Side effects of repatha

Contents

Repatha Side Effects

Generic Name: evolocumab

Medically reviewed by Drugs.com. Last updated on Jan 28, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Pregnancy
  • Reviews
  • More

Note: This document contains side effect information about evolocumab. Some of the dosage forms listed on this page may not apply to the brand name Repatha.

For the Consumer

Applies to evolocumab: subcutaneous solution

Along with its needed effects, evolocumab (the active ingredient contained in Repatha) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking evolocumab:

Incidence not known

  • Difficulty with breathing or swallowing
  • fever
  • hives, itching, or rash
  • nausea
  • reddening of the skin, especially around the ears
  • swelling of the eyes, face, or inside of the nose
  • unusual tiredness or weakness

Some side effects of evolocumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Back pain
  • bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • blurred vision
  • body aches or pain
  • chills
  • cough
  • dry mouth
  • ear congestion
  • flushed, dry skin
  • fruit-like breath odor
  • headache
  • loss of voice
  • muscle aches
  • sneezing
  • sore throat
  • stomach ache
  • stuffy or runny nose
  • sweating
  • troubled breathing
  • unexplained weight loss
  • vomiting

Less common

  • Bladder pain
  • bloody or cloudy urine
  • diarrhea
  • difficult, burning, or painful urination
  • difficulty with moving
  • dizziness
  • frequent urge to urinate
  • loss of appetite
  • lower back or side pain
  • muscle or joint pain
  • muscle stiffness
  • nervousness
  • pain or tenderness around the eyes and cheekbones
  • pounding in the ears
  • slow or fast heartbeat
  • swollen joints

For Healthcare Professionals

Applies to evolocumab: subcutaneous solution

General

The more commonly reported adverse reactions have included nasopharyngitis, upper respiratory tract infection, back pain, and injection site reactions.

Hypersensitivity

Common (1% to 10%): Hypersensitivity reactions (including rash, eczema, erythema, urticaria)

Postmarketing reports: Angioedema

Cardiovascular

Common (1% to 10%): Hypertension

Gastrointestinal

Common (1% to 10%): Diarrhea, gastroenteritis, nausea (1.8%)

Genitourinary

Common (1% to 10%): Urinary tract infection

Local

Common (1% to 10%): Injection site reaction (including erythema, pain, bruising)

Musculoskeletal

Common (1% to 10%): Back pain, myalgia, musculoskeletal pain, arthralgia (1.8%)

Nervous system

Common (1% to 10%): Headache, dizziness

Uncommon (0.1% to 1%): Neurocognitive events (0.2%)

Other

Common (1% to 10%): Influenza, fatigue (1.6%)

Uncommon (0.1% to 1%): Contusion

Respiratory

Common (1% to 10%): Influenza, fatigue (1.6%)

Uncommon (0.1% to 1%): Contusion

Immunologic

Rare (less than 0.1%): Development anti-drug antibody

1. “Product Information. Repatha (evolocumab).” Amgen USA, Thousand Oaks, CA.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Related questions

  • How much does Repatha cost?
  • How does Repatha work?

Medical Disclaimer

More about Repatha (evolocumab)

  • During Pregnancy
  • Dosage Information
  • Pricing & Coupons
  • 283 Reviews
  • Drug class: PCSK9 inhibitors
  • FDA Approval History

Consumer resources

  • Repatha
  • Repatha Pushtronex
  • Repatha SureClick
  • Repatha (Advanced Reading)

Professional resources

  • Repatha (AHFS Monograph)
  • … +1 more

Related treatment guides

  • Cardiovascular Risk Reduction
  • High Cholesterol
  • High Cholesterol, Familial Heterozygous
  • High Cholesterol, Familial Homozygous

No surprise: Repatha reality is messier than initial reports suggested

Ever since Amgen teased the public with claims of a landmark study showing that its new heart drug Repatha significantly reduced the risk of cardiovascular events, anticipation has been building for the day when Amgen would release the data to back up its bravado.

That day finally came on Friday, and the wall-to-wall news coverage suggests that Amgen’s public relations strategy was quite effective.

But what about the drug itself? How big was the “significant” reduction that Amgen touted in its news release (which some news outlets reported uncritically in the weeks preceding publication of the data)?

And more importantly, how carefully did news stories evaluate the results and did they provide consumers with the information they need to make informed decisions about treatment?

The coverage runs the gamut and I can only paint in broad strokes.

