Emerging Therapeutics in Clinical Lipidology

Lipid therapeutics over the past three decades have focused on oral drugs that targeted lipid metabolism through mechanisms that regulate clearance of apoprotein B-containing lipoproteins (through the LDL receptor, such as statins, bile acid resins and ezetimibe) or the synthesis/clearance of triglyceride-containing lipoproteins (such as fibrates, niacin and omega 3 fatty acids). Modulation of HDL cholesterol was also thought to be of benefit, and drugs that favorably increased HDL-C, such as fibrates, niacin, and CETP inhibitors (except anacetrapib) were tested as add-on to statins in randomized trials but revealed no incremental benefit. The results of the 30,000 patient REVEAL (HPS3, TIMI55) outcome study evaluating the impact of anacetrapib on CVD events should be announced soon.

Recent genetic studies have confirmed that high LDL-C, high lipoprotein (a), and triglyceride-rich lipoproteins are causal for atherosclerotic cardiovascular disease (ASCVD).1-3 This has supported the development of drugs which target mediators of abnormal lipid metabolism with unique mechanisms of action (antisense oligonucleotides, monoclonal antibodies and RNA interference). These new targets include microsomal triglyceride transport protein (MTP), apoprotein B synthesis, proprotein convertase subtilisin-kexin 9 (PCSK9), apoprotein (a) synthesis, apoprotein C3 and angiopoietin-like protein 3 (ANGPTL3). The question of whether the use of any of these therapies along with maximally-tolerated statin treatment will reduce ASCVD further and are safe, will require more extensive evaluation.

In this article, we will describe some of the new treatments that are available for rare lipid disorders as orphan indications as well as those that are in early, preapproval trials which modulate LDL-C, triglyceride-rich lipoproteins, and HDL-C.

Treatments for rare diseases

Lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), was approved in 2013 for the treatment of homozygous familial hypercholesterolemia (HoFH). By inhibiting MTP, lomitapide prevents the incorporation of cholesterol ester, triglycerides and apoprotein B into a mature VLDL particle in the liver. This results in a reduction in triglyceride-rich lipoproteins (TGRL) and a lower LDL-C because of reduced remodeling of TGRL to LDL. Since a functioning LDL receptor is not necessary for the drug to reduce LDL-C, trials in HoFH subjects have demonstrated up to a 40% reduction in LDL-C at a maximum dose of 60 mg/day.4 The major downside with lomitapide is the side effect profile. Inhibition of triglyceride incorporation into VLDL in the liver can result in steatosis, and the inhibition of chylomicron formation in the intestine causes steatorrhea with consumption of fat in the diet.

Mipomersen, an antisense oligonucleotide (ASO) to apoprotein B, was also approved in 2013 for the treatment of HoFH. The antisense oligonucleotide binds to apo B 100 messenger RNA and prevents translation, thereby inhibiting apo B synthesis. A once weekly subcutaneous injection of 200 mg results in a 25% reduction in LDL-C, apo B and Lp(a) in HoFH subjects.5,6 Similar to lomitapide, inhibiting apo B synthesis can also lead to hepatic steatosis, and providers must participate in a risk evaluation and mitigation (REMS) program for both drugs in order to prescribe them.

Familial chylomicronemia syndrome (FCS) is a rare disorder due mostly to deficiency of lipoprotein lipase (LPL) or less commonly, apoprotein C2. Patients with FCS have severe hypertriglyceridemia as children and may have pancreatitis at a young age. There are two new therapies targeting FCS. Early studies of an ASO to apo C3 (volanesorsen) showed that inhibiting apo C3 in FCS patients resulted in a 56-80% reduction in triglycerides.7 A recent phase 3 study, COMPASS, showed that volanesorsen reduced triglycerides 71% from a baseline of 1260 mg/dL in non-FCS patients, and 73% from a baseline of 2280 mg/ dL in 5 FCS patients.8,9 Although not published yet, the phase 3, 52 week APPROACH study in FCS patients reported a 77% reduction in triglycerides with volanesorsen from a baseline of 2255 mg/dL.10 Further studies with volanesorsen are focusing on patients with severe hypertriglyceridemia that is not FCS. There is a gene replacement therapy for FCS called alipogene tiparvovec that replaces LPL, however this is only approved in Europe.

Finally, lysosomal acid lipase (LAL) deficiency is a rare autosomal recessive (LIPA gene) disorder of systemic lysosomal accumulation of cholesterol ester and triglycerides.11 It is called Wolmans disease in infants and cholesterol ester storage disease (CESD) in children and adults. Wolmans disease results in hepatic failure and death in infants by age 1. CESD presents with hepatic disease (steatosis/fibrosis) and dyslipidemia. There is an enzyme replacement treatment by IV infusion called sebalipase alpha that was approved by the FDA in 2015. 

