Emerging Therapeutics in Clinical Lipidology – an Update

After an article by Drs. Peter H. Jones and James M. McKenney in LipidSpin one year ago1 that reported on emerging therapeutics in clinical lipidology, it is still a very exciting time for the development of novel treatments for dyslipidemic patients.

Genome-wide association studies (GWAS) and mechanistic studies in patients affected by monogenic forms of dyslipidemia have provided strength and rationale behind novel targets for treating lipid abnormalities and altering atherosclerotic risk. And the advancements in our ability to manipulate pathways with approaches that go beyond the use of small molecules has provided the opportunity to develop treatments that only require administration from every few weeks to even months.

In this article, we will review the progress made in the last few years in the development of novel treatments that are at various stages of development and will likely be a part of the toolkit for clinical lipidologists and lipid specialists to use in their patients in the near future.

Targeting LDL-C
Low-density lipoprotein cholesterol (LDL-C) lowering and statin treatment remains the cornerstone for primary and secondary prevention of cardiovascular events. Lowering LDL-C with statins2 or a combination of statin and ezetimibe3 and PCSK9 inhibitors4 is associated also with a decrease in cardiovascular morbidity and mortality. Furthermore, recent outcome trials provide evidence that 1) the protective effect observed is similar in men and women who have a similar risk profile2,5; 2) lowering cholesterol below LDL-C target levels is still associated with improved clinical outcome4,6; and 3) intensive lipid-lowering therapy and maintenance of very low levels of LDL-C in high-risk patients are associated with a longer-term safety profile similar to that of patients with higher LDL-C levels.6

Despite these advances, management of hypercholesterolemia still remains challenging for some patients, including patients with statin intolerance or with substantial residual risk despite maximally-tolerated therapy, in patients with familial hypercholesterolemia and in patients with elevated lipoprotein(a) [Lp(a)]. Additionally, particularly in the United States, patients may have limited access to currently approved PCSK9 inhibitors given their high price, so that development of less costly therapeutic approaches is warranted.

PCSK9 inhibitors
PCSK9 remains a well sought-after therapeutic target. Inclisiran is a small interfering RNA that promotes the degradation of PCSK9 mRNA transcripts and seems to have similar efficacy to that of the approved PCSK9 monoclonal antibodies, but with a longer duration of action. A phase 2 trial in patients with elevated LDL-C and high cardiovascular disease (CVD) risk was recently completed and showed that inclisiran was well-tolerated and lowered PCSK9 and LDL-C levels in a dose-dependent fashion.7 These results suggest that inclisiran could be a valuable addition to statins in subjects that may not be reaching their target LDL-C level. Currently, several phase 3 studies are being conducted in patients with atherosclerotic CVD (NCT03400800, NCT03399370) and with heterozygous familial hypercholesterolemia (NCT03397121), as well as a trial in homozygous familial hypercholesterolemia (HoFH) (NCT02963311). Given its long half-life, in these studies, inclisiran (or placebo) is administered as a subcutaneous injection on Day 1, Day 90 and then every 6 months–a regimen that may be especially appealing to patients averse to medications requiring self-injection.

ANGPTL3 inhibitors
The majority of drugs used in reducing LDL-C levels, including statins, ezetimibe and PCSK9 inhibitors, affect the LDL receptor pathway. Recent intriguing data suggests that a significant impact on LDL-C levels may be also obtained by modulating LDL receptor-independent pathways. The protein angiopoietin-like 3 (ANGPTL3) is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase. Carriers of loss of function mutations in the gene for ANGPTL3 have lower triglycerides as well as lower LDL-C levels and a lower incidence of cardiovascular disease as compared with non-carriers.8-10 Currently, both monoclonal antibodies and antisense oligonucleotide (ASO) approaches targeting ANGPTL3 are being developed for the treatment of hypertriglyceridemia (see below). In addition, ANGPTL3 inhibition with evinacumab (monoclonal antibody) or ANGPTL3-LRx (antisense oligonucleotide) significantly reduces LDL-C.10,11 Interestingly, in a proof-of-principle open label study in patients with HoFH, administration of evinacumab substantially reduced LDL-C levels by 49%.12 The mechanism by which ANGPTL3 inhibition may cause reductions in LDL-C levels is not yet well understood, but given the results observed in HoFH, it is likely that the mechanism is at least in part independent of the LDL receptor. Currently several studies are being conducted, or starting imminently, in hypercholesterolemic patients and in patients with familial hypercholesterolemia using either evinacumab (NCT03175367; NCT03399786) or ANGPTL3-LRx (NCT02709850).