  • The New York Times’ somewhat breathless coverage leads with the claim that this new class of drugs “has the potential to improve the health and longevity of millions of Americans with heart disease, the nation’s leading killer, accounting for one in four deaths.” It’s not until the ninth paragraph that we learn, no, the drug “did not show a benefit in overall death rates from cardiovascular causes.”
  • NPR’s piece, written by Yale cardiologist Harlan Krumholz, had much more balanced framing: “Pricey New Cholesterol Drug’s Effect On Heart Disease Is More Modest Than Hoped.” The relatively small reduction in cardiovascular events receives prominent emphasis in NPR’s story. “ over about two years of study, reduced the risk of cardiovascular events, including heart attacks and stroke, by about 15 percent. For about every 66 people treated, one person avoided one of these events. There was no reduction, however, in the risk of death.”
  • I was pleased to see that cost featured prominently in many stories, including Kaiser Health News’ piece in USA Today that was headlined, “Cholesterol drug prevents heart attacks — but costs $14K a year.” Journalist Larry Husten, writing on the Cardiobrief blog, wondered if “the modest efficacy of the drugs is worth their immodest cost.”

What should patients and the public take away from this?

The patient perspective was covered very thoroughly by patient advocate Dave deBronkart, also known as e-Patient Dave. His excellent round-up of news stories about the study encourages patients to “avoid relative risk reduction (headlines about percentages) and look instead for actual (absolute) numbers of patients helped.”

Here’s what those numbers look like and how those numbers impact cost:

-Major heart problems or strokes happened to 11.3% of patients WITHOUT the new drug, and 9.8% of patients WITH the new drug. In other words, 1.5% of patients avoided a problem event, but 9.8% still experienced a problem event despite taking the drug.

-1.5% means on average, 1 patient in 67 benefits from the drug. That’s the NNT – the number of patients needed to treat for one to get any benefit.

-Note, though, that the drug did not save lives: the same percent died whether or not they got the drug. So it prevented 1.5% of these major cardiac events, but didn’t alter death rates – at least not during the time of this study.

-The drug costs $14,000/year, and these patients were watched a median of 2.2 years, so the cost was about $30,800 per patient.

-The 67:1 ratio means each prevented heart attack came at a cost of 67 x $30,800 = $2.06 million.

-No new side effects were discovered. That’s good – many new drugs bring new risks, too. (But …this study was pretty short, so more news about side effects may come out later.)

deBronkart adds that “this study included very high risk patients, and if your risk isn’t as bad, then the benefits of the drug would not be comparable. You’d be much less likely to benefit, so the NNT for patients like you would be much larger.”

Beware of claims made without data

Bottom line: Patients, doctors and policymakers will have to make their own decisions about whether treatment with this drug makes sense for individuals and for society more generally. But those decisions should be based on complete information that has been thoroughly analyzed and reported.

Claims of “landmarks” and “breakthroughs” should be viewed skeptically in the absence of data. The evidence-based reality is almost always messier than initial reports would have you believe.

What are the benefits of this drug (results of trials used to assess efficacy)?

The efficacy of REPATHA was investigated in three double-blind, placebo-controlled trials that included 764 patients with atherosclerotic cardiovascular disease (ASCVD) and HeFH and one that evaluated 49 patients with HoFH. Table 3 below summarizes the results for the primary efficacy endpoint, the mean percent change in LDL-C from baseline for REPATHA compared with placebo, for each trial.

Table 3. Percent (%) Change in LDL-C at Week 12 (Week 52 for Trial 2) by trial

Statistical Review

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: REPATHA worked similarly in men and women.
  • Race: The majority of patients in the trials were white. Differences in response to REPATHA among races could not be determined.
  • Age: REPATHA worked similarly in all age groups studied.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Figure 7 summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12 (week 52 in Trial 2), by sex, age, race, and ethnicity.

Data are provided combining Trials 1 and 2 in ASCVD patients and Trial 3 in HeFH patients to allow for the largest possible sample sizes in each subgroup and since comparisons of the treatment effect across subgroups were consistent across trials. Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Figure 7. Difference (95% Confidence Interval) in Average Percent Change in LDL-C (Repatha minus placebo); Trials 1 to 3 Combined (ASCVD and HeFH)

Statistical Review

Figure 8 summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12, for Trial 4 in HoFH patients, by sex, age, race, and ethnicity. Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Figure 8. Difference (95% Confidence Interval) in Average Percent Change in LDL-C (Repatha minus placebo); Trial 4 (HoFH)

Statistical Review

What are the possible side effects?

The most common side effects are common cold, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising where the injection is given.