Therapies to reduce LDL-C and Lp(a)

In 2015, the FDA approved two human monoclonal antibodies (alirocumab and evolocumab) for subcutaneous administration that inhibit PCSK9 and lower LDL-C by reducing the degradation of the LDL receptor. These drugs can reduce LDL-C by 50-60% when given either every two weeks (both compounds) or monthly (evolocumab), and will achieve this efficacy regardless of background lipid therapy, including use as monotherapy in statin-intolerant patients.12 They also have been shown to reduce Lp(a) by about 25%.13,14 A humanized monoclonal antibody to PCSK9, bococizumab, was recently discontinued from clinical development because of the lack of sustained efficacy resulting from antidrug and neutralizing antibodies.15 The safety of these drugs appears to be good, with no issues seen on rates of new-onset diabetes or on cognition, especially with very low on-treatment LDL-C levels.16 Cardiovascular outcomes trials with these drugs are either completed (FOURIER with Evolocumab)17 or nearly completed (ODYSSEY Outcomes with Alirocumab).17 The FOURIER study confirms an incremental benefit on MACE in ASCVD patients receiving maximal statin treatment, and has a good safety profile.

A novel delivery method of a drug that interferes with RNA and leads to the inhibition of PCSK9 has been recently described. The drug inclisarin is a long-acting small molecule that inhibits RNA-induced silencing complex (RISC) which cleaves the messenger RNA for PCSK9.19 Inclisarin is administered subcutaneously and is conjugated with triantennary N-acetylgalactosamine (termed GalNAc) in a nanoparticle. This GalNAc conjugate is recognized by the hepatic asialoglycoprotein receptor (ASGPR), which targets the drug specifically to the liver.20 A single injection of inclisarin reduces LDL-C by 40-50% for four months or more. A multiple injection schedule reduces LDL-C 40-50% for up to six months.19 If further studies with inclisarin support this data, this therapy could potentially be used every 3-4 months for sustained LDL-C reduction.

An oral drug, bempedoic acid (ETC-1002), has been shown to reduce LDL-C by a mechanism that upregulates the LDL receptor. The drug is an inhibitor of adenosine triphosphate citrate lyase (ATP-ACL) which reduces hepatic cholesterol synthesis upstream from the statin target, HMG CoA reductase, and upregulates the LDL receptor through SREBP2. According to the analysis of two phase II studies, the placebo-adjusted, mean percent LDL-C lowering from baseline with bempedoic acid 180 mg/day is 32% as monotherapy, 22% when added to stable statin therapy, and 50% when combined with ezetimibe 10 mg/day.21-23

The phase 3 CLEAR Harmony study is enrolling 1950 high risk patients on optimal statin therapy to test the efficacy and safety of bempedoic acid 180 mg/day. The CV outcomes trial, CLEAR Outcomes, has just begun to enroll > 12,000 high risk patients who are intolerant of optimal statin therapy.

Another oral drug, gemcabene, is an inhibitor of acetyl CoA carboxylase (ACC) and possibly apo C3 and results in a reduction in hepatic triglyceride and cholesterol synthesis as well as enhanced clearance of VLDL. Phase II studies have shown modest reductions in LDL-C (up to -23%) and TG (up to -40%) as well as an increase in HDL-C (up to 18%).24 The mean placebo-adjusted LDL-C reduction in more recent phase II studies with the 600 mg/day dose (the dose that is being tested in phase III) was 20%.25 Gemcabene also lowers high sensitivity C-reactive protein (hsCRP). Presently, the drug is undergoing phase III testing for use as a lipid modulating therapy.

Finally, high Lp(a) has been shown to be causal for ASCVD and aortic valve stenosis.26,27 The European Atherosclerosis Society (EAS) and the National Lipid Association (NLA) have recognized a Lp(a) > 50 mg/ dL (80th population percentile) as an important factor for consideration of risk for ASCVD. However, Lp(a) is not a target of therapy because of limited therapeutic options and limited evidence of incremental outcomes benefit. While it is known that statins do not lower Lp(a) despite stimulating LDL receptor activity, the PCSK9 inhibitors alirocumab and evolocumab have shown Lp(a) reductions of 25%. A new robust method of lowering Lp(a) is with an ASO to apo (a) that uses the GalNAc delivery technique. Preliminary trials with IONIS-Apo(a)-Lrx in single and multiple ascending subcutaneous doses in a small group of patients demonstrates a 66-92% reduction in Lp(a) at one month, with no injection site reactions.28

Therapies to reduce triglycerides

We are eagerly anticipating the completion of the REDUCE IT study to determine if lowering triglycerides > 200 mg/dL in very high risk patients on optimal statin treatment utilizing 4 gm/day of EPA can finally answer whether targeting high triglycerides will provide incremental CV outcomes benefit. In the meantime, a new selective PPAR alpha modulator (SPPARM) called pemafibrate has demonstrated a reduction in triglycerides, remnant cholesterol and apo C3.29,30 A CV outcomes trial with pemafibrate, called PROMINENT, is currently recruiting 10,000 high risk patients with type 2 diabetes (with and without ASCVD) on optimal statin treatment who have residual triglycerides > 200 mg/dL.

