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How Cost-Effective Are New Drugs for Myasthenia Gravis? An ICER Review Weighs the Options

An ICER review of eculizumab and efgartigimod for Myasthenia Gravis found that the current evidence available shows moderate drug potency and efficacy, but upon examination of the quality-adjusted life year system, determined that neither drug was cost-effective. Kimberly Grant, a clinical pharmacist with IPD Analytics, participated on the panel and opined on possible formulary management strategy if approved. Treatment will likely be restricted to patients with anti-AChR antibodies.


A new analysis from the Institute for Clinical and Economic Review said the evidence available to date shows moderate effectiveness of two newer drugs for myasthenia gravis—eculizumab and efgartigimod—but found their price exceedingly high and their use not cost-effective.

A clinical and economic assessment of new and emerging treatments for generalized myasthenia gravis (MG) found that both eculizumab (Soliris) and efgartigimod appear to be at least somewhat effective, but the October 20 review expressed serious concern about the price of both drugs.

Eculizumab, a monoclonal antibody produced by Alexion Pharmaceuticals, has been in use since 2017, when the US Food and Drug Administration (FDA) approved it for adults with generalized MG who are positive for anti-acetylcholine receptor (AChR) antibodies and who have not responded to the standard treatments—high-dose corticosteroids combined with or followed by steroid-sparing immunosuppressive drugs. Used to treat autoimmune disease, eculizumab requires intravenous infusion every two weeks.

In October, the Institute for Clinical and Economic Review (ICER), an independent agency that conducts treatment assessments, said the evidence available to date shows moderate certainty that eculizumab provides a small benefit over conventional therapy and the possibility of a substantial benefit.

Efgartigimod, which argenx is developing for several autoimmune diseases, is an antibody fragment that lowers the level of immunoglobulin (IgG) antibodies in the bloodstream. It is expected to receive FDA approval in December.

In a randomized, placebo-controlled phase 3 trial, reported in July in Lancet Neurology, efgartigimod was infused weekly at 10 mg/kg for four weeks, then as needed, depending on the clinical response no sooner than eight weeks after initiation of the previous cycle. The drug was well tolerated and 68 percent of those who showed a two-point improvement in the MG-Activities of Daily Living scale (MG-ADL), the primary endpoint in the trial, responded to the treatment in the first treatment cycle compared with 30 percent in the placebo group.

The trial did not reveal the effectiveness of different dosing frequencies, so how it will be used in clinical practice is not yet known. The investigators said longer term safety and efficacy data will be “informed by the ongoing open-label extension” trial.

Based on the short-term benefits shown in clinical trials, ICER's review found moderate certainty that efgartigimod is at least comparable to conventional therapy alone and has the possibility of delivering a substantial benefit for adults with generalized MG who are positive for anti-AChR antibodies.

In a randomized double-blind phase 3 trial of eculizumab, AChR-positive patients were infused weekly for five weeks, then every two weeks for the remainder of the 26-week REGAIN (Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis) study, as reported in Lancet Neurology in 2017. The study authors did not report a statistically significant finding for those on eculizumab versus placebo for its primary endpoint—a change in the MG-ADL score from baseline to week 26. But patients who received the drug did perform much better on secondary endpoints, including the Quantitative Myasthenia Gravis (QMG) score and the Myasthenia Gravis Quality of Life (MG-QOL15) score.

Subsequently, 117 patients in the REGAIN study continued in an open-label extension to determine whether eculizumab helped patients achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations, meaning that a patient has no functional limitation from generalized MG but muscle examination shows some weakness. After 130 weeks of eculizumab treatment, 88 percent of patients achieved improved status on the measure and 57 percent achieved minimal manifestations status, as reported in Neurology in January.

ICER said the evidence was insufficient to compare eculizumab and efgartigimod with each other or with rituximab or maintenance IVIg, two corticosteroid-sparing immunosuppressive drugs that are standard-of-care options.

About 20 percent of patients with generalized MG are negative for anti-AChR antibodies. Although antibody-negative patients were included in the clinical trial, ICER said there is insufficient evidence to compare efgartigimod with conventional therapy alone for those individuals.

Expert Review at ICER Meeting

At an ICER-convened meeting to discuss the assessment on September 24, one of ICER's expert reviewers—A. Gordon Smith, MD, FAAN, professor and chair of neurology at Virginia Commonwealth University (VCU)—expressed enthusiasm about both therapies.

“I'm incredibly excited about the efficacy of these agents and the impact they're going to have on patients' lives,” said Dr. Smith, the Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research (Neurology) at VCU. “The positive end of the response in the clinical trials is very impressive.”

Exactly how the new treatments should be used remains to be seen, said Pushpa Narayanaswami, MD, FAAN, associate professor of neurology at Harvard Medical School.

When eculizumab first became available, Dr. Narayanaswami prescribed it only after two or sometimes three other treatments failed. “Now, I look more at the side-effect angle,” she said. “I usually use it after a first or a second treatment has failed but I don't go beyond that—it's within the first six or seven months after diagnosis.”