Allergic reactions have also been reported in patients treated with REPATHA.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions reported in at least 3% of REPATHA-treated patients and occurred more frequently than in placebo-treated patients in the 52-week trial (referred to as Trial 2) in patients with primary hyperlipidemia.

Table 4. Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-Treated Patients and More Frequently than with Placebo in Trial 2

† includes erythema, pain, bruising
REPATHA Prescribing Information, Table 1

The table below summarizes adverse reactions in seven pooled 12-week controlled trials.

Table 5. Adverse Reactions Occurring in Greater than 1% of REPATHA-Treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies

† 140mg every 2 weeks and 420mg once monthly combined
REPATHA Prescribing Information, Table 2

Prescribing Information for REPATHA includes a summary of adverse effects observed in the 12-week trial of 49 patients with HoFH. The adverse reactions that occurred in at least two REPATHA-treated patients, and more frequently than in placebo-treated patients, included:

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: The risk of side effects was similar in men and women.
  • Race: The majority of subjects were white. Differences in side effects among races could not be determined.
  • Age: The risk of side effects was similar among age groups studied.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes allergic reaction by subgroup in a pool of the 52-week trial and seven 12-week trials. The population represented is the Safety population, which includes any patients who received at least one dose of trial drug (REPATHA or placebo).

Table 6. Subgroup Analysis of Allergic Reactions—Pooled Trials

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved REPATHA based on evidence including that from 9 clinical trials of 4,226 patients. This includes two trials that specifically enrolled patients with HeFH and one that enrolled patients with HoFH.

Figure 1 summarizes how many men and women were enrolled in the 8 clinical trials used to evaluate the side effects of REPATHA in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH). MORE INFO includes a table outlining the demographics of 3 trials that evaluated the benefit of the drug.

Figure 1. Baseline Demographics by Sex—Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Clinical Trial Data

The figure below summarizes how many men and women were enrolled in the trial that enrolled patients with HoFH. These patients are described in separate figures because patients with HoFH are generally younger and have a disease that is very different than the patients represented in Figure 1.

Figure 2. Baseline Demographics by Sex –Trial of Patients with HoFH

Clinical Trial Data

Figure 3 and Table 1 summarize the percentage of patients by race enrolled in the clinical trials used to evaluate side effects in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH).

Figure 3. Demographics by Race–Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

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Clinical Trial Data

Table 1. Baseline Demographics by Race–Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Race Number of Patients Percentage

American Indian or Alaska Native

8 0%

Asian

359 9%

Black or African American

228 5%

Native Hawaiian or Other Pacific Islander

7 0%

White

3508 84%

Other

67 2%

Clinical Trial Data

Figure 4 and Table 2 summarize how many by race were enrolled in the trial of patients with HoFH.

Figure 4. Baseline Demographics by Race –Trial of Patients with HoFH

Clinical Trial Data

Table 2. Baseline Demographics by Race–Trial of Patients with HoFH

Race Number of Patients Percentage
White 44 90%
Asian 2 4%
Other 3 6%

Clinical Trial Data

The figure below summarizes how many patients by age were enrolled in the clinical trials used to evaluate side effects in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH).

Figure 5. Baseline Demographics by Age– Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Clinical Trial Data

The figure below summarizes how many by race were enrolled in the trial of patients with HoFH.

Figure 6. Baseline Demographics by Race–Trial of Patients with HoFH

Clinical Trial Data

Who participated in the trials?

The first table below summarizes baseline demographics for a pooled population from 3 trials that supported the efficacy of REPATHA: patients with primary hyperlipidemia and clinical atherosclerotic cardiovascular disease from 2 trials, and patients with heterozygrous familial hypercholersterolemia from 1 trial. These trials and populations are also described in the Prescribing Information for REPATHA.

The second table below summarizes baseline demographics for the pooled population from 8 trials that supported the safety of REPATHA.

Table 7. Baseline Demographics for Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH in 3 Pooled Trials

Clinical Trial Data

Table 8. Baseline Demographics for 8 Pooled Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Clinical Trial Data

The table below summarizes baseline demographics for the trial that enrolled patients with HoFH.

Table 8. Baseline Demographics for the Trial of HoFH Patients

Clinical Trial Data

How were the trials designed?

There were nine placebo-controlled trials that contributed to the evaluation of the side effects of REPATHA, including one 52-week placebo-controlled trial and eight 12-week placebo-controlled trials, including two that specifically enrolled participants with HeFH and one that enrolled participants with HoFH. Four of these trials were also central to the evaluation of the benefit of REPATHA. In each of these trials, patients were randomly assigned to receive REPATHA or placebo injections. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.

