A drug ingredient called thalidomide caused a terrible congenital disability crisis due to its side effects in the 1950s. However, the drug is still used today. The case shows that there is no such thing as a “bad drug.” Certain drugs undervalued in the past are reassessed today. Depending on when, how, and to whom the drug is used, it can become an “innovative” medicine. A pharmaceutical product is a product after all. Drugmakers compete to sell their drugs and to appeal them to doctors. Celebrating the second anniversary, Korea Biomedical Review runs “Pharma Battle,” a series of articles to compare rival medicines. KBR’s assessments referenced studies, market situations, and expert opinions. – Ed.
|Amgen's dyslipidemia treatment Repatha (right) and Sanofi's Praluent|
Pharmaceutical industry officials would mostly agree that statin is one of the most popular drugs for dyslipidemia or an abnormal buildup of lipids in the blood. Statin is dominating the dyslipidemia treatment market as it has strong efficacy in reducing low-density lipoprotein cholesterol (LDL-C), long-proven safety, and low price.
However, some patients need additional control of LDL-C after using statin or those who cannot try statin due to its side effects.
PCSK9 (Proprotein Convertase Subilisin/Kexin type9) inhibitors are targeting such unmet needs. They are biological agents that inhibit the activity of PCSK9 proteins, which plays a vital role in the degradation of the LDL receptor, thereby lowering LDL-C levels in the blood.
Although highly-priced PCSK9 inhibitors in injectable forms are used for patients who cannot take a statin, studies on their LDL-C lowering effect and safety are likely to enhance the status of PCSK9 inhibitors.
According to the 2018 guidelines for dyslipidemia by the Korean Society of Lipid and Atherosclerosis, PCSK9 inhibitors lowered LDL-C by 45-70 percent, ApoB lipoprotein by 40-50 percent, and lipoprotein by 30-35 percent. They also reduce neutral fat by 8-10 percent and increase HDL-C by 8-10 percent, and ApoA1 lipoprotein by 4-5 percent.
In the domestic market, Sanofi’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab) are fiercely competing against each other. Both are classified as PCSK9 inhibitors.
Repatha offers a broad scope of treatment with insurance coverage
Between the two PCS9 inhibitors, Repatha has more indications than Praluent. Repatha obtained approval from the Ministry of Food and Drug Safety in April 2017 for treatment of homozygous familial hypercholesterolemia (HoFH). It is the only PCSK9 inhibitor that benefits from insurance coverage.
In August 2018, Repatha’s indications expanded to include treatment of hypercholesterolemia, mixed dyslipidemia, and cardiovascular reduction for patients with atherosclerotic cardiovascular disease (ASCVD).
Amgen is seeking to push for Repatha’s insurance coverage for a treatment to reduce cardiovascular risk in patients with ASCVD. The company targets patients with ASCVD who need a quick and robust control of LDL-C due to high risk of recurrence of cardiovascular events, rather than hypercholesterolemia patients who are mostly controlled by statin and ezetimibe.
As Praluent has yet to obtain an indication for cardiovascular risk reduction in patients with ASCVD in Korea, Repatha’s winning of insurance coverage for the indication will enable Amgen to lead the local PCSK9 inhibitor market.
Praluent is authorized only for lowering lipids in the treatment of hypercholesterolemia and mixed dyslipidemia. Although the agent provided efficacy in reducing cardiovascular risks in ODYSSEY OUTCOMES study, it will take some time to get insurance benefit. Sanofi Korea is expected to seek approval within this year.
Praluent offers customized treatment tips for predictable patients
As researchers found that LDL-C was the most significant factor in preventing ASCVC, guidelines recommend PCSK9 inhibitors for patients who failed to reach their LDL-C targets.
For patients with ASCVD, physicians should lower the LDL-C target below 70mg/dL or by 50 percent compared with the base level, according to guidelines. The guidelines also recommend using statin with PCSK9 inhibitors for them if they cannot achieve the LCL-C target with a high dose of statin alone.
Cardiovascular disease is the key target of PCSK9 inhibitors. Sanofi and Amgen have been conducting studies to evaluate detailed and more explicit therapeutic effects of Praluent and Repatha in patients with high cardiovascular risks.
The FOURIER trial, which was used as a basis for Repatha’s indication for lowering cardiovascular risk in patients with ASCVD, tested the drug on 27,564 people.
The study results showed that the medicine reduced the risk of the primary composite endpoint of hospitalization for unstable angina, coronary revascularization, myocardial infarction, stroke, or cardiovascular death. It also lowered the risk of the secondary endpoint of myocardial infarction, stroke, or cardiovascular death.
Praluent also proved its efficacy in cardiovascular risk reduction in ODYSSEY OUTCOMES trial.
ODYSSEY OUTCOMES tested Praluent on 18,924 patients who had acute coronary syndrome (ACS) with acute myocardial infarction or unstable angina within the previous 12 months.
Praluent reduced by 15 percent the risk of the death from coronary artery disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization in the primary endpoint assessment.
In the secondary endpoint assessment through “hierarchical testing,” the treatment reduced the overall risk of death by all causes including cardiovascular and non-cardiovascular events by 15 percent. It was the first non-statin agent to show association with a reduction of all deaths.
The significant difference between the two studies is the sub-analysis. In the FOURIER study, a sub-analysis of peripheral arterial disease, stroke, and diabetic patients demonstrated a consistent reduction in cardiovascular risk regardless of baseline LDL-C, concomitant disease, and treatment history.
The sub-analysis of ODYSSEY OUTCOMES also showed that the higher the baseline LDL-C was, the greater the risk of major cardiovascular events and deaths, and the bigger Praluent’s effect in reducing risks.
Praluent, Repatha offer different dosage, treatment options
The two PCSK9 inhibitors have two different dosages and treatment options.
Praluent comes in the prefilled injection (75mg) and prefilled pen (150mg) and is subcutaneously injected once every two weeks. Depending on baseline LDL-C levels, treatment target, response, and patient’s condition, dosing can be adjusted individually. Thus, Sanofi emphasizes that Praluent offers customized treatment.
On the other hand, Repatha comes in prefilled syringe/pen 140mg only. Patients can take Repatha 140mg once every two weeks, or 420mg once every four weeks. The therapeutic effects of the two different administration periods are identical.
Patients or families should administer the drug directly, after receiving training from medical professionals. Some patients might find it easier to take the same dose of the medication, rather than adjusting the dosing for customized treatment. However, others might prefer adjustable dosage if they fail to reach LDL-C target with conventional statin therapy.
In summary, there is no significant difference in efficacy and safety between the two PCSK9 inhibitors. However, considering the scope of indications, availability of reimbursement, and drug compliance, Repatha provides more advantages than Praluent. Still, it remains to be seen whether Praluent will expand the indication for reduction of cardiovascular risks, obtain reimbursement, and benefit from Sanofi’s marketing strategy.
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