Bempedoic acid and gemcabene
Two small molecules are being developed that are associated with LDL-C lowering and may provide additional benefit on top of treatment with statins at a cost that is potentially lower than that of a biologic. Bempedoic acid (ECT-1002) is an inhibitor of the adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. It has been extensively studied in phase 2 trials and significantly reduces LDL-C in hypercholesterolemic patients with or without statin intolerance.13,14 Several phase 3 studies are currently being conducted in patients with elevated LDL-C (NCT03001076), statin intolerance (NCT02988115) or those at high risk for CVD (NCT02991118). Gemcabene is an inhibitor of de novo cholesterol and triglycerides synthesis by inhibiting acetyl CoA carboxylase. It may also have an inhibitory effect on apolipoprotein C-III (apoC-III). Similarly to bempedoic acid, several studies have been conducted in the past that have shown gemcabene to significantly reduce LDL-C when used in addition to statin therapy.15 A study in patients with HoFH (NCT02722408) ended recently and results are expected soon. A study in severe hypertriglyceridemia is still ongoing (see below).

Gene Therapy for HoFH
The last decade has been a very exciting time for the development of treatments for HoFH, a rare condition that, despite the progress made, remains very challenging to treat. In addition to the recent approval of lomitapide (an MTP inhibitor) and, in the United States, mipomersen (an ASO against apolipoprotein B), other novel approaches are being developed for these patients, including the above-mentioned trials with evinacumab, ANGPTL3-LRx and gemcabene. Additionally, a phase 1/2a gene therapy trial in patients with HoFH is ongoing (NCT02651675) that utilizes an adeno-associated virus (AAV) as a vector to deliver the LDL-receptor gene to the liver.16

Targeting Lp(a)
Elevated lipoprotein(a) [Lp(a)] levels are a causal risk factor for atherosclerotic cardiovascular disease and aortic stenosis, independently from LDL-C levels.17-19 Although several lipid-lowering drugs have been associated with a reduction of Lp(a), including niacin, PCSK9 inhibitors, and mipomersen, no specific Lp(a)-lowering agent existed until recently. An ASO targeting apo(a) (ISIS 681257) is currently in development and has shown promising results in early phase trials. A phase 2 placebo-controlled trial (NCT 02414594), reported a significant dose-dependent reduction in mean Lp(a) concentration with escalating subcutaneous dose injections of the active study drug.20 A phase 2 study evaluating the efficacy and safety of lower doses of the agent in participants with elevated Lp(a) levels and a history of cardiovascular disease is currently ongoing (NCT 03070782), results from this study and future data showing the effect of Lp(a) lowering by this therapy on cardiovascular disease endpoints will be of great interest.

Targeting triglycerides
The goal when treating hypertriglyceri-demia has generally depended on the severity of the triglyceride elevation. For more moderately elevated triglyceride levels that are less than 500mg/dL, the goal is to reduce cardiovascular disease risk, typically using statins, and to prevent worsening of the hypertriglyceridemia. For severe hypertriglyceridemia with triglyceride levels greater than 500mg/dL, the goal is to lower triglyceride levels to reduce the risk for pancreatitis. Studies have shown that in patients with triglyceride levels greater than 1000mg/dL, up to 20% develop at least one episode of acute pancreatitis.21 Fibrates and/or omega-3 fatty acids in parallel with dietary changes that includes reducing saturated fat intake are the first-line treatment to reduce triglyceride levels. However, there remain patients for whom these traditional agents are insufficient in reducing triglycerides to goal.

Omega-3 fatty acids
The prescription omega-3 fatty acids (Lovaza, Vascepa, and Epanova) contain the long chain fatty acids DHA (docosahexaenoic acid) and/or EPA (eicosapentaenoic acid). At doses of 3-4 grams/daily, they reduce plasma triglycerides by about 25-50% mainly by reducing hepatic production of very-low density lipoprotein (VLDL), a triglyceride rich lipoprotein particle, and increasing VLDL clearance.22 Two ongoing clinical trials will evaluate the impact of omega-3 fatty acids on long term cardiovascular disease outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT; NCT01492361) is a phase 3b trial of Vascepa versus placebo as an add-on to statin therapy in patients with either a history of cardiovascular disease or with diabetes and at least one risk factor for cardiovascular disease, with triglyceride levels between 150 and 500 mg/dL. The trial began enrollment in 2011 and is due to finish this year.23 The Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia (STRENGTH; NCT02104817) is also a phase 3b placebo controlled trial evaluating the addition of Epanova versus placebo (corn oil) to statin therapy that is scheduled to reach completion in 2019. The trial includes over 13,000 participants with triglyceride levels between 180 and 500 mg/dL and with a history of prior cardiovascular disease or least one risk factor for cardiovascular disease. While the effect on triglyceride level with the use of omega-3 fatty acids is known, results from these trials will help determine what the impact is on hard cardiovascular disease endpoints for patients with mild to moderate levels of hypertriglyceridemia.

