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Ionis announces AstraZeneca’s initiation of the Phase 2b clinical study of its antisense medicine targeting PCSK9 to lower LDL-cholesterol | News

CARLSBAD, Calif., Nov. 30, 2020 /PRNewswire/ — Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) today announced that the biopharmaceutical company AstraZeneca has initiated a Phase 2b clinical trial of ION449 (AZD8233), an investigational antisense medicine designed to reduce blood cholesterol levels in patients with dyslipidemia by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), an important regulator of low-density lipoprotein cholesterol (LDL-C). PCSK9 is an enzyme that controls the number of LDL receptors on the surface of cells. People with genetic variations that reduce PCSK9 function have lower LDL-C levels in the blood and a lower risk for major cardiovascular events. ION449 is a LIgand Conjugated Antisense (LICA) medicine being developed by AstraZeneca as part of a collaboration between Ionis and AstraZeneca.

The Phase 2b, randomized, double-blind, placebo-controlled trial will enroll approximately 108 participants, aged 18-75, who have LDL-C levels between 70 and 190 mg/dL and are receiving moderate- or high-intensity statin therapy as defined by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on blood cholesterol management. The primary objective is to assess the effect of different doses of ION449 on LDL-C compared to placebo at Week 12 in patients taking baseline statin therapy.  The study will evaluate three dose levels of ION449 versus placebo, all administered once a month by subcutaneous injection. Safety and tolerability will be evaluated along with a number of secondary endpoints. Learn more about the trial at: https://clinicaltrials.gov/ct2/show/NCT04641299. 

In a Phase 1 study reported at the American Heart Association (AHA) Scientific Sessions on November 13, single subcutaneous doses of ION449 (AZD8233) demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels of >90 percent and up to 70 percent, respectively, in subjects who had a baseline LDL-C between 100 and 190 mg/dL without concomitant statin therapy. Doses up to 120 mg were evaluated. ION449 was observed to be safe and well-tolerated at all dose levels. 

“Results from the Phase 1 study showed that ION449 potently reduces PCSK9 and LDL cholesterol. ION449 demonstrated best-in-class potential for PCSK9 inhibition and LDL-C reduction, supporting larger clinical trials that are now underway to further evaluate efficacy and safety,” said Sotirios “Sam” Tsimikas, M.D., senior vice president, clinical development and cardiovascular franchise leader at Ionis. “The growing evidence supporting Ionis’ advanced LICA technology in cardiovascular disease holds promise for more effective approaches to lower LDL-C and to address cardiovascular disease, the leading cause of death worldwide.”

Dr. Tsimikas will provide an update on Ionis’ cardiovascular programs during Ionis’ Virtual Investor Day, Dec. 7, 2020, beginning at 12 p.m. EST.

Ionis earned a milestone payment of $20 million from AstraZeneca for the Phase 2b clinical trial initiation of ION449. Ionis and AstraZeneca are collaborating on potential treatments for kidney disease, cardiometabolic disease and cancer.

About Ionis Pharmaceuticals, Inc.

As the leader in RNA-targeted drug discovery and development, Ionis has created an efficient, broadly applicable, drug discovery platform called antisense technology that can treat diseases where no other therapeutic approaches have proven effective. Our

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Ionis announces third investigational antisense medicine to treat nonalcoholic steatohepatitis (NASH) enters development

CARLSBAD, Calif., Nov. 23, 2020 /PRNewswire/ — Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) announced today that the biopharmaceutical company AstraZeneca has licensed ION455, an investigational antisense medicine being developed as a potential treatment for nonalcoholic steatohepatitis (NASH). ION455 is the second medicine for the treatment of NASH that Ionis has partnered with AstraZeneca. The companies have also partnered on ION839 (AZD2693), which is designed to inhibit the production of patatin-like phospholipase domain-containing 3 (PNPLA3) protein, a major genetic determinant of NASH progression. Separately, Ionis is also developing a wholly owned NASH program. ION224 is designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, for treating patients with NASH. ION224 is one of more than 20 medicines in the growing Ionis-owned pipeline that the company is prioritizing and preparing for commercialization.

