Nav: Home

Promising clinical trial results for drug for rare disease in which patients can't eat fat

August 08, 2019

People with familial chylomicronemia syndrome are born with a genetic mutation that means they can't produce an enzyme called lipoprotein lipase. Without the enzyme, their bodies can't break down dietary-derived fat in the blood. Instead, fat-carrying molecules called chylomicrons build up in the blood, causing many life-threatening symptoms, most notably pancreatitis. People living with this condition must follow a strict low-fat diet, but there is no treatment.

Joseph Witztum, MD, professor of medicine at University of California San Diego School of Medicine, recently helped lead a global research team that tested how well the drug volanesorsen reduces fat accumulation in the blood (triglycerides) of participants with familial chylomicronemia syndrome. In a randomized, double-blind Phase III clinical trial, 33 participants received the drug and 33 received a placebo.

Volanesorsen reduced triglyceride levels by an average of 77 percent. In contrast, for participants who received a placebo, triglyceride levels increased by an average of 18 percent.

These results will publish August 8, 2019 in the New England Journal of Medicine.

Chylomicrons carry dietary triglycerides from the gut into the blood, where they are normally broken down by the enzyme lipoprotein lipase. Without that enzyme, chylomicrons accumulate and thicken the blood of people with familial chylomicronemia syndrome.

"Chylomicrons are what you see when you see cream form on the top of milk," Witztum said. "For most people, when you eat a fatty meal for dinner at 6:00 p.m., the triglycerides are transported into the blood by chylomicrons and then lipoprotein lipase clears those out of the blood by 9:00 p.m. That's definitely not the case for patients with familial chylomicronemia syndrome."

Triglyceride levels are regulated by a molecule called apolipoprotein C-III, which is made in the liver, and then secreted into the blood. Volanesorsen, an antisense drug developed by Ionis Pharmaceuticals, is designed to block the mRNA in the liver that encodes apolipoprotein C-III. Reducing apolipoprotein C-III in the blood in turn reduces triglyceride levels. Triglycerides are often used as a measure for heart health, as high levels are associated with heart disease, even in otherwise healthy people.

Trial participants began by receiving 300 milligrams of volanesorsen under the skin once a week. The most common side effects were skin reactions at the injection site (20 of 33 participants who received volanesorsen vs. none in the placebo group) and thrombocytopenia (15 of 33 participants who received volanesorsen vs. none in the placebo group). Thrombocytopenia, or low levels of blood cells known as platelets, can limit the body's ability to form blood clots. Later in the trial, the doses were reduced to once every other week to reduce these side effects. The trial lasted for one year. Participants were aged 20 to 75 years old, 80 percent were white and 55 percent were female.

Volanesorsen was recently approved for clinical use in Europe, as an adjunct to diet in adult patients who have genetically confirmed familial chylomicronemia syndrome and are at high risk for pancreatitis, and who haven't responded to diet and triglyceride-lowering therapy. The team is now waiting for Food and Drug Administration approval to market the drug in the United States.

According to Witztum, this clinical trial also helped unravel some of the basic biology underlying dietary fat processing. Researchers had previously thought that lipoprotein lipase was a necessary intermediate that allowed apolipoprotein C-III to raise triglycerides levels. This trial revealed that that's not always the case -- apolipoprotein C-III has a second role independent of lipoprotein lipase, in which it inhibits the liver from taking up triglyceride-carrying particles.

"This is the sort of information that could help inform better prevention methods and treatments for many types of heart disease, not just this particular rare condition," Witztum said.
-end-
Co-authors include: Daniel Gaudet, Université de Montréal and ECOGENE 21; Steven D. Freedman, Beth Israel Deaconess Medical Center; Veronica J. Alexander, Qingqing Yang, Steven G. Hughes, Richard S. Geary, Ionis Pharmaceuticals; Andres Digenio, Karren R. Williams, Louis O'Dea, Akcea Therapeutics; Marcello Arca, Sapienza Università di Roma; Erik S.G. Stroes, Academic Medical Center, Department of Vascular Medicine, Amsterdam; Jean Bergeron, Centre Hospitalier Universitaire de Québec-University Laval; Handrean Soran, Manchester University Hospital NHS Foundation Trust; Fernando Civeira, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza; Linda Hemphill, Massachusetts General Hospital; Sotirios Tsimikas, UC San Diego and Ionis Pharmaceuticals; Dirk J. Blom, University of Cape Town; and Eric Bruckert, La Pitie-Salpetriere Hospital, Institut de Creation et d'Animation Numeriques.

This Phase III clinical trial, known as APPROACH, was funded by Ionis Pharmaceuticals and their affiliate, Akcea Therapeutics. The ClinicalTrials.gov number is NCT02211209.

Disclosure: Sotirios Tsimikas currently has an appointment at UC San Diego and is an employee of Ionis Pharmaceuticals, Inc. Joseph Witztum is a consultant with Ionis, receives compensation from and holds publicly acquired stock in the company. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

University of California - San Diego

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.