The benefit of REPATHA (the percent change in LDL C blood levels) was measured at 12 weeks in all trials except for one in which it was measured at 52 weeks.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

Back to Drug Trials Snapshots

Nissen’s study results were also published online Nov. 15 in the Journal of the American Medical Association.

Drugs such as Repatha and Inclisiran spur the liver to flush more LDL cholesterol out of the bloodstream by blocking a protein called PCSK9.

Unfortunately, first-generation PCSK9 inhibitors like Repatha require patients to receive 12 to 24 injections a year, making them inconvenient and expensive, Ray said.

Inclisiran is a next-level PCSK9 inhibitor, which works on a genetic level to prevent cells from producing PCSK9 in the first place, Ray said.

The Inclisiran clinical trial involved 500 people who were assigned to either a “control” group or one of four groups that received different doses of the drug.

One dose of Inclisiran at 300 milligrams or greater caused a 51 percent drop in LDL cholesterol that lasted at least 90 days, while two doses caused a 57 percent reduction that lasted up to six months, Ray reported.

Based on these results, Ray and his colleagues estimate patients would only need an Inclisiran injection two or three times a year to control their cholesterol.

However, Dr. Borge Nordestgaard noted that these are early results.

“The key question is, will the LDL cholesterol reduction, which is very impressive, be sustainable over time,” said Nordestgaard, a clinical professor with Herlev-Gentofte Hospital in Herlev, Denmark.

There are similar questions regarding the reduction of arterial plaque related to PCSK9 inhibitors, said Dr. Robert Eckel, a professor of cardiology at the University of Colorado Anschutz Medical Campus.

While drastically lowering LDL cholesterol does reduce arterial plaques, Eckel said he is waiting for the clinical trials to show whether this will actually reduce heart attacks and strokes in these patients.

If the remaining arterial plaques are softer and less dense, they might actually pose an increased risk because they are more likely to break free and block an artery, Eckel explained.

“We have to wait to see if this will impact patient outcomes,” Eckel said.

Both clinical trials showed side effects from the drugs similar to those reported by people taking either statins or placebos, the researchers reported. Muscle aches, headache, fatigue, back pain, high blood pressure, diarrhea and dizziness were the most common side effects.

Of the 59 cardiologists surveyed, 21 have no patients on Repatha and 19 have no patients on Praluent. The survey, however, found that could change if the risk reduction is met. By three years after the trial data is released, the physicians estimate that about half of their patients who do not benefit from a statin would be prescribed a PCSK9 inhibitor.

The trial data, by the way, will be released at different times. The results from the Amgen study are expected later this year, while the results from the study run by Sanofi and Regeneron are due next year, but a widely anticipated interim analysis is also due later this year.

An Amgen spokeswoman wrote us to say that its own survey of doctors found that patient reluctance to injections was not a “primary barrier to prescribing.” She added that internal company data showed that about 75 percent of patients – whose diagnosis was consistent with the FDA approved indication – were prescribed Repatha, but were denied insurance coverage “after numerous, lengthy appeals, sometimes taking up to several months.”

We asked Sanofi and Regeneron for comment and will update you accordingly.

This post was updated to include a response from Amgen.

This much-hyped cholesterol drug costs $14,100 a year. Doctors aren’t sure it’s worth it.

If you watch or read the news lately, you might think that an amazing new miracle drug to combat high cholesterol is about to change the world.

Last week, the New England Journal of Medicine published a big new study about a cholesterol drug called Repatha. The hype has been pretty hard to miss. Late-night news is trumpeting a “breakthrough,” anecdotes about patient miracles abound, and there have been wall-to-wall commercials urging people to ask their doctor about the treatment.

When the Food and Drug Administration first approved Repatha in 2015, it indeed seemed promising. Since the 1980s, people with high cholesterol have had one main treatment option: statins, such as Lipitor. Repatha, and other similar cholesterol-lowering medicines known as PCSK9 inhibitors, seemed to dramatically reduce cholesterol levels — even more so than statins.

But a huge question remained: Could these drugs actually cut the incidence of strokes or heart attacks? That’s what the new NEJM study sought to find.

After reading the study, and talking about it with doctors and researchers, I’m skeptical about the hype. Repatha isn’t as promising as many of the news reports suggested. In fact, the drug is raising questions about whether there’s a threshold for cholesterol lowering, beyond which health benefits simply may not manifest.