NASH is the most severe form of nonalcoholic fatty liver disease (NAFLD). It is related to the epidemic of obesity, pre-diabetes and diabetes. Unlike liver disease caused by alcohol consumption, NAFLD is the result of an accumulation of fat in the liver, which can lead to inflammation and cirrhosis, an advanced scarring of the liver that prevents the liver from functioning normally. About 20 percent of NASH patients are reported to develop cirrhosis and 30 to 40 percent of patients with NASH cirrhosis experience liver-related death.i Currently, a liver transplant is the only treatment for advanced cirrhosis and liver failure. Because of the high prevalence of NASH, it has recently become the third most common indication for liver transplantation in the U.S.

“Today, there are no FDA-approved medicines to specifically treat nonalcoholic steatohepatitis. However, due in large part to the progress made by our cardio-metabolic franchise, three Ionis-discovered novel medicines are now in development. These are encouraging advances that we hope will one day bring therapeutic benefit to patients who have limited treatment options,” said Brett P. Monia, Ph.D., Ionis’ chief executive officer. 

ION455 is the fourth medicine to reach development in partnership with AstraZeneca. Ionis earned $30 million from AstraZeneca for licensing ION455 and is eligible to earn up to $300 million in milestone payments plus royalties on net sales. AstraZeneca will have responsibility for further development of ION455, including regulatory filings, and commercialization.

In addition to NASH, Ionis and AstraZeneca are collaborating on potential treatments for kidney disease, cardiovascular disease and cancer.

Ionis’ Forward-looking Statement

This press release includes forward-looking statements regarding Ionis’ business and the therapeutic and commercial potential of ION455, ION839 (AZD2693), ION224 and Ionis’ technologies and products in development. Any statement describing Ionis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those related to the impact COVID-19 could have on our business, and including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for

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Promising new data for Ionis’ antisense medicine targeting PCSK9 presented at American Heart Association (AHA) Scientific Sessions 2020

CARLSBAD, Calif., Nov. 13, 2020 /PRNewswire/ — Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) announced today that new data for ION449, an investigational antisense medicine designed to reduce plasma levels of proprotein convertase subtilisin/kexin type 9, or PCSK9, were presented today at the American Heart Association (AHA) Scientific Sessions. PCSK9 is integrally involved in the regulation of LDL-cholesterol (LDL-C). Genetic studies have shown that individuals with life-long reduction of LDL-C due to reduced function of PCSK9 have substantially reduced risk of cardiovascular disease.

(PRNewsfoto/Ionis Pharmaceuticals, Inc.)

ION449, also known as AZD8233 for subcutaneous administration and AZD6615 for oral administration, is being developed as part of a collaboration between Ionis and the biopharmaceutical company AstraZeneca. ION449 incorporates Ionis’ advanced Generation 2.5 and LIgand Conjugated Antisense, or LICA, technology. In a Phase 1 study, single subcutaneous doses of ION449 demonstrated dose-dependent reductions in circulating plasma PCSK9 protein and LDL-C levels of up to >90 percent and up to ~70 percent, respectively, in humans with a baseline LDL-C between 100 and 190 mg/dL.Doses of 4, 12, 20, 30, 60, 90 and 120 mg were evaluated. The single 90 mg dose was the minimum dose required to achieve maximum reduction in PCSK9 and LDL-C. ION449 was observed to be safe and well tolerated at all dose levels.

In addition, the feasibility of oral administration of ION449 was established in three in vivo studies:

  • A study in rats demonstrated liver bioavailability of 5 percent with ION449 following intrajejunal administration, mimicking oral administration of tablets not feasible in rodents.
  • A study in dogs demonstrated liver bioavailability of 7 percent following ION449 oral tablet administration for 28 days.
  • A study in healthy monkeys found repeated oral administration of ION449 tablets for 14 days resulted in LDL-cholesterol reductions of 45–50 percent.

An oral formulation of ION449 is currently being evaluated in a Phase 1 study in healthy volunteers.

“Even with existing treatments, cardiovascular disease remains the leading cause of death worldwide, affecting tens of millions of people. Additional treatments are clearly needed for patients still at risk. The data from these studies are very encouraging and demonstrate the best-in-class potential of ION449 for lowering LDL-C via PCSK9 reduction for the treatment of patients with high cholesterol who are at risk of cardiovascular disease,” said Brett P. Monia, Ph.D., chief executive officer at Ionis.

