Evolucumab – Good News about Bad Cholesterol?

Browse By

There’s a new kid on the block that promises to combat ‘bad’ cholesterol like never before. It’s none other than the drug Evolucumab which has got both the scientific community and the pharma companies talking. But is this all just a hype to promote a blockbuster drug by the pharma giant or does it live up to its expectations?

Just what is Evolucumab & how does it work?

We all know that a build up of ‘bad’ cholesterol (known as LDL-C) in our body can lead to life-threatening diseases such as heart attacks and strokes. Statins have long been the standard of care for patients with abnormally high levels of cholesterol in their blood (a condition known as hypercholesterolemia).

Statins are drugs that lower LDL-C levels in the blood by inhibiting the activity of HMG CoA reductase – the enzyme that is necessary to synthesize cholesterol.

But unlike statins that lower cholesterol, Evolucumab block PCSK9 – a protein hindering liver cells from removing cholesterol further from the blood by breaking down its receptors completely. Instead, the drug causes the receptor to be reused by the cell to take up more cholesterol from the blood to be used up by the cell. This is well explained by the illustration given below:

ldl

a. The mechanism of PCSK9 and b. when Evolucumab is present it inhibits PCSK9 activity. Courtesy Nature Cardio (Dadu et al. 2014)

Evolucumab (generic name: Repatha) belong to a class of antibody-based drugs also called as PCSK9 inhibitors. Another drug called Alirucumab, targeting familial hypercholesterolemia patients manufactured by Regeneron/Sanofi, works pretty much on the same principle.

Familial Hypercholesterolemia is a genetic disorder wherein patients, due to mutations in proteins involved in lipid metabolism have high levels of cholesterol. PCSK9 when mutated can cause Familial Hypercholesterolemia.

Here’s the deal breaker. In the trials conducted so far, Evolucumab was effective in heart patients that poorly responded to statin therapy by decreasing cholesterol up to 61% which was greater than with statin therapy alone.

The Silver Bullet?

With these results, Amgen’s heart drug has been touted as a game changer in treating patients with high cholesterol,  preventing heart attacks and strokes. To get a perspective, nearly  18 million people around the world die of heart attacks and strokes with hypercholesterolemia being one of the major risk factors involved.

amgn-repathaa_large

However, some members of the scientific community do not share the enthusiasm as they feel this wouldn’t be much of a good idea. This was due to the fact that there has been a slightly increased number of deaths in study population under Evolucumab as compared to the control population. Another issue that raised concern was the appearance of neurocognitive effects in patients treated with Evolucumab which was not seen in placebo patients. Some argue that decrease in the incidence of cardiac events in the study patients is not that impressive as compared to its effects on lowering cholesterol.

With the FDA providing the green signal albeit insisting better guidelines, it is important to note that clinical trials with longer time points would give clearer insight on whether Evolucumab is the poster child of Amgen to fight the ‘bad’ cholesterol after all.

Interesting reads:

  1. American Heart Association. Why cholesterol matters. April 21, 2014. www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp#.Vi4sRWTBwXA. Accessed September 21, 2014.
  2. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nature reviews. Cardiology. 2014 Oct 1;11(10):563.
  3. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May 4;2017(376):1713-22.
  4. “Should you be Worried about the neurocognitive effects side effects of the new cholesterol drugs?” https://www.forbes.com/sites/larryhusten/2015/03/16/should-you-be-worried-about-the-neurocognitive-side-effects-of-the-new-cholesterol-drugs/#dff6902341a8
  5. Names of clinical trials of PCSK9 inhibitors: FOURIER study, OSLER-1 and 2 and ODESSEY study