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Q&A: RNA therapies aimed at solving cardiometabolic and lipid disorders
January 2016
by Lloyd Dunlap  |  Email the author
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As Thomas Edison said (apparently in various ways on more than one occasion), “Genius is 1 percent inspiration, 99 percent perspiration.” With a tagline of “Inspired Momentum. Now. Welcome to Akcea,” on its website home page, it’s clear that relative newcomer Akcea Therapeutics has the inspiration to go with the “quieter” line, on that same page describing itself as “A company committed to transforming cardiometabolic lipid disorders.” That quieter sentence, of course, is where the perspiration comes in, and Akcea President and CEO Paula Soteropoulos is here to tell us about that.
 
DDNews: Please tell our readers about Akcea Therapeutics, how it originated and its experience to date.
Paula Soteropoulos: Akcea Therapeutics was established in January 2015 to develop and commercialize new treatments for serious cardiometabolic diseases. The company has clinical trials for therapies in development that range from preclinical through two Phase 3 programs. All of these are advanced RNA-targeted antisense therapeutics designed to address rare lipid disorders and more prevalent serious cardiometabolic diseases with significant unmet medical need.
Akcea Therapeutics is a wholly owned subsidiary of Ionis Pharmaceuticals Inc., a leader in RNA-targeted therapeutics. Akcea’s portfolio, based on the antisense technology platform developed at Ionis, is focused on development and commercialization of therapies with the potential to transform the treatment of serious cardiometabolic diseases.
2015 was an exciting year for us. Our lead drug, volanesorsen, which prevents the formation of the protein Apo C-III, reached two important milestones: we closed enrollment for our pivotal study in patients with familial chylomicronemia syndrome (FCS), and we initiated our Phase 3 study in patients with familial partial lipodystrophy (FPL). Results from the Phase 2 program for volanesorsen were reported in two separate publications in the New England Journal of Medicine. We also had several announcements related to the progress of our antisense program targeting extreme levels of Lp(a), an independent, genetic contributor to aggressive, premature heart disease, including a report on a clinical study that was published in The Lancet.
           
DDNews: What encouraged you to join the company as CEO?
Soteropoulos: I have a wonderful history with the Ionis team from my days working in collaboration with them while at a previous company. When they reached out to me about an opportunity to start a new company based on these very important medicines, it was a no-brainer. At the time I was working at a preclinical-stage start-up company. I realized that my passion was working on drug programs that were closer to patients. I found that I really missed the late-stage development and commercialization aspects of drug development. With Akcea and the resources and capabilities from Ionis, we can focus on building a world-class team to advance medicines that can transform patients’ lives. Akcea is a start-up, but with the advantage of being able to hit the ground running with an exciting pipeline of late-stage drugs and also the depth of an early-stage clinical pipeline. To be involved in a startup with the potential represented by these drugs is a unique experience with many compelling opportunities to make a positive difference.
 
DDNews: How does RNA targeting work to treat cardiovascular disease and lipid disorders?
Soteropoulos: There are underserved cardiometabolic diseases that, despite significant research progress in the last decade, still have limited or no treatment options. For both rare cardiometabolic diseases and others that affect broader patient populations, we desperately need new approaches to treatment options.
While traditional drugs modify proteins associated with diseases, antisense drugs are designed to prevent the formation of these proteins in the first place. They mirror a specific sequence in the RNA that codes for a particular protein. This precise match-up of drug to target RNA is what makes antisense drugs so highly specific. And because antisense drugs target RNA instead of proteins, they are able to reach disease targets that often cannot be addressed through other drug technologies.
One advantage of using antisense drugs to target lipid disorders and cardiovascular disease is due to the fact that, while antisense drugs can distribute to a wide variety of tissues, they accumulate especially well in the liver. This is advantageous because a number of proteins associated with cardiovascular and lipid disorders are produced in the liver and can be effectively targeted with antisense drugs.
 
