Lipid Luminations: Evolving Therapeutic Options for Treating Familial Hyperchylomicronemia Syndrome

Volanesorsen is a novel pharmacotherapy designed to treat patients with Familial Chylomicronemia Syndrome (FCS). This is a highly comorbid disease without any currently available pharmacotherapies to help reduce triglycerides or the more feared complication, pancreatitis. This has left a void in treatment that volanesorsen has attempted to address. As with many rare diseases, there are several challenges to develop effective therapy including identifying a proper target, creating a safe and effective molecule to intervene on that target, and then studying the novel agent in a large enough patient population to demonstrate safety and efficacy. When there are so few patients to recruit from, the clinical trials are often small and limited.

FCS is a rare, debilitating disorder characterized by increased levels of chylomicrons, large, triglyceride-rich particles present in the blood. When the triglyceride (TG) level gets very high, chylomicronemia can be present. There is no clear-cut number above which chylomicrons form, but a triglyceride level above 500 mg/dl is used as a guideline for more aggressive management to help prevent chylomicron formation and pancreatitis.¹ In actuality, the risk for pancreatitis goes up as triglycerides increase above 750 mg/dl. The risk is even higher when triglycerides rise above 1,000 mg/dl.¹

There is no universally accepted definition for FCS, though it is characterized by persistent chylomicronemia not due to a secondary cause, TGs above 880 mg/dl, and is refractory to traditional therapies such as fibrates and omega 3s. Patients also often have abdominal pain and pancreatitis, which can be a recurring problem.³ FCS is considered a homozygous monogenic disease with 5 genes that are responsible for the disorder. These genes are lipoprotein lipase (LPL), Apolipoprotein A-V (Apo A5), glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1), Apolipoprotein C2 (ApoC2), and lipase maturation factor 1 (LMF1).³ This is a very rare, functionally homozygous condition affecting one or two people per million,³ which translates to between 3,000 and 5,000 patients globally.² Ultimately, the result of these genetic mutations is a deficiency or malfunction of the lipoprotein lipase, which is responsible for the hydrolysis of chylomicrons and, ultimately, their clearance.⁶ The most serious adverse event associated with FCS is pancreatitis, which can be life-threatening,² evidenced by the fact that triglyceride-induced pancreatitis has an overall worse prognosis and morbidity than pancreatitis from other causes, such as gallstones or alcohol.⁴ The accumulation of chylomicrons appears to play a key role in triglyceride-induced pancreatitis.⁷

There are no pharmacologic therapies approved by the U.S. Food and Drug Administration (FDA) to treat FCS, and the current treatment strategy involves a very low-fat diet — less than 20 g/day or less than 2 tablespoons of olive oil daily⁶ — with medium-chain triglyceride (MCT) as an alternative source of fat. This type of restrictive diet can lead to social isolation, emotional distress and feelings of hopelessness. Frequent physical symptoms, worry about future episodes of pancreatitis, and economic difficulties because of hospital costs and under/unemployment because of the patient’s inability to maintain steady work make this a very difficult condition.⁸ There are multiple therapies in development targeting very high triglycerides. The furthest along that is targeting FCS specifically (instead of TG-induced pancreatitis or very high TGs) is volanesorsen, an antisense oligonucleotide (ASO) against Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglycerides.9 The triglyceride-raising mechanism of ApoCIII had been thought to work via direct inhibition of LPL. However, because volanesorsen is able to lower TGs by inhibiting ApoCIII in an LPL-deficient population, it is thought that ApoCIII must affect TG metabolism by other mechanisms, including its ability to inhibit TG-rich lipoprotein uptake by hepatic lipoprotein receptors.^10,11

The pivotal Phase 3 trial compared volanesorsen to placebo in patients with FCS confirmed either by genetic testing or by documentation of LPL deficiency.¹² There were a total of 66 patients in the trial with the baseline triglyceride level above 2,000 mg/dl in each arm. The volanesorsen arm showed a 76.5% reduction in triglycerides, to 590 mg/dl at 3 months, while the placebo arm showed a slight increase.¹² Although the study was not powered or conducted long enough to demonstrate a reduction in pancreatitis episodes, the results were encouraging in regards to helping address the main driving force behind pancreatitis in this population. There were, however, certain adverse reactions in the study that deserve careful evaluation in the larger studies under way. The key issue is an unexplained and unpredictable thrombocytopenia. The mechanism of this is unknown, and the thrombocytopenia can be severe and persistent even after stopping the medication.¹² Because of the unpredictable nature of the thrombocytopenia, it has been proposed that there be an ongoing platelet-monitoring program for patients to help guide surveillance, medication dosing, and dosing interval, similar to that done with international normalized ratio (INR) monitoring with warfarin, but more rigorous.¹²

Ultimately, the FDA decided to issue a complete response making US approval much more challenging; however approval for volanesorsen is still being sought in Canada and Europe. The details of the complete response are unknown, but it appears as though FCS patients in the US may have to wait for an alternative pharmacologic option.

Disclosure statement: Dr. Davidson has received honoraria from Akcea, Sonofi, Regeneron and Amgen.

References can be found here.