Drugs like Repatha lower cholesterol by dramatic amounts — but that hasn’t yet translated into cutting people’s risk of death

So far, there are two PCSK9 inhibitors on the market: Amgen’s evolocumab (a.k.a. Repatha) and alirocumab (brand name Praluent), which is produced by Sanofi and Regeneron Pharmaceuticals. These drugs are self-injected every two weeks, and work by blocking the PCSK9 protein, which is believed to slow the body’s ability to rid the blood of LDL (or “bad”) cholesterol, a major risk factor for cardiovascular disease.

The early clinical studies on PCSK9 inhibitors showed they lowered cholesterol by truly dramatic amounts. In the big 2015 clinical trial on Repatha, also published in NEJM, the drug reduced patients’ LDL cholesterol levels by 61 percent, from a median of 120 milligrams per deciliter to 48 milligrams per deciliter. Another big study on Praluent uncovered a similar result. Even patients already on statins saw their blood cholesterol levels drop further when they injected these drugs.

These studies were important, but they did not delve into whether the drugs had an impact on real-world outcomes, such as death and disease, above changing lab markers like cholesterol.

That’s why there’s been so much coverage of this new Repatha study: It’s the first high-quality, real-world trial on the effects of PCSK9 on death and disease — giving doctors, researchers, and insurance companies a clearer picture of what all that cholesterol lowering does to people’s health in the longer term.

The study followed more than 27,000 patients, at more than 1,200 sites in 49 countries, for about two years. The patients were assigned either to take Repatha and statins together or to take statins along with a placebo. Repatha reduced the combined risk of heart attacks, strokes, and other cardiovascular problems by 15 percent compared with the placebo group.

But this is also important: The drug had no effect at all on mortality. So despite lowering cholesterol considerably, and reducing the risk of strokes and heart attacks, it didn’t cut people’s risk of death. These results weren’t nearly as dramatic as what industry watchers and doctors had hoped for. (Cardiologists have said anything less than a 20 percent cardiovascular risk reduction means the drugs aren’t clinically relevant, and Amgen’s stock dropped by 7 percent after the study was published.)

To understand why, let’s look at the study in more detail. The findings suggest that if a person took Repatha on top of her statins for about two years, she’d decrease her risk of a heart attack by about a percentage point, from 4.6 percent to 3.4 percent. She’d also cut her risk of stroke from about 2 percent to 1.5 percent, or half a percentage point.

In real terms, that means 80 people would have to take the drug for about two years to prevent one heart attack, and 250 would have to take it to prevent one stroke. If you think that sounds pretty good, consider this: The drug costs $14,100 a year for patients, which is about 50 times the cost of generic statins — drugs that doctors have pointed out carry about the same level of benefit as Repatha.

“This may be worth it to some people,” said Vinay Prasad, a professor of medicine at Oregon Health and Sciences University. “To others, that may be a lot of injections and a lot of hassle to prevent one stroke.”

By Prasad’s estimation, only 40 people would need to take statins to prevent one heart attack, and 83 to prevent a stroke. What’s more, he added, statins have also shown mortality benefits — and Repatha hasn’t yet been proven to reduce the risk of death. So statins seem to be a much better deal for patients.

The fact that Repatha can cut cholesterol so significantly, but not deliver dramatic benefits to health, also raises questions about the impact of cholesterol lowering beyond a certain point.

“There could be an LDL threshold below which more clinical benefit not likely attained,” said Eric Topol, a cardiologist and director of Scripps Translational Science Institute. “We don’t know.”

Topol was also skeptical about the hype. “The trial was disappointing due to the disproportionate, large reduction of LDL but only modest effect on outcomes heart attack and stroke reduction,” he said.

Still, he pointed out that perhaps the two-year follow-up in the study wasn’t long enough to uncover a mortality benefit, so more studies may eventually show that effect. Amgen has been arguing as much in its defense, but as drug developer Derek Lowe wrote on his blog, that argument is a little dubious since Amgen helped design the trial, presumably choosing a study design that would generate the most favorable data.

At more than $14,100 per year, are the drugs worth it?

The big question this raises now: Is Repatha worth it?

Again, the drug costs $14,100 per year. Until now, insurance companies and pharmacy benefit managers have been rejecting a majority of the claims for Repatha (and the other PCSK9 inhibitor, Praluent) because the drugs’ effects on cutting health risks and hospitalizations weren’t known before the latest NEJM study.

It’s not clear whether the new data will make them change their minds. At Repatha’s current price, it costs $2.4 million to prevent a single heart attack and $7.5 million to prevent a stroke, according to Prasad.

“These numbers are incredibly high,” he said. There may be cheaper ways to achieve similar benefits, he added, such as simply increasing statin doses in patients.

