, overruling an advisory panel that recommended it for approval by a 9-3 vote.While tafamidis remains the only drug on the market for ATTR-CM, competition is likely on its way in the indication from BridgeBio as the FDA is reviewing its application for TTR stabilizer acoramidis. Friday, analysts at ISI Evercore said that while the data on Amvuttra were "obviously positive," the idea that the drug "would emerge the undisputed best-in-class therapy appears to be fading." Likewise, Mizuho's Salim Syed wrote in a note he'd seen "nothing suggestive that vutrisiran is better" than acoramidis. BridgeBio's shares jumped 10% in the wake of Alnylam's data release.

Clinical ResultDrug ApprovalPhase 3AHAPriority Review

28 Aug 2024

·www.businesswire.com

Alnylam to Webcast Presentations at Upcoming September Investor Conferences

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences: Wells Fargo 2024 Healthcare Conference on Wednesday, September 4, 2024 at 9:30 am ET in Boston Morgan Stanley 22 nd Annual Global Healthcare Conference on Wednesday, September 4, 2024 at 1:05 pm ET in New York City A live audio webcast of each presentation will be available on the Investors section of the Company’s website at www.alnylam.com/events . A replay will be available on the Alnylam website within 48 hours after each event. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO ® (patisiran), AMVUTTRA ® (vutrisiran), GIVLAARI ® (givosiran), OXLUMO ® (lumasiran), and Leqvio ® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “ Alnylam P 5 x25 ” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam , or on LinkedIn , Facebook , or Instagram .

siRNA

07 Aug 2024

·www.businesswire.com

Alnylam to Present Detailed Results from the HELIOS-B Phase 3 Study of Vutrisiran▼ in Patients with ATTR Amyloidosis with Cardiomyopathy at the European Society of Cardiology Congress 2024

