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EAS 2017 April 25: Rare dyslipidemias make the news

26 April 2017   (0 Comments)
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Novel treatments for rare inherited lipid disorders were the focus of attention in the late breaking clinical trials session at EAS Congress Prague on Tuesday. Two key studies were presented by Professor Daniel Gaudet (Université de Montréal, Canada). The first, the APPROACH study: A Study of Volanesorsen (Formerly ISIS-APOCIIIRx) in Patients With Familial Chylomicronemia Syndrome,1 attracted much interest.

Familial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disorder, categorized as an orphan disease, caused by a decrease or an absence of lipoprotein lipase (LPL) activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridaemia, typically >1000 mg/dl or 11 mmol/L. Clinically, FCS is associated with pancreatitis, eruptive xanthoma, lipaemia retinalis, abdominal pain, and/or abnormal enlargement of the liver and/or spleen, which together confer a substantial morbidity burden on patients.2 There is currently no treatment for this condition beyond dietary restriction.

Volanesorsen (formerly ISIS-APOCIIIRx) is an antisense inhibitor of apolipoprotein (apo)C-III, and has been previously studied in patients with hypertriglyceridaemia (≥5.7 mmol/L or 500 mg/dL). The APPROACH Study extended the indications studied to FCS. This was a global study of 66 patients, who had a confirmed loss-of-function (LOF) variant and documented LPL activity 20% normal with a documented history of pancreatitis or hospitalization for severe abdominal pain consistent with acute pancreatitis. Fasting triglycerides were ≥8.5 mmol/L or 750 mg/dl at baseline. All patients agreed to follow a restrictive diet with 20g fat per day. Key patient characteristics are summarized below.


Placebo (n=33)

Volanesorsen (n=33)

Female, %



Mean age (range)

46 (20-68)

47 (22-75)

Baseline triglycerides mmol/l (mg/dl)

24.3 (2252)

25.6 (2267)

% with genetic confirmation of LOF variant



History, n (%)



Acute pancreatitis

26 (79)

24 (73)

Eruptive xanthomas

9 (27)

6 (18)

Lipaemia retinalis

9 (27)

5 (15)

Lipid lowering therapy, n (%)




5 (15)

9 (27)


15 (46)

17 (52)

Fish oil

9 (27)

10 (30)

The primary endpoint of the study, the percent change in fasting triglycerides at 13 weeks, showed a significant benefit for volanesorsen (mean reduction by 77% or 19 mmol/L versus an increase of 18% on placebo (p<0.0001). At this time, 77% of volanesorsen-treated patients had triglycerides <8.5 mmol/l (750 mg/dl), the threshold for chylomicronaemia (versus 9.7% on placebo, p=0.001), and 50% had triglycerides <5.7 mmol/l (<500 mg/dl), the guideline threshold for severe hypertriglyceridaemia (versus none in the placebo group, p=0.003). Treatment with volanesorsen was also associated with significant reduction in patient reported abdominal pain (p=0.02).

Reduction in plasma triglycerides with volanesorsen was sustained at 52 weeks (mean reduction 50.1%, range 28.7% to 71.4%).

There had been previous concerns about the risk of thrombocytopenia in the early conduct of both COMPASS and APPROACH, with termination of treatment in 5 patients due to severe thrombocytopenia; all patients subsequently recovered. It is, however, important to bear in mind that fluctuation in platelet count is itself a manifestation of FCS, with systematic review of medical records indicating that more than half of patients had thrombocytopenia before the trial, and therefore it is difficult to differentiate whether the condition itself or the treatment was causative.  With a managed plan of surveillance, this was not an issue in subsequent patients enrolled in the studies.

As anticipated given the mode of treatment, injection site reactions were the most frequently reported adverse events with volanesorsen, although most of were mild intensity, and much less severe than has been reported with mipomersen, another antisense agent.

In his concluding remarks, Professor Gaudet commented that the results with volanesorsen in FCS were promising, with the benefits accrued from treatment exceeding the risk of adverse events, especially given the lack of pharmacological therapeutic options in this rare and debilitating condition.