It is possible that more and better data might come out that shows Repatha is the miracle we’ve been waiting for. It’s also possible that with longer follow-up times, more side effects could be uncovered too. The clinical trial showed an increased risk of diabetes in Repatha users, for example. Topol pointed out at least four in 1,000 patients will develop diabetes induced by the drug. That picture could change as we learn more.

For now, the drug seems to hold the most promise for people who can’t take statins or in whom the drugs don’t always work well, such as some people with familial hypercholesterolemia. Repatha may be helpful for this small group — it just may not be the blockbuster breakthrough the industry and patients had been hoping for.

Praluent

SIDE EFFECTS

The following adverse reactions are also discussed in the other sections of the labeling:

  • Allergic Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Common Adverse Reactions

The data in Table 1 are derived from 9 primary hyperlipidemia placebo-controlled trials that included 2476 patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks, including 2135 exposed for 6 months and 1999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were Caucasian, 4% were Black or African American, and 3% were Asian.

Adverse reactions reported in at least 2% of PRALUENT-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1.

Table 1: Adverse Reactions Occurring in Greater Than or Equal to 2% of PRALUENT-Treated Patients and More Frequently Than with Placebo

Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with PRALUENT and 5.1% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with PRALUENT were allergic reactions (0.6% versus 0.2% for PRALUENT and placebo, respectively) and elevated liver enzymes (0.3% versus <0.1%).

In an analysis of ezetimibe-controlled trials in which 864 patients were exposed to PRALUENT for a median of 27 weeks and 618 patients were exposed to ezetimibe for a median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above.

In a cardiovascular outcomes trial in which 9451 patients were exposed to PRALUENT for a median of 31 months and 9443 patients were exposed to placebo for a median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included non-cardiac chest pain (7.0% PRALUENT, 6.8% placebo), nasopharyngitis (6.0% PRALUENT, 5.6% placebo), and myalgia (5.6% PRALUENT, 5.3% placebo).

Local Injection Site Reactions

In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks (Q2W), local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with PRALUENT (7.2% versus 5.1% for PRALUENT and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for PRALUENT and placebo, respectively), but patients receiving PRALUENT had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo.

In a 48-week placebo-controlled trial evaluating PRALUENT 300 mg every 4 weeks (Q4W) and 75 mg Q2W, in which all patients received an injection of drug or placebo every 2 weeks to maintain the blind, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg Q4W as compared to those receiving PRALUENT 75 mg Q2W or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg Q4W discontinued treatment due to local injection site reactions versus no patients (0%) in the other 2 treatment groups.

In a cardiovascular outcomes trial, local injection site reactions were reported in 3.8% of patients treated with PRALUENT versus 2.1% patients treated with placebo, and led to permanent discontinuation in 26 patients (0.3%) versus 3 patients (<0.1%), respectively.

Allergic Reactions

Allergic reactions were reported more frequently in patients treated with PRALUENT than in those treated with placebo (8.6% versus 7.8%). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with PRALUENT (0.6% versus 0.2%). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using PRALUENT in controlled clinical trials .

Liver Enzyme Abnormalities

In the primary hyperlipidemia trials, liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with PRALUENT and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with PRALUENT and 1.4% of patients treated with placebo.

Low LDL-C Values

In the placebo-controlled and active-controlled primary hyperlipidemia trials using an every 2 week or every 4 week dosing interval, 914 PRALUENT-treated patients had two consecutive calculated LDL-C values <25 mg/dL, and 335 had two consecutive calculated LDL-C values <15 mg/dL. LDL-C values <25 mg/dL and <15 mg/dL were observed more frequently in patients treated with the PRALUENT 150 mg Q2W or 300 mg Q4W dosing regimens. Changes to background lipid-altering therapy (e.g., maximally tolerated statins) were not made in response to low LDL-C values in these trials, and PRALUENT dosing was not modified or interrupted on this basis.

In a cardiovascular outcomes trial, 4305 PRALUENT-treated patients had two consecutive calculated LDL-C values <25 mg/dL, and 782 had two consecutive calculated LDL-C values <15 mg/dL. Because PRALUENT dosing was decreased or discontinued in the event of two consecutive LDL-C values <15 mg/dL in this trial, the effects of prolonged very low LDL-C with PRALUENT are unknown.