CAMBRIDGE, Mass.--( BUSINESS WIRE )--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the Company will present results from the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy at the European Society of Cardiology (ESC) Congress 2024, taking place in London, UK, on August 30 - September 2, 2024. The Company recently announced positive topline results of the study which met the primary endpoint, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events, as well as all secondary endpoints, in both the overall population and in the monotherapy population, along with an acceptable safety profile and tolerability, consistent with its established profile. The Company will also host an Investor Webcast to discuss the HELIOS-B results on August 30, 2024. Vutrisiran is in development for the treatment of ATTR amyloidosis with cardiomyopathy. In addition, the Company will present findings from a subgroup analysis of the KARDIA-2 Phase 2 study of zilebesiran, an investigational RNAi therapeutic in development for the treatment of hypertension, as well as new data from post-hoc analyses of the APOLLO-B Phase 3 and APOLLO-OLE studies of patisiran in patients with ATTR amyloidosis with cardiomyopathy. Patisiran is not approved for the treatment of ATTR amyloidosis with cardiomyopathy. ESC Presentation Details Primary Results from HELIOS-B, a Phase 3 Study of Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy London: Hot Line 1 Friday, August 30, 2024, 11:00 a.m. (BST), 6:00 a.m. (ET) Presenter: Marianna Fontana, M.D., Ph.D. Subgroup Results from KARDIA-2: Impact of Demographic and Baseline Disease Characteristics on Zilebesiran Response in Patients with Hypertension Uncontrolled by a Standard Oral Antihypertensive Science Box 4: Pharmacological Management in Hypertension Friday, August 30, 2024, 2:30 p.m. (BST), 9:30 a.m. (ET) Presenter: Manish Saxena, MBBS, MSc, FBHS Long-term Effects of Patisiran on Survival and Cardiac Parameters in Patients with Transthyretin-Mediated Cardiac Amyloidosis: Post-hoc Analyses of APOLLO-B and Cardiac Subpopulation of APOLLO-OLE Science Box 1: Advances in Amyloidosis Sunday, September 1, 2024, 5:36 p.m. (BST), 12:36 p.m. (ET) Presenter: Olivier Lairez, M.D. Investor Webcast Information Alnylam Management will discuss the HELIOS-B results via webcast on August 30, 2024, at 1:00 p.m. (BST), 8:00 a.m. (ET). A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events . An archived webcast will be available on the Company’s website approximately two hours after the event. About AMVUTTRA ® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of mutant and wild‑type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, vutrisiran is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. In the UK, vutrisiran is specifically indicated for the treatment of hATTR in adult patients with stage 1 or stage 2 polyneuropathy. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease. For US Media only : For more information about vutrisiran, including the full U.S. Prescribing Information , visit AMVUTTRA.com . For UK Media: For the UK Summary of Product Characteristics, see https://www.medicines.org.uk/emc/product/14060 . About ONPATTRO ® (patisiran) ONPATTRO ® (patisiran) is an RNAi therapeutic designed to silence TTR messenger RNA and reduce the production of TTR protein in the liver. Administered intravenously, patisiran is approved in forty countries for the treatment of the polyneuropathy of hereditary transthyretin-amyloidosis (hATTR-PN) in adults. For US Media only : For more information about patisiran, including the full U.S. Prescribing Information , visit ONPATTRO.com . For UK Media: For the UK Summary of Product Characteristics, see https://www.medicines.org.uk/emc/product/10368 . About ATTR Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000 – 300,000 people worldwide. About Zilebesiran Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure (BP) regulation and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II. Zilebesiran utilizes Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables infrequent subcutaneous dosing with increased selectivity and the potential to achieve tonic blood pressure control demonstrating consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after a single dose of zilebesiran. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche. About Hypertension Uncontrolled hypertension is the chronic elevation of blood pressure (BP), defined by the 2017 ACC/AHA guidelines as ≥130 mmHg systolic blood pressure (SBP) and ≥80 mmHg diastolic blood pressure (DBP). More than one billion people worldwide live with hypertension. Approximately one in three adults are living with hypertension worldwide, with up to 80% of individuals remaining uncontrolled despite the availability of several classes of oral anti-hypertensive treatments. Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications, resulting in inconsistent BP control and an increased risk for stroke, heart attack and premature death. In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with poor medication adherence and in patients with high cardiovascular risk. About RNAi 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 class of medicines known as RNAi therapeutics is now a reality. 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 or disease pathway 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. About Alnylam Pharmaceuticals Alnylam (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “ Alnylam P 5 x25 ” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. Alnylam Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, Alnylam’s expectations regarding the planned presentation of detailed results from the HELIOS-B study as well as from other studies, the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, and the potential for Alnylam to achieve its Alnylam P 5 x25 vision of becoming a leading biopharma company should be considered forward-looking statements. 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, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its “ Alnylam P 5 x25 ” strategy; Alnylam’s ability to successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; and any delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q and in its other SEC filings. 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.

Clinical ResultPhase 3Drug ApprovalPhase 2

100 Deals associated with Patisiran sodium

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KEGG	Wiki	ATC	Drug Bank
D10794	Patisiran sodium	N07XX12	DB14582

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Polyneuropathies	LI	Alnylam Netherlands BV	27 Aug 2018
Polyneuropathies	IS	Alnylam Netherlands BV	27 Aug 2018
Polyneuropathies	NO	Alnylam Netherlands BV	27 Aug 2018
Polyneuropathies	EU	Alnylam Netherlands BV	27 Aug 2018
Amyloidosis, Hereditary, Transthyretin-Related	US	Alnylam Pharmaceuticals, Inc.	10 Aug 2018

