National Lipid Association

National Lipid Association

May 20, 2017
5 min read

New therapeutic approaches for familial chylomicronemia syndrome in development

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PHILADELPHIA — A number of new therapeutic approaches may change the treatment approach for patients with familial chylomicronemia syndrome, a speaker said at the National Lipid Association Scientific Sessions.

Patients with familial chylomicronemia syndrome (FCS) “are among our worst patients in the lipid clinic because of how sick they are,” Richard L. Dunbar, MD, assistant professor of medicine in the Cardiovascular Risk Intervention Program at University of Pennsylvania, and from the Lipid Clinic at the Philadelphia VA Medical Center, said during a presentation.

Patients with FCS typically have triglyceride levels above 1,000 mg/dL, or often, above 2,000 mg/dL; latescent plasma; a high triglyceride-total cholesterol ratio; and low apolipoprotein B.

The mainstay of therapy for FCS is a very-low-fat diet — less than 20 g per day (15% of total energy requirement). Dunbar acknowledged that such a diet is very difficult for patients to follow, nothing that patients with FCS “need a lot of coaching and you need to revisit the diet periodically because they will fall off the bandwagon.”

In this difficult-to-manage population, the “usual workhorse drugs just don’t work,” he said. For example, treatment with fibrates, niacin or fish oil would typically be expected to elicit at least a 20% drop in triglycerides among patients with polygenic hypertriglyceridemia; however, the same benefit is not generally observed in patients with FCS, he said.

“Our sickest patients are the least responsive to therapy in some cases,” he said. “I am grateful to report that there are many drugs being developed at this point.”

Dunbar provided an overview of the therapeutic landscape for FCS.

New drugs are being developed that target the triglycerides themselves, and there are also drugs that target the chylomicron. Both of these contribute to the ‘triglyceride pool.’ Imagine a pond [where] you’d like to lower the water level. There are two conceptual approaches [to FCS treatment]: you can divert the stream that is feeding the pond (drugs that target synthesis) or you can open the dam and drain the pool (drugs that target catabolism),” he told the audience.

Examples of new therapeutic approaches for FCS can be found below.

ApoC-III inhibitors

Apolipoprotein C-III (ApoC-III) inhibits lipoprotein lipase (LPL), so a successful inhibitor therefore disinhibits LPL, according to Dunbar.

ApoC-III for treatment of FCS is currently being investigated in two ways. One is an anti-sense oligonucleotide (volanesorsen [Akcea Therapeutics/Ionis Pharmaceuticals]), which is in development. The other is RNA interference, for which preclinical results are available, according to Dunbar.

In March, Akcea announced that the pivotal phase 3 APPROACH study of volanesorsen met its primary endpoint of reducing triglyceride levels in patients with FCS. The randomized, double blind, placebo-controlled, phase 3 study was conducted over 52 weeks in 66 patients with FCS (mean triglyceride level, 2,209 mg/dL). Patients treated with volanesorsen achieved a 77% mean reduction in triglycerides after 3 months compared with an 18% increase among those treated with placebo. This treatment effect was sustained over the 52-week treatment period.

In addition, pancreatitis was rare during the study period among those assigned volanesorsen, and a reduction in abdominal pain was observed compared with placebo treatment, according to a company press release.

ANGPTL3 inhibitors

Angiopoietin-like 3 is a hepatically secreted protein that inhibits LPL and endothelial lipase. A loss-of-function mutation of ANGPTL3 leads to “pan-hypolipidemia,” which is characterized by low triglycerides, low LDL and low HDL, Dunbar said.

There are two ANGPTL3 inhibitor strategies under development. One is an anti-RNA antisense oligonucleotide [ASO] and RNA inhibitor (IONIS-ANGPTL3-LRX, Ionis) and the other is a human monoclonal antibody (evinacumab, Regeneron).