Further data from proof-of concept study with evinacumab

In another report, Professor Gaudet presented an update on results from a proof-of-concept study with evinacumab, (REGN1500), a human monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), in nine patients with homozygous familial hypercholesterolaemia (FH) (three characterized as null homozygotes). Baseline LDL cholesterol levels were 9.7 mmol/L overall and 15.5 mmol/L in null homozygotes.3 Initial results for four patients were presented at last year’s EAS Congress in Innsbruck. ANGPTL3, a protein expressed almost exclusively in liver, plays a key role in lipoprotein metabolism. The precise mechanism for ANGPTL3 is not elucidated, although it is known to act as an inhibitor of LPL and endothelial lipase.  Genetic studies have shown that people with one loss-of-function mutation in ANGPTL3 have lower LDL cholesterol levels; those with two loss-of-function mutations not only have >50% lower LDL cholesterol levels, but also >75% lower plasma levels of triglycerides compared with unaffected individuals, providing a rationale for study in homozygous FH.4,5 Studies in LDLR deficient animal models which showed that inhibition of ANGPTL3 with the monoclonal antibody evinacumab reduced plasma lipids provided further rationale for development.6

After 4 weeks, there was a 49% reduction in LDL cholesterol (mean absolute reduction 4.1 mmol/L), and this response was sustained at 12 weeks (mean reduction 52%).  There was, however, variability in the response to treatment with two patients showing reduction in LDL cholesterol by more than 90%. The tolerability profile was acceptable.

The question posed by some is why a monoclonal antibody to ANGPTL3 should be effective in a condition that is predominantly due to mutations in the LDL receptor. Experimental studies suggest that the effects of evinacumab on LDL cholesterol and LDL particle number may involve a combination of canonical and noncanonical pathways acting mainly upstream of LDL particle production. In conclusion, these results suggest that evinacumab may have therapeutic potential as an add-on treatment in patients with homozygous FH, including null homozygotes.

Experimental science latebreakers

There were experimental science latebreakers presented in an afternoon session.  One study from the University of Texas Health Science Center at San Antonio, Texas, USA provided mechanistic evidence that glutaredoxin 1, a member of the thioltransferases superfamily, may offer potential as a target for preventing cardiometabolic disease.7 Glutaredoxin 1 plays a key role in combating oxidative stress by reversing oxidative modifications on protein thiols. Deficiency in monocytic glutaredoxin 1 in mice accelerated weight gain and the formation of atherosclerotic lesions induced by a high-fat diet. The underlying mechanism may involve “metabolic priming” of blood monocytes, making monocytes hyper-responsive to chemoattractants and leading to the over-recruitment of dysfunctional monocyte-derived macrophages into the adipose tissue and the vascular wall.

Another report from the CORGENE study8 suggested that LDL instability, the intrinsic susceptibility of human LDL to aggregate, may be predictive of future cardiovascular events independent of conventional risk factors. A causative role of LDL lipid composition in LDL instability was established by in vitro and in vivo studies.


1. Gaudet D, Digenio A, Alexander V et al. The APPROACH Study: A randomized, double-blind, placebo-controlled, Phase 3 study of volvanesorsen administered subcutaneously to patients with familial chylomicronaemia syndrome (FCS).  

2. Ahmad Z, Halter R, Stevenson M. Building a better understanding of the burden of disease in familial chylomicronemia syndrome. Expert Rev Clin Pharmacol 2017;10:1-3.

3. Gaudet D, Gipe D, Hovingh GK et al. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolaemia; a single arm, open-label, proof of concept study.

4. Musunuru K, Pirruccello JP, Do R et al. Exome Sequencing, ANGPTL3Mutations, and Familial Combined Hypolipidemia. N Engl J Med 2010;363:2220–7.

5. Pisciotta L, Favari E, Magnolo L et al. Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet 2012;5:42-50.

6. Gusarova V, Alexa CA, Wang Y et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res 2015;56:1308-17.

7. Asmis R, Downs K, Tavakoli S, Short J, Nguyen H-N. Monocytic glutaredoxin 1 protects mice against obesity, hyperglycemia and atherosclerosis.

8. Ruuth M, Nguyen SD, Vihervaara T et al. Instability of LDL particles predicts future cardiovascular deaths.

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