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Transthyretin Amyloid Cardiomyopathy	NDA/BLA	US	Alnylam Pharmaceuticals, Inc.	21 Feb 2023
Hematopoietic stem cell transplantation	NDA/BLA	US	Gamida Cell Ltd.	02 Jun 2022
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	MX	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	CA	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	KR	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	MY	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	AR	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	BR	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	TR	Alnylam Pharmaceuticals, Inc.	16 Jul 2015
Amyloidosis, Hereditary, Transthyretin-Related	Phase 3	TW	Alnylam Pharmaceuticals, Inc.	16 Jul 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01960348 \| NCT02510261 (APOLLO, Pubmed) Manual	Phase 3	Amyloidosis, Hereditary, Transthyretin-Related A97S gene variant	18	Patisiran	(yquzoooblo) = rzegegudvb lcclhoeiqr (kbrhqzyvhk, -45.5 to -7.5)	Positive	27 Mar 2024
NCT02510261 (APOLLO, CTgov)	Phase 3	Amyloidosis, Hereditary, Transthyretin-Related	211	Patisiran (Prior Placebo Group of Study 004)	libipbbcsw(cfsmsphlai) = ntcrlfuexu olvgezamdk (vljclmzgyr, onvvyrwfae - occiaromgr) View more	-	06 Dec 2023
				Patisiran (Prior Patisiran Group of Study 004)	libipbbcsw(cfsmsphlai) = wxsvqdriag olvgezamdk (vljclmzgyr, geegdvunjg - ephwuzyrdr) View more
NCT03997383 (APOLLO-B, Pubmed \| N Engl J Med)	Phase 3	Transthyretin cardiac amyloidosis hereditary \| variant \| wild-type	360	Patisiran 0.3 mg/kg	(xsxaohgumn) = edmtxhtluy oxgewxvwky (jzhgxtmesm, lower)	Positive	26 Oct 2023
				Placebo	(xsxaohgumn) = ltbyylsqtj oxgewxvwky (jzhgxtmesm, higher)
NCT03997383 (APOLLO-B, Biospace) Manual	Phase 3	Transthyretin Amyloid Cardiomyopathy	360	Patisiran 0.3 mg/kg	(gfotbzgelc) = hxkezmuqte dqmnxqcocy (nidnumqnjd, 0.69-28.69 - P=0.02) Met View more	Positive	25 Oct 2023
NCT03997383 (APOLLO-B, CTgov)	Phase 3	Amyloidosis, Hereditary, Transthyretin-Related \| Transthyretin Amyloid Cardiomyopathy	360	Placebo (Placebo (DB)/Patisiran (OLE))	dhtmexsdgl(awoxidhctf) = bhywvgqyfj muybdbwzor (tlfemaohkg, aparvvynqu - rwtoiyixio) View more	-	18 Oct 2023
				OLE+Patisiran (Patisiran (DB+OLE))	dhtmexsdgl(awoxidhctf) = lnjmravzgb muybdbwzor (tlfemaohkg, yxpegoszsz - najlinamrg) View more
NCT03997383 (APOLLO-B, ESC2023)	Phase 3	Amyloidosis transthyretin (TTR) amyloid \| N-terminal prohormone B-type natriuretic peptide \| troponin I ... View more	360	Patisiran	yisenpzgjq(kqxszzwsta): OR = 1.58 (95% CI, 1.03 - 2.42) View more	-	26 Aug 2023
				Placebo
ESC2023	Not Applicable	Transthyretin Amyloid Cardiomyopathy	-	Patisiran	ydfhepiunb(xvhthhifdu) = wqrwtwkcuu xpbsnuujgo (bjteqjttas )	-	25 Aug 2023
				Inotersen	ywssvkjdos(saqnktadws) = hcxooxkxme paampqlbvk (pmmiplryhj ) View more
ESC2023	Not Applicable	Cardiomyopathies	13	Patisiran	(drpvnxjpup) = could not be performed due to impairment related to polyneuropathy xjqrliiwzo (gwkdczqmib )	-	11 May 2023
NCT03997383 (APOLLO-B, Corporate Publications) Manual	Phase 3	Amyloidosis	359	Patisiran sodium	jdseglgyhi(frkzjijvjj) = Patisiran demonstrated a benefit or trend toward benefit in change from baseline of most echocardiographic parameters compared with placebo at Month 12 xmhfnxiktc (ufxsdoanka )	Positive	30 Sep 2022
				Placebo
NCT03759379 \| NCT01960348 (APOLLO, ANA2022)	Phase 3	Polyneuropathies NfL	-	Patisiran	ikwblczfnv(puuvfkdemt) = nbtsenkrav xnkjlszhaz (rvbrtukoqz )	Positive	14 Sep 2022
				Vutrisiran	ikwblczfnv(puuvfkdemt) = uwoembslhb xnkjlszhaz (rvbrtukoqz )

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