DDNews: Is ISIS 304801 your most advanced therapy? What was the gist of the article in the New England Journal of Medicine?
Soteropoulos: Akcea’s lead product candidate, volanesorsen (formerly known as ISIS-APOCIIIRx or ISIS 304801), is in Phase 3 studies for the treatment of two rare and severe lipid disorders: FCS and FPL. Volanesorsen prevents the formation of the protein ApoC-III, a key regulator of triglyceride levels in the blood. Reducing ApoC-III levels has been shown to lower triglyceride levels.
FCS is a rare genetic disorder that is also known as Fredrickson type 1 hyperlipoproteinemia or familial lipoprotein lipase deficiency. Patients with FCS are unable to effectively clear lipid particles containing triglycerides called chylomicrons, resulting in risk of potentially life-threatening pancreatitis.
FPL is a rare metabolic disorder characterized by abnormal fat distribution across the body. Patients with FPL are unable to store fat or triglycerides in normal fat stores. Instead, excess triglycerides are stored in the liver and muscle, and accumulate at high levels in the bloodstream, which increases the risk of pancreatitis, hepatic steatosis and NASH, enlarged livers, polycystic ovarian syndrome and premature cardiovascular and liver disease. Patients with FPL also often have severe insulin resistance and, in affected women, display features of hyperandrogenism.
Results from two Phase 2 studies of volanesorsen were published in two separate articles in the New England Journal of Medicine. Phase 2 results in patients with FCS were reported in December 2014 and Phase 2 results in patients with less severe forms of hypertriglyceridemia were published in July 2015. In both studies, patients treated with volanesorsen showed an approximately 70-percent reduction in triglycerides. In FCS patients, Apo C-III levels were reduced up to 90 percent, triglyceride levels were reduced up to 86 percent and all patients achieved triglyceride levels below 500 mg/dL, a level that is recognized to be below the level associated with elevated risk of pancreatitis. Results in FCS patients also indicate the potential existence of additional, complementary pathways for triglyceride clearance that were not previously well characterized. We have completed enrollment for our Phase 3 pivotal study for patients with FCS, and we very much look forward to seeing what we learn from the results from this study and our FPL Phase 3 study.
 
DDNews: How do antisense therapies differ from others?
Soteropoulos: Antisense drugs, also often referred to as antisense oligonucleotides (ASOs), are short synthetic analogues of natural nucleic acids designed to specifically bind to a target messenger RNA (mRNA) by Watson-Crick hybridization. Antisense drugs differ from small molecules and antibodies in several key ways.
First, antisense drugs are designed to address a specific target after binding to the target RNA. They can then work via one of several different mechanisms. Depending on how the drug was designed, antisense drugs can either increase or decrease the production of the specific protein coded for by the target RNA. They can also work to degrade toxic RNAs.
Second, antisense drugs are large- to medium-sized (6k-10k Dalton) pharmaceutical molecules. Compared with small-molecule drugs such as aspirin or biologics such as insulin, the relatively large size, negative molecular charge, water-solubility and high serum protein binding of ASOs make them impermeable to the blood-brain and placental barriers. Because antisense drugs are water-soluble and bind with low affinity but high capacity to serum proteins, they distribute well to tissues throughout the body without the need for special formulations.
Lastly, ASOs are metabolized by endonucleases and do not interact with CYP450 pathways. Reflecting these attributes, there are no known drug-drug interactions associated with antisense drugs in general. This is important because patients with complex cardiometabolic disorders such as FCS and FPL may take multiple medications due to comorbidities and complications.
 
DDNews: When do you anticipate your first regulatory review of an Akcea therapy?
Soteropoulos: The data from our Phase 3 pivotal trial in FCS will be available in the first half of 2017. We are positioned to file for approval and, pending regulatory approval, advance rapidly to commercialization in the U.S., Europe and other global markets.
We feel very privileged to be actively engaged in bringing these promising therapies forward with the potential to significantly improve quality of care in patients with serious cardiometabolic diseases.

Paula Soteropoulos joined Akcea as president and CEO upon its formation in January 2015. Prior to joining Akcea, she was a member of the executive leadership team of Moderna Therapeutics as the Cardiometabolic Business Unit general manager and senior vice president of strategic alliances. Prior to Moderna, Soteropoulos spent 21 years at Genzyme Corp. where she was instrumental in advancing new products from discovery through clinical development and commercialization, with significant roles driving strategy, sales and marketing, and business development. Additionally, Paula led manufacturing process development, strategic capacity planning and supply chain development.
 
Code: E011632

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