Alirocumab

Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

Common side effects include nasopharyngitis (cold), injection site reactions, and influenza.

It was approved for medical use in the United States and in the European Union in 2015.[3]

Medical uses

Alirocumab is used as a second-line treatment to lower LDL cholesterol for adults who have a severe form of hereditary high cholesterol and people with atherosclerosis who require additional lowering of LDL cholesterol when diet and statin treatment have not worked.[4] It is administered by subcutaneous injection.[4] As of July 2015, it is not known whether alirocumab prevents early death from cardiovascular disease or prevents heart attacks;[4] a clinical trial to determine outcomes was ongoing at that time, the results of which were expected in 2017. Multiple studies have shown that alirocumab reduces major adverse cardiovascular events like heart attack or stroke. One large clinical trial conducted in 2018 found that among patients with recent acute coronary syndrome and consistently high LDL cholesterol despite maximal statin therapy, alirocumab reduced the absolute risk of these events by 1.6% over 2.8 years compared to placebo.[5] This finding was supported by a recent meta-analysis by Wang H-F et al. which reported a reduction in the absolute risk of these events by 2.85% over 1.56 years.

Side effects

Side effects that occurred in more than 2% of people treated with alirocumab in clinical trials and that occurred more frequently than with placebo, included nose and throat irritation, injection site reactions and bruising, flu-like symptoms, urinary tract infection, diarrhea, bronchitis and cough, and muscle pain, soreness, and spasms.[4]

There are no available data on use of alirocumab in pregnant women to assess risks to the fetus. There is data to support the use of alirocumab in paediatric populations with familial hypercholesterolaemia. The systematic review and meta-analysis completed by Xiao et al.,[36] assessing the safety and efficacy of alirocumab and evolocumab found that alirocumab significantly reduces LDL-C in paediatric populations and is also beneficial in the reduction of apolipoprotein B and lipoprotein-a [36]. This was supported in the phase 3 randomised control trial assessing the efficacy of alirocumab in paediatric cohorts with heterozygous familial hypercholesterolemia which found that in both 2 weekly and 4 weekly dosing, there was a significant reduction in LDL-C, with reductions of -43% and -46.4% respectively [37]. The main dose finding study "ODYSSEY KIDS" assessing the safety and efficacy of doses and frequency of administration of alirocumab found that both 2 weekly and 4 weekly dosing cohorts had reduced LDL-C to targets of below 130mg/dL at week 8 for 89% of the 2 weekly dosing cohort and 73% of the 4 weekly dosing cohort [35]. All of the studies discussed above had no serious adverse drug reactions reported, however there were discontinuations to therapy in a minor cohort of patients generally due to neutropenia or fatigue, however this was not associated with the alirocumab intervention [35][36][37].

Pharmacology

Alirocumab works by inhibiting the PCSK9 protein.[15] PCSK9 binds to the low-density lipoprotein receptor (LDLR) (which takes cholesterol out of circulation), and that binding leads to the receptor being degraded, and less LDL cholesterol being removed from circulation. Inhibiting PCSK9 prevents the receptor from being degraded, and promotes removal of LDL cholesterol from circulation.[16]

After subcutaneous administration of alirocumab, maximal suppression of free PCSK9 occurs within 4 to 8 hours and has an apparent half-life of 17 to 20 days. Inhibition is dose-dependent. The antibody is distributed through the circulation, and it is eliminated at low concentrations by binding to its target, and at higher concentrations through a proteolytic pathway.[4]

Chemistry

Alirocumab is a human monoclonal antibody of the IgG1 isotype. It is made of two disulfide-linked human heavy chains, each disulfide-linked to a human light chain. It has an approximate molecular weight of 146 kDa.[4]

It is produced using Chinese hamster ovary cells transfected with recombinant DNA, that are grown in tanks.[4]

History

The importance of PCSK9 as a biological target for drug discovery emerged in 2003, when a series of discoveries led to identification of the protein and its gene, its role in causing some cases of familial hypercholesterolaemia when some mutations are present, and its role in causing very low levels of LDL cholesterol when other mutations are present.[17]

The discovery and validation of the target set off a race among pharmaceutical and biotech companies.[18][19]

Alirocumab was discovered by Regeneron Pharmaceuticals using its "VelocImmune" mouse,[20] in which many of the genes coding for antibodies have been replaced with human genes.[21]

Society and culture

In 2014 as PCSK9 inhibitors approached regulatory approval, market analysts estimated that the overall market for these drugs could be $10B per year, with each of alirocumab and Amgen's competing drugs having sales of $3B per year, and other competitors dividing the remaining $4B, based on estimates of an annual price for alirocumab of $10,000 per year.[39] At the same time, pharmacy benefit managers such as Express Scripts and CVS Caremark, while recognizing that the new drugs could help patients who were otherwise left with uncontrolled cholesterol levels, and recognizing that injectable biopharmaceuticals will always be more expensive than pills, and especially more expensive than generic pills, expressed concerns about the burden of the new costs on the health care system.[39]

When the drug was approved in July 2015, the announced price was higher than analysts had predicted: $14,600 a year.[40] Pharmacy benefit managers continued expressing their concerns, as did insurance companies and some doctors, who were especially concerned over the price, in light of the fact that the