As previously mentioned, volanesorsen (an ASO to apo C3) has shown significant reductions in triglycerides in patients with severe hypertriglyceridemia (with and without FCS). Angiopoietin-like protein 3 (ANGPTL3) has a role in triglyceride lipoprotein metabolism through inhibition of LPL and possibly hepatic lipase. It is known that a loss-of­function mutation in a single copy of ANGPTL3 results in a reduction in LDL-C whereas a LOF in both copies of ANGPTL3 results in low LDL-C, low HDL-C, and low triglycerides. A human monoclonal antibody to ANGPTL3, called evanicumab, has shown a reduction in LDL-C of 55% at one month in 4 HoFH patients.31 Further studies are planned in HoFH, and other dyslipidemic populations may be studied in the future.

Therapies to modulate HDL-C

The inverse relationship between HDL-C and CVD risk has caused scientists to seek ways of increasing HDL-C to reduce risk. As mentioned in the introduction, this strategy has not yet been successful. Now scientists are more focused on the function of HDL particles. For example, the presence of a small population of people outside of Milan, Italy, who have an Apo A1 Milano gene mutation that appears to confer protection from atherosclerotic disease and longevity ostensibly by enhancing cholesterol efflux from macrophages to pre-beta HDL particles, has caused scientists to look for ways to mimic this system. Over a decade and a half ago, Esperion scientists were successful in developing a formulation containing recombinant Apo A1 Milano complexed with phospholipids (ETC-2016). When this product or placebo was infused weekly for 5 weeks into patients who had experienced a recent acute coronary syndrome (ACS), transvascular ultrasound measurements of segments of coronary vessels revealed a remarkable reduction in percent atheroma volume (PAV) of 1.06% with ETC-2016 compared with an increase in PAV of 0.14% with placebo.32

Now more than a decade later, it appears that interest in developing and testing recombinant Apo A1 Milano HDL appears has reemerged. The original ETC-2016 formulation has been reformulated and renamed (MDCO-2016) and another intervention in patients with a recent ACS using transvascular ultrasound has been implemented and should soon report out study results (clinicaltrials.gov, PILOT, NCT02678923).

An engineered lipoprotein particle mimicking pre-beta HDL and consisting of recombinant human apo-A1 and two phospholipids has been developed, CER-001. This product has been shown to rapidly mobilize large amounts of cholesterol into the particle upon infusion. Various doses of CER-001 has been compared with placebo with weekly infusions for 6 weeks into 507 post-ACS patients in the CHI-SQUARE Trial; changes in PAV were similar in all study groups.33 A follow-up analysis of this study showed that a significant reduction in PAV in those patients with greater atheroma burden at baseline.34 The same product was also evaluated in 23 HoFH patients with 12 bi-weekly infusions; the study found that a significant reduction in carotid mean vessel wall area occurred in those receiving CER-001.35 Two other trials have been planned with CER-001, one being implemented in patients with hypoalphalipoproteinemia (clinicaltrials.gov, TANGO NCT02697136)  and another now completed in ACS patients (clinicaltrials.gov, CARET  NCT02484378).

Another plasma-derived human Apo A1 was reconstituted into a disk- shaped lipoprotein with phosphatidylcholine (CSL112). The AEGIS-I trial was developed to determine whether CSL112 provides a benefit to patients immediately after an acute myocardial infarction.36 This was a phase II, dose-ranging, randomized, placebo-controlled trial carried out in 1258 patients who had experienced an acute myocardial infarction. Patients received various doses of CSL112 or placebo in four consecutive weekly infusions. The study demonstrated safety of the product and importantly confirmed its ability to acutely enhance cholesterol efflux. The occurrence of MACE however over the succeeding 12 months was similar in patients receiving CSL112 or placebo. A larger phase III study is being planned to further define the product’s safety and attempt to demonstrate efficacy in reducing CV events.

Conclusions

While great strides have been made to lower the risk of CVD by intensively lowering LDL-C, a substantial residual risk persists even in the most optimally treated patients, which is a testament that further intervention will be necessary. The PCSK9 inhibitors have a chance of substantially advancing this residual risk-reduction goal, but other interventions are likely to be needed. This brief review has described some very innovative and promising investigational products under development which may soon give us more ability to further diminish this devastating disease.

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