Although 2017 was not awash with exciting novel therapies or practice-changing research, the importance of managing lipid levels to reduce the risk of cardiovascular (CV) disease was reinforced, although access to treatment remained a key issue.

 

The ‘bad’ cholesterol is the ‘bad’ cholesterol…

Notably, the weight of evidence supporting low-density lipoprotein (LDL)-cholesterol, often referred to as the ‘bad’ cholesterol, as the chief lipid target continues to grow. The phrase “lower for longer is better” surely now sums up the consensus among physicians in terms of managing LDL-cholesterol. Several drug classes have demonstrated that reducing LDL-cholesterol levels can reduce the risk of CV events. Furthermore, new research has shown that even half of the middle-aged population with no CV risk factors still have subclinical atherosclerosis that can cause heart attacks and strokes. This suggests that even “controlled” LDL-cholesterol levels may still be contributing to CV risk.1 To top it off, a consensus statement from the European Atherosclerosis Society declared that, “consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.”2 So there you have it.

 

…or is it?

However, some researchers suggest that the focus should be on apolipoprotein B (Apo B) rather than LDL-cholesterol. The crux of the thesis is that Apo B represents the number of cholesterol laden particles in the blood and this appears to be a better predictor of CV risk than cholesterol levels, according to proponents. Although opinions amongst thought leaders on its application appear to be split (www.sciencemag.org/news/2017/12/it-time-retire-cholesterol-tests; accessed February 14, 2018), the evidence supporting Apo B is growing.

 

And the ‘good’ cholesterol isn’t that good

During 2017, the reputation of LDL-cholesterol as the ‘bad’ cholesterol has been enhanced. In contrast, the hypothesis that high-density lipoprotein (HDL)-cholesterol is ‘good’ has taken a few more hits. In yet another trial failure, an HDL mimetic has not provided the benefits that epidemiological studies suggest are derived from high levels of HDL. A 3 mg/kg infusion of Cerenis Therapeutics’ CER-001 was investigated in the Phase II CARAT trial, but data presented at ACC.17 showed that CER-001 “did not meet its primary efficacy endpoint of regression of atherosclerotic plaques in post-ACS patients” (Cerenis press release, March 20, 2017). Then in August 2017, Merck announced that its investigational cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, which dramatically increases HDL-cholesterol levels, only provided a 9% CV benefit over placebo during the REVEAL trial (Merck press release, August 29, 2017). Subsequently, Merck discontinued development of the agent as “the clinical profile for anacetrapib does not support regulatory filing” (Merck press release, October 11, 2017). With lingering safety concerns, doubts over the mechanism driving efficacy, and the seemingly greater benefits obtained with Repatha, it appears that Merck were not convinced over the commercial success for anacetrapib.

 

Fewer CV events does not mean greater access

In late 2016, Amgen baited our breath with news that the FOURIER CV outcomes trial for its proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor Repatha (evolocumab) were positive, but we had to wait until ACC.17 for the details, which were… okay. There was a significant 15% reduction in the primary endpoint versus placebo, a composite of CV events and death, which thought leaders suggest is clinically meaningful, but further analyses revealed no significant reduction in CV deaths.3 Mixed feelings were vented at the conference. Some were unsurprised there was no reduction in mortality given the short time frame of the trial and population under study. However, others were disappointed considering the hype surrounding the class and substantial impact on LDL-cholesterol levels. Arguments that the short time frame for the trial was a commercial and not a clinical decision were put forward. Nonetheless, these results demonstrated that ultra-low levels of LDL-cholesterol appeared to be safe and improved patient outcomes, with the FDA updating Repatha’s label as a consequence. Despite this new evidence, access to this highly efficacious but highly expensive drug did not appear to improve over the course of 2017. In fact, independent studies continued to suggest that Repatha at its list price is not cost effective even after the FOURIER results are incorporated into analyses. ODYSSEY OUTCOMES, the CV outcomes trial for Sanofi/Regeneron’s Praluent, a direct competitor to Repatha, is due to be presented at ACC.18. Will it demonstrate meaningfully better results? Repatha and Praluent have been neck and neck in terms of safety and efficacy thus far. Interestingly, unlike Amgen prior to FOURIER, Sanofi and Regeneron have been rather quiet regarding top-line results from ODYSSEY OUTCOMES…

 

Filling the gaps

Despite the CV benefits now shown with Repatha (and likely to be shown with Praluent), the high cost of PCSK9 inhibitors is likely to limit their use to those most at risk or to those who can afford them. However, new competition is on the horizon, which could help meet the need for LDL-cholesterol reduction in more people. The Medicines Company and Alnylam Pharmaceuticals’ inclisiran is another drug targeting PCSK9, albeit by preventing production of the protein. At ACC.17, a 6-monthly dosing regimen offered LDL-cholesterol reductions similar to those for the PCSK9 inhibitors already on the market.4 Although, this drug is expected to be much closer in price to Repatha and Praluent than a generic statin, its novel formulation and longer duration of action could allow it to be priced low enough to gain traction in the market with cost-sensitive payers and providers. For those at lower risk or with tighter budgets, the availability of generic versions of AstraZeneca and Shionogi’s Crestor and Merck’s Zetia/Ezetrol are will make these effective agents more accessible. In particular, generic ezetimibe-based products will enable more statin-intolerant patients to reduce their CV risk. Furthermore, Esperion Therapeutics announced that the FDA had confirmed a regulatory pathway for the development of a bempedoic acid and ezetimibe oral combination pill, which could be an important therapeutic option for statin-intolerant patients (Esperion press release, June 26, 2017).

 

New kid on the block

Kowa’s Parmodia (pemafibrate) was approved in July 2017 by Japanese authorities for the treatment of hyperlipidemia. This novel selective peroxisome proliferator-activated receptor (PPAR)-alpha modulator is hoping to offer the benefits of the older fibrate class without some of the safety concerns linked to the class. High triglyceride levels independently contribute to CV risk and are more common among patients with obesity and diabetes.5

 

All in all, a solid year for the dyslipidemia drug market, with the importance of lipid modifying therapies reinforced and the arrival of generic competition for key therapies allowing more people to benefit.

 

For more information on DRG’s assessment of the Dyslipidemia market, please click here.

 

 

References

 

  1. Fernández-Friera L, et al. Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. J Am Coll Cardiol. 2017 Dec 19;70(24):2979-2991.
  2. Ference BA, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472.
  3. Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722.
  4. Ray KK, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440.
  5. Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol. 2017 Oct 4;16(1):124.

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