Praluent (Alirocumab): Potential blockbuster cholesterol reducing medication

Alirocumab is a new to the market drug that has received a lot of attention due to its potential to significantly lower cholesterol levels. Initial research has shown it to be an effective low density lipoprotein (LDL) reducer in patients who have high cholesterol levels that are not able to be controlled by conventional diet and statin treatment. It belongs to a wider family of drugs known as PCSK9 inhibitors.

PCSK9 and the management of high cholesterol

In 2003, a group of French researchers revealed high levels of a protein known as PCSK9 (propotein convertase subtilisin/kexin type 9) in a family with familial hypercholestrolaemia (1), an inherited condition that results in dangerously high cholesterol levels and a significantly increased risk of cardiovascular disease. PCSK9 itself had been discovered by researchers in Canada who had been researching the process of liver regeneration around 12 months earlier (2), and a number of subsequent studies and research articles discovered that patients who exhibited higher than average levels of PCSK9 were able to stop LPL receptors from functioning. In 2006, a large scale population study published in the New England Medical Journal that investigated the links between LDL levels and coronary heart disease incidence found that individuals with genetic variations linked to reduced PCSK9 function also had lower than average LDL levels. Subsequently, they were also less at risk of coronary heart disease than the general population (3).

From this point onwards the hypothesis that PCSK9 activity inhibition could reduce cholesterol has become an important and high profile research topic, gaining more funding and attention as pharmaceutical companies look to discover an effective cholesterol reducing agent that can be used on the mass market.

Effectiveness of alirocumab?

Research conducted more recently has shown that alirocumab is particularly effective in controlling high levels of cholesterol in conjunction with diet and maximally tolerated statin therapy.

As regulatory bodies move to approve its use, it is generally done so on the provision that it is used only in very high risk groups rather than the general population.

In the US, the FDA has approved its use only in patients who are genetically susceptible to significantly higher levels of cholesterol (i.e. adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol) (4).

Most regulatory bodies are only approving certain routes of administration in line with the existing evidence base: as such, the drug is largely given subcutaneously , twice weekly, as this has been shown to be effective as a lipid modifying therapy.

Concerns for safety and efficacy

As with all new drugs to market, the lack of available data over a significant period of time does tend to cause some caution in the medical and pharmaceutical community regarding its initial use.

There are no undue concerns regarding its safety, although it does carry many of the same side effects of other drugs administered via injection – itching, swelling and possible pain at the site of administration, and hypersensitivity vasculitis (a skin rash associated with the inflammation of small blood vessels). Because the clinical data regarding the longer term use of alirocumab is not available, long term cohort studies that monitor clinical outcomes will be crucial to determining its success in the longer term for high risk patients.

The potential of alirocumab

Two large scale randomised controlled trials (RCT), known as the ODYSSEY programme of research, have been undertaken to provide a further body of evidence on which regulators are able to base their decision.

Conducted by a group of researchers across Europe, with the findings presented at the European Society of Cardiology annual congress, the results of the trial show that for patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe (a drug that lowers plasma cholesterol levels) and has a similar safety profile (5).

The study compared the alirocumab injections with ezetimibe in over 700 patients, aged 62 and above, with high cholesterol or other risks of cardiovascular disease who were already taking as high a dose of statin as they could tolerate. Patients who received alirocumab had two injections a week of a 75 mg to 100 mg dose; those randomised to ezetimibe took 10 mg daily. The results showed the alirocumab injections reduced patient LDL cholesterol by 50% more than ezetimibe at both 24 and 52 weeks - and over three-quarters of the alirocumab group achieved LDL cholesterol of 1.8 mmol/L (70 mg/dl) or lower, compared with less than half of the ezitimibe group. Adverse events between the two groups were recorded as similar, with no sign of increased injection site reactions.

For patients in high risk categories (such as those with HeFH), another study undertaken as part of the ODYSSEY programme of research discovered that twice weekly administered alirocumab reduced LDL levels by just under half (49%) from baseline when compared with placebo over the course of two weeks (6).

Barriers to its use

As with all new drugs to the market, cost is usually a prohibitive factor in making it widely available to the patients who would benefit from its intervention. As such, its initial use is only likely to be purchased and used in patients who are significantly statin intolerant and carry a high cardiovascular risk. For patients who do not have excessively dangerous LDL levels, it is likely that healthcare professionals will continue to prescribe low cost, scientifically established, tried and tested treatments for hard to treat patients.

References

1. Abifadel M, Varret M, Rabès JP (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia Nature Genetics 34:154–156
2. Seidah NG, Benjannet S, Wickham L (2003) The secretory proprotein converstase nueral apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation Proceedings of the National Academy of Sciences USA 100:928–933
3. Cohen JC, Boerwinkle E, Mosley TH Jr et al (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease NEJM 354(12):1264–1272
4. FDA News Release: FDA approves Praluent to treat certain patients with high cholesterol. Available online at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm (last accessed 1st November 2015)
5. Cannon CP, Cariou B, Blom D, McKenney JM et al (2015) Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial Eur Heart J 14:36(19):1186-94
6. Colhoun HM, Robinson JG, Farnier M, Cariou B et al (2014) Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials BMC Card Dis 20:14:121-126