The full poster presentations, “Single Dose Safety, Pharmacokinetics, and Pharmacodynamics of a Potent PCSK9 Synthesis Inhibitor, AZD8233, in Subjects With Elevated LDL Cholesterol” (Poster #MP515) and “An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans” (Poster #P244) are available to view on the AHA Scientific Sessions website.

Ionis’ collaboration with AstraZeneca focuses on leveraging Ionis’ pioneering antisense technology to discover and develop antisense therapies and AstraZeneca’s expertise in drug development and commercialization. In addition to cardiovascular programs, the companies are also collaborating to discover and develop antisense drugs to treat cancer, metabolic and other diseases.

About Ionis Pharmaceuticals, Inc.
As the leader in RNA-targeted drug discovery and development, Ionis has created an

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medicine

Ionis’ third novel antisense medicine for ALS, its first designed to treat a broad ALS population, begins clinical trial

CARLSBAD, Calif., Oct. 22, 2020 /PRNewswire/ — Ionis Pharmaceuticals, Inc. (NASDAQ: IONS), the leader in antisense therapeutics, today announced that the first patients have been dosed with ION541 (also known as BIIB105), an investigational antisense medicine being developed as a potential therapy to treat most forms of amyotrophic lateral sclerosis (ALS) regardless of family history. This is another milestone in the continuing progress of Ionis’ ambitious program to develop novel treatments for ALS. Almost all cases of ALS share the pathological hallmark of TDP-43 protein aggregation in motor neurons. ION541 targets ataxin-2 RNA (ATXN2), which has been shown to prevent or reverse TDP-43 toxicity in preclinical models of ALS.

(PRNewsfoto/Ionis Pharmaceuticals, Inc.)

ALS is a rare, progressive and fatal neurodegenerative disorder that affects approximately 55,000 people globally.i  About 90 percent of ALS cases occur in people who have no apparent family history of the disease. People with ALS experience muscle weakness, loss of movement, and difficulty breathing and swallowing, resulting in a severely declining quality of life and potentially death.

“As our third medicine designed to treat different forms of ALS to enter clinical trials, ION541 represents yet another example of the power of Ionis’ antisense technology to potentially target root causes of devastating neurodegenerative diseases,” said Frank Bennett, Ph.D., Ionis’ chief scientific officer and franchise leader for neurological programs. “Initiation of this clinical trial for ION541 marks an important milestone in Ionis’ ALS program and reaffirms our commitment to the ALS community.”

Ionis received a payment of $10 million from Biogen for initiation of this Phase 1/2 clinical trial of ION541. Biogen is developing ION541 as part of a broad strategic collaboration with Ionis to advance novel antisense therapies for the treatment of neurological disorders.

Learn more about the Phase 1/2 trial of ION541 at: https://clinicaltrials.gov/ct2/show/NCT04494256?term=biib105&draw=2&rank=1

Ionis’ other leading investigational medicines to treat ALS are tofersen (BIIB067) and IONIS-C9Rx (BIIB078), both partnered with Biogen. Tofersen is designed to reduce the production of superoxide dismutase 1 (SOD1), the cause of a genetic form of ALS, referred to as SOD1-ALS, that results from mutations in the SOD1 gene. SOD1-ALS is the second most common genetic form of ALS, accounting for up to 20 percent of genetic ALS. Tofersen is currently in a Phase 3 clinical trial in SOD1-ALS patients with data expected in 2021. IONIS-C9Rx is designed to selectively reduce the mutant C9ORF72 RNA and associated neurotoxicity. Mutations in the C9orf72 gene account for greater than 30 percent of genetic ALS cases and five to 10 percent of all patients with ALS. It is the most common genetic form of ALS worldwide. IONIS-C9Rx is the first drug to enter clinical development that specifically targets the mutant C9ORF72 RNA and is a potentially first-in-class therapy for patients with C9orf72-ALS, referred to as C9-ALS. IONIS-C9Rx, which earlier this year received Fast Track designation from the U.S. Food and Drug Administration, is currently in a Phase 1/2 trial in C9-ALS patients.

Ionis’ Forward-looking Statement

This press release includes forward-looking

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