Fibrates, the other mainstay of triglyceride lowering therapy, do so by activating transcription factors for the peroxisome proliferator-activated receptors (PPARs).24 By activating the subtype PPAR-α, fibrates lower hepatic apoC-III production and increase lipoprotein lipase (LPL)-mediated lipolysis of triglycerides and triglyceride-rich lipoproteins. Pemafibrate, a newcomer to this line of agents, is a selective PPAR-α agonist with higher efficacy than earlier generation fibrates which were weaker agonists of all PPAR subtypes (α/δ/γ). In phase 2 trials, use of pemafibrate was shown to have a 50% reduction in fasting plasma triglyceride levels when combined with statin therapy in patients with fasting triglyceride levels greater than 200 mg/dL at baseline.25 A phase 3 trial of pemafibrate, Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT; NCT03071692), is underway to assess long-term cardiovascular outcomes. There has also been interest in the development of dual PPAR agonists that serve as an activator of both PPAR-α and PPAR-γ, which is associated with insulin sensitization and enhance glucose metabolism. These agents are appealing for use in the population with elevated triglycerides and diabetes. However, development of many of these agents has been halted at various stages due to safety concerns, including edema, increased risk for heart failure and other cardiovascular events, and renal injury.

Gene therapy
One of the first gene therapies to be approved for clinical use was for the treatment of familial lipoprotein lipase (LPL) deficiency. Familial LPL deficiency is a rare autosomal recessive disorder that results in severe hypertriglyceridemia and hyperchylomicronemia, and recurrent acute pancreatitis in affected patients.26 Alipogene tiparvovec (Glybera), is an adeno-associated virus vector carrying the LPL gain of function variant. In clinical studies, one time administration was associated with significant triglyceride reductions during the 12-14 week study period. Although triglyceride levels returned to pre-treatment levels between 16-26 weeks, patients had sustained improvements in post-prandial chylomicron metabolism with sustained LPL gene expression. Further, 6 years of follow-up data has revealed clinically relevant reductions in pancreatitis and acute abdominal pain events in treated patients.27

ApoC-III antisense oligonucleotide
ApolipoproteinC-III (apoC-III) inhibits LPL, decreasing lipolysis of triglycerides and promoting hypertriglyceridemia. Large scale studies have shown that loss of function mutations in the gene encoding for apo C-III (APOC3) were associated with lower triglyceride levels and reduced risk for coronary heart disease.28,29 Targeting apoC-III, specifically, blocking its activity which in effect disinhibits LPL, should thereby lead to a lowering of triglyceride levels. This is currently being investigated with an ASO against APOC3 (volanesorsen).30 ASOs are short strands of modified nucleotides that target the mRNA to “turn off” the associated gene. Initial reports from a phase 3 trial, COMPASS [not an acronym] (NCT02300233), showed a 70% mean triglyceride reduction with weekly volanesorsen administration in patients with hypertriglyceridemia and in patients with Familial Chylomicronemia Syndrome (FCS) that was sustained through the 26-week follow-up period. Investigators are now evaluating volanesorsen in a phase 2 study in patients with moderate hypertriglyceridemia (200-500 mg/dL) with established cardiovascular disease (NCT03385239).

ANGPTL3 inhibitors
As described above, there are two ANGPTL3 inhibitor strategies under development for triglyceride lowering and LDL-C lowering. In a phase 1/2 trial, an ASO against ANGPTL3 (IONIS-ANGPTL3-LRX, NCT02709850) was shown to be associated with 33-63% reduction in triglycerides in healthy volunteers with elevated triglycerides.11 In an early phase trial comparing evinacumab, a monoclonal antibody, to placebo in patients with varying degrees of dyslipidemia, results revealed a favorable triglyceride response (60% to 80%) to a single dose of ANGPTL3 inhibitor administered intravenously.10

Gemcabene, as mentioned earlier, blocks triglyceride production in the liver. A phase 2 trial assessing the efficacy and safety of gemcabene in patients with severe hypertriglyceridemia (500-1500 mg/dL) is slated to finish later this year (NCT02944383).

The management of lipids both in the broader population for risk reduction and in the smaller population with genetic disorders of lipid metabolism is quickly changing. Genetic association studies have unveiled the importance of mediators, such as apoC-III and ANGPTL3, in modulating lipid levels. And, therapeutic advances, such as the development of antisense oligonucleotides and interfering RNA molecules, have broadened our abilities to target these mediators in patients for whom traditional and standard therapies have not completely met the needs of their disease. Results from ongoing clinical trial studies of agents such as the ASO targeting Lp(a) and the monocolonal antibody against ANGPTL3 for patient groups ranging from those with high triglycerides to those with HoFH, are highly anticipated and expected to change the future direction of the field.

Disclosure statement: Dr. Cuchel has received funding for clinical trials from Regeneron, RegenexBio, and Akcea Therapeutics. Dr. Bajaj has no disclosures to report.

References available here

Article By:


Research Associate Professor of Medicine
Division of Translational Medicine and Human Genetics
University of Pennsylvania
Philadelphia, PA


Post-doctoral Fellow
Division of Translational Medicine and Human Genetics
University of Pennsylvania
Philadelphia, PA

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