Dunbar and colleagues presented first-in-human study data at the American Heart Association Scientific Sessions in November 2016 comparing evinacumab (n = 62) vs. placebo (n = 21). Results showed favorable triglyceride response (60% to 80%) to a single IV infusion of the ANGPTL3 inhibitor, he said.

LPL replacement

Recently, it has been shown that it is “actually possible to replace LPL by genetic replacement therapy,” Dunbar said here.

One example is the alipogene tiparvovec (Glybera). The agent, which is administered by a series of intramuscular injections, was approved in the European Union for patients with LPL deficiency. However, uniQure announced in April that it will not pursue renewal of the Glybera marketing authorization in Europe when it is scheduled to expire on Oct. 25, 2017. According to a company statement, “Glybera’s usage has been extremely limited and we do not envision patient demand increasing materially in the years ahead.”

Despite the marketing changes in Europe ahead, Dunbar referenced data from Daniel Gaudet, MD, PhD, professor of medicine at the University of Montreal, and colleagues on 14 patients with FCS which found a 40% reduction in triglycerides with tiparvovec treatment over 3 to 12 weeks of treatment. However, long-term effects were variable. An encouraging finding from this research group is that people who receive this gene therapy had less recurrence of pancreatitis, according to Dunbar.


ApoC-II mimetic peptide

Apolipoprotein C-II is a cofactor for LPL. Infusion of ApoC-II potentiates can be given via fresh frozen plasma outright or by therapeutic plasma exchange, Dunbar said. “It can help people get out of the hospital quicker; I’ve used this method in preventing pancreatitis in outpatients to be able to substantially lower triglycerides and keep them out of hospital,” he said.

An ApoC-II mimetic peptide is under clinical development. The obvious population of benefit is patients with ApoC-II deficiency; however, there is a question of whether this mimetic peptide would potentiate LPL in other populations, Dunbar said.

ApoE mimetic

AEM-28 (Capstone/LipimetiX) is a 28-amino acid ApoE mimetic peptide that has been shown to enhance catabolism.

Thus far, investigators have reported phase 1 human data from a hypercholesterolemia population who received AEM-28 showing reductions in both VLDL and triglycerides. The full results have not yet been reported, “but these are very encouraging results,” Dunbar said.

DGAT inhibitors

Diacylglycerol O-acyltranferase (DGAT) mediates triglyceride synthesis. DGAT is expressed in the gut, liver and adipose. There are two forms: DGAT1 and DGAT2.

Pradigastat is an oral DGAT1 inhibitor. It has been studied in an open-label, crossover study of six patients with FCS who were assigned 3 fixed-dose sequences of pradigastat over 21 days: 20 mg, 40 mg or 10 mg. While the 10-mg dose was not associated with significant differences, the 20-mg dose lowered triglycerides by about 40% and the 40-mg dose lowered triglycerides by about 70%. Dunbar noted that this inhibitor “may be easier to use in the clinic because it is an oral drug.”

MTP inhibitors

Microsomal triglyceride transfer protein (MTP) is a protein that assembles the various lipoprotein components. One example is lomitapide (Juxtapid, Aegerion), which is currently approved only for patients with homozygous familial hypercholesterolemia. Dunbar noted that it would be “way off-label to use this in someone with FCS.” However, small case reports have shown that the drug may reduce triglycerides in patients with FCS. Lomitapide is limited by its gastrointestinal effects, including nausea, vomiting and diarrhea, he said.

‘Help is on the way’

According to Dunbar, “help is on the way,” in the form of new therapeutics for FCS in development.

However, given the rarity of FCS, “this effort is slowed by the rarity of potential study subjects,” he said. He urged the audience at NLA 2017 to consider referring patients with FCS to research studies, noting that the studies are listed on – by Katie Kalvaitis


Dunbar RL. New Therapeutic Approaches to FCS. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Dunbar reports working as a clinical trialist working with several lipid-altering compounds, including with Amarin, Amgen, Arizona Pharmaceuticals, AstraZeneca, Esperion, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Regeneron, UniQuire and Zydus.