She expects that, for patients who are AChR-antibody positive, the choice of efgartigimod is likely to be based primarily on insurance coverage and patient preference, rather than efficacy or side effects. After the first four weekly infusions, some patients in the clinical trial went up to 12 weeks without needing another round of treatment, making it more convenient than other options.

She also thinks efgartigimod may be useful for patients who are negative for anti-AChR antibodies, even though the trial did not provide robust evidence of that. “I think it's a good option, even if the data are not clear, if my seronegative patient is not doing well with other treatments,” Dr. Narayanaswami said.

Dr. Smith said the two therapies may be good options to use while waiting for corticosteroid-sparing immunosuppressive drugs such as azathioprine or mycophenolate to kick into action.

“Steroid-sparing agents take six months to a year to work,” he said. “It's very easy to see how either of these agents, which work pretty quickly and are very effective for some patients, could be used to bridge people towards the time where their steroid- sparing agents are effective.”

Effective but Not Cost-Effective

Many insurance companies use ICER cost-effectiveness assessments to determine their coverage policies. Even though eculizumab and efgartigimod both appear to be clinically effective, neither is cost-effective, in ICER's view.

ICER assesses cost-effectiveness using the concept of quality-adjusted life years (QALY), a measure that assumes health is a function of both length of life and quality of life. A year of life lived in perfect health is worth 1 QALY; death is equal to 0 QALYs. The value of health states between 1 and 0 is derived from studies of patients, caregivers, and others.

If a drug is priced at more than $175,000-per-QALY, ICER considers it to be “low value.” Using this standard, eculizumab, currently priced at $653,100 a year, is clearly not worth its price, ICER said.

“Eculizumab through the years has been a poster child for what's been viewed as egregious pricing, by many people,” ICER President Steven Pearson, MD, said.

Indeed, the drug would be cost-effective only if it cost between $13,200 and $19,400 per year, a 97 percent discount off its current price.

ICER contends that efgartigimod should be priced in the $18,300- to $28,400-per-year range, based on the amount of improvement in overall health that patients will receive from the treatment. Argenx has not announced the price for efgartigimod yet, but ICER used comments by a company official to estimate an annual net price of $418,400 per year.

“While both are very exciting treatments, the price (or estimated price for efgartigimod) is too high and not justified,” Dr. Smith said.

Dr. Narayanaswami agreed. “There is clearly a need to look further at the value of these drugs, where value is outcomes divided by cost,” she said.

Determining that value requires robust research into outcomes in real-world practice, evaluating both the medical and other direct costs of treatment and indirect costs, including lost employment and caregiver burden.

Health services researcher Brian Callaghan, MD, MS, FAAN, the Fovette E. Dush Early Career Professor of Neurology at the University of Michigan Medical School, who conducts health services research, said that the drugs are clearly overpriced relative to their clinical benefit.

“The medications are likely effective, but it is not clear that they are better than the medications we already have,” Dr. Callaghan said in an email. “Despite the small incremental advance in the field, they are priced as if they are curative therapies or major breakthroughs. Unfortunately, we are paying astronomical prices regardless of the impact of the medications on the field.”

The efgartigimod trial was not limited to patients who had not responded to previous treatments, and until the FDA issues its approval, it is unknown whether it will restrict its use to patients who did not respond to conventional therapy.

Regardless, Kimberly Grant, a clinical pharmacist with IPD Analytics, an advisory firm for insurers and others, said she expects insurers will require other therapies to be tried before they will approve efgartigimod.

“Assuming it's going to be approved, we will have two approved drugs for myasthenia gravis that are very expensive...and I do foresee them requiring one to two immunosuppressant therapies and trialing them for at least a year,” she said at the ICER meeting. “I can see that as being a very real possibility.”

Dr. Narayanaswami said that restriction would be inappropriate because the drug may be needed as a first-line treatment in some patients. By way of analogy, she said she is currently using eculizumab—typically used only after other treatments have failed—for a patient with multiple comorbidities.

“I'm very hesitant of putting her on steroids, frankly, and I cannot wait for [the steroid-sparing immunosuppressive] mycophenolate to kick in,” she said. “I'm worried about renal insufficiency with IVIG and a multitude of factors. To be told that, for this patient, I cannot have access to this drug would be a problem.”

It is also unknown whether the FDA label will restrict efgartigimod only to patients who are positive for anti-AChR antibodies. Grant, the IPD Analytics pharmacist, said the lack of evidence that the drug works for antibody-negative patients makes that likely.

“Even if the [FDA] label is broad and doesn't specify antibody-positive patients, I think it's a really easy decision for a payer to decide to exclude antibody-negative patients because of that limited data and because of the cost of the drug,” she said.


Dr. Smith has received funding from Alexion, argenx, Eidos, and Lexicon. Dr. Narayanaswami has received funding from argenx and UCB, as well as has received research support from Momenta/Janssen, Alexion, and UCB.


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