In published genetic studies as well as clinical and observational trials with lipid lowering therapies, an increased risk of new onset of diabetes has been associated with lower levels of LDL-C.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with PRALUENT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PRALUENT in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a cardiovascular outcomes trial, 5.5% (504/9091) of patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks (Q2W) had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% (149/9097) of patients treated with placebo. Persistent ADA responses, defined as at least 2 consecutive post-baseline samples with positive ADA separated by at least a 16-week period, were observed in 0.7% of patients treated with PRALUENT and 0.4% of patients treated with placebo. Neutralizing antibody (NAb) responses were observed in 0.5% of patients treated with PRALUENT and in <0.1% of patients treated with placebo. Efficacy based on reductions in LDL-C was mostly similar in patients with or without ADA.

However, some patients treated with PRALUENT with persistent or neutralizing antibodies experienced attenuation in LDL-C efficacy.

A higher incidence of injection site reactions were observed in patients with treatment-emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%). In a pool of ten placebo-controlled and active-controlled trials of patients treated with PRALUENT 75 mg and/or 150 mg Q2W as well as in a separate clinical study of patients treated with PRALUENT 75 mg Q2W or 300 mg every 4 weeks (including some patients with dose adjustment to 150 mg Q2W), the incidence of detecting ADA and NAb was similar to the results from the trial described above.

The long-term consequences of continuing PRALUENT treatment in the presence of ADA are unknown.

Postmarketing Experience

The following adverse reactions have been reported during postapproval use of PRALUENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders And Administration Site Conditions

Flu-like illness

Read the entire FDA prescribing information for Praluent (Alirocumab for Solution for Subcutaneous Injection)

What Are the Injectable Alternatives to Statins?

According to the U.S. Centers for Disease Control and Prevention, about 610,000 people die of heart disease in the United States every year. Heart disease is also the leading cause of death for both men and women.

Since high cholesterol is such a widespread problem, new medications have been in the works to help control and manage it. PCSK9 inhibitors are the newest line of medications in the war against cardiovascular disease.

These cholesterol-lowering injectable drugs work to increase your liver’s ability to remove “bad” LDL cholesterol from your blood and thus decrease your risk of heart attack or stroke.

Keep reading to get the latest on PCSK9 inhibitors, and how they could potentially benefit you.

About PCSK9 Inhibitors

PCSK9 inhibitors can be used with or without the addition of a statin, however they can help reduce LDL cholesterol by as much as 75 percent when used in conjunction with a statin drug.

This could be especially beneficial for those who can’t tolerate the muscle aches and other side effects of statins or those who simply can’t get their cholesterol under control by using statins alone.

The recommended starting dose is 75 mg injected once every two weeks. This dosage may be increased to 150 mg every two weeks if your doctor feels your LDL levels aren’t responding adequately to the smaller dose.

While the research and testing results with these injection drugs are still relatively new, they show great promise.

Newest Inhibitor Treatments

The U.S. Food and Drug Administration (FDA) recently approved Praluent (alirocumab)‎ and Repatha (evolocumab)‎, the first cholesterol-lowering injection treatments in the new class of PCSK9 inhibitors. They’re designed to be used in combination with statin therapy and dietary changes.

Praluent and Repatha are for adults with heterozygous familial hypercholesterolemia (HeFH), an inherited condition that causes high levels of LDL cholesterol in the blood, and those with clinical cardiovascular disease.

These drugs are antibodies that target a protein in the body called PCSK9. By inhibiting PCSK9’s ability to work, these antibodies are able to get rid of LDL cholesterol from the blood and decrease overall LDL cholesterol levels.

Latest Research

Trials and research have shown positive results for both Praluent and Repatha. In a recent trial on Repatha, participants with HeFH and others with high risk factors for heart attack or stroke lowered their LDL cholesterol by an average of 60 percent.

The most common reported side effects of Repatha were:

  • upper respiratory tract infection
  • nasopharyngitis
  • back pain
  • flu
  • and bruising, redness, or pain at the injection site

Allergic reactions, including hives and rash, were also observed.

Another trial using Praluent also showed favorable results. These participants, who were already using statin therapy and had HeFH or increased risk of stroke or heart attack, saw a 36 to 59 percent drop in LDL cholesterol.

Side effects from Praluent use were similar to Repatha, including:

  • pain and bruising at the injection site
  • flu-like symptoms
  • nasopharyngitis
  • allergic reactions, such as hypersensitivity vasculitis

Cost

As is the case with most pharmaceutical advancements, these new injection drugs will come with a hefty price tag. While the cost for patients will depend on their insurance plan, wholesale costs start at $14,600 per year.

In comparison, brand name statin drugs cost only $500 to $700 per year, and those figures drop considerably if purchasing the generic statin form.

Analysts are expecting the drugs to advance to bestseller status in record time and bring in billions of dollars in new sales.

The Future of PCSK9 Inhibitors

Experiments are still ongoing as to the effectiveness of these injection drugs. Some health officials worry the new drugs pose the potential for neurocognitive hazards, due to some study participants reporting difficulties with confusion and the inability to pay attention.

Large clinical trials will be completed in 2017. Until then experts urge caution since the trials conducted thus far have been short-term, making it uncertain whether PCSK9 inhibitors can actually reduce the risk of heart disease and extend lives.

The new, potent cholesterol-lowering drugs: An update

For people at high risk, PCSK9 inhibitors may prevent heart attacks and save lives. But gaining access to these pricey drugs remains a challenge.

Published: June, 2018


Image: © Shidlovski/Getty Images

Three years ago, the FDA approved two drugs that lower harmful LDL cholesterol values dramatically — by more than 50%. The drugs, alirocumab (Praluent) and evolocumab (Repatha), belong to a new category of medications known as PCSK9 inhibitors. Both are given by a self-administered injection once or twice a month.

They’re intended for people whose cholesterol levels remain stubbornly high, despite making lifestyle changes (such as diet and exercise) and taking the maximum dose of a high-potency statin and other cholesterol-lowering drugs. In the past two years, results from two large studies found that both PCSK9 inhibitors lowered the risk of serious heart-related events such as heart attack and stroke by 15%.

“Now we know that this class of drugs will prevent cardiovascular events, and in some settings, lower the risk of dying,” says cardiologist Dr. Christopher Cannon, professor of medicine at Harvard Medical School. Results from the recent alirocumab study, known as the ODYSSEY Outcomes trial, were especially encouraging, he noted.

Fewer deaths

Researchers followed nearly 19,000 people with a recent heart attack or unstable angina (worsening chest pain, often at rest, that required hospitalization) who were already taking maximal doses of statins. They took alirocumab or a placebo for an average of nearly three years. Among those whose LDL cholesterol levels started out at 100 milligrams per deciliter (mg/dL) or higher, alirocumab cut deaths by 29% compared with the placebo. Doctors encourage heart attack survivors to strive for an LDL of 70 mg/dL or lower; in this study, the average LDL values for those taking alirocumab were 40 to 50 mg/dL.

Prohibitive pricing

But to date, the high price of these potent drugs has limited their use. The wholesale cost of a year’s supply of one of these drugs is about $14,500, although pharmacy benefit managers (middlemen companies that negotiate prices with drug companies on behalf of employers and insurers) pay about 30% less. To help contain costs, these companies require doctors to document that each patient is an appropriate candidate for a PCSK9 inhibitor. That designation includes people with an inherited form of very high cholesterol (familial hypercholesterolemia) and those with atherosclerotic heart disease and an LDL level of 70 mg/dL or higher, despite taking different high-dose statins.

“If someone has had trouble with statins in the past, we have to provide the dose, the dates, and the person’s response to at least two and sometimes three different statins,” Dr. Cannon explains. The person also must have tried adding the cholesterol-lowering drug ezetimibe (Zetia).

Even with that evidence, about two-thirds of the requests for PCSK9 inhibitors are denied. For the remaining third that are approved, the out-of-pocket copay is often at least $300 per month, says Dr. Cannon. Sanofi-Regeneron (which makes alirocumab) and Amgen (which makes evolucumab) also offer payment-assistance programs. But many people with Medicare and other health insurance plans often can’t take advantage of such programs.

“Recently, I filled out a six-page form to get one of the companies to help pay for the drug for one of my patients because she couldn’t afford the $700 monthly copay,” says Dr. Cannon. “We are waiting to see if they can help.”

Increased access?

However, Sanofi-Regeneron recently announced that it would lower the wholesale price of alirocumab to less than $8,000 a year, a figure an outside group deemed to be cost-effective. But there was a condition: pharmacy benefit managers would be required to grant appropriate access to alirocumab to eligible patients. This potential pricing structure change could mean more people will be able to afford these drugs in the future, says Dr. Cannon.

The ODYSSEY Outcomes results also reaffirmed the importance of lowering LDL for preventing repeat heart attacks. In addition, it’s a good reminder to people with worrisomely high LDL values who have not had a heart attack to pay close attention to their cholesterol, Dr. Cannon says.

And if you’re in that smaller, high-risk group of people who are good candidates for a PCSK9 inhibitor, being proactive can make a difference. “We found that if a patient gets directly involved in arguing with the pharmacy benefit manager and challenging the denial, that’s often more successful than the doctor alone,” says Dr. Cannon.

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