Expanding Treatment Options for Myasthenia Gravis: Why… : Neurology Today – LWW Journals

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With the approval of a new drug for myasthenia gravis in December, neuromuscular specialists say they now have a host of new options for managing symptoms of the disorder. Four myasthenia gravis experts assess the current options and discuss their criteria for choosing one therapy over another.

Patients with myasthenia gravis (MG) will have another treatment option now that the US Food and Drug Administration approved a new targeted therapy in December, efgartigimod. The drug, which will sell under the brand name Vyvgart, is intended for adults with generalized myasthenia gravis who are positive for the anti-acetylcholine receptor (AChR) antibody.

Neurologists say the novel drug is likely to enhance the already growing ability to treat MG, a rare autoimmune disorder of the postsynaptic neuromuscular junction commonly characterized by a depletion of AChR. The Myasthenia Gravis Foundation estimates that 36,000 to 60,000 people in the US have MG, though the number could be higher because the disease is thought to be underdiagnosed.

I have really never felt so optimistic in terms of speaking with patients about their different options, Amanda C. Guidon, MD, MPH, assistant professor of neurology at Harvard Medical School. We have more therapies and there is this rich pipeline for drug development that will target therapies at (MG) pathophysiology.

Dr. Guidon, who directs the MGH Myasthenia Gravis Clinic at Massachusetts General Hospital, said MG mortality has decreased from 40 percent to 5 percent, though.

Still, she said, there is still a long way to go in terms of reducing MG symptoms, as well as achieving a understanding which therapies, from thymectomy to plasma exchange to oral and infused medications, are best suited for which patients.

MG typically is marked by fluctuating weakness in muscles controlling the arms, legs, face, mouth and throat. It can present as generalized or ocular disease.

Efgartigimod is the first in a new class of medication, according to the approval announcement by the FDA. The drug, which is infused, is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing FcRn from recycling immunoglobulin G (IgG) back into the circulation. The drug reduces overall levels of IgG, including the abnormal AChR antibodies.

We are in a new phase of revolution in how we manage patients, said James Howard, MD, professor in the department of neurology at the University of North Carolina, who led clinical trials of efgartigimod. With additional targeted drugs for MG under development, the treatment landscape over the next five to 10 years will radically change.

Dr. Howard was the principal investigator for the phase 3 ADAPT trial that served as a basis for the FDA approval of efgartigimod. The 26-week multicenter, international study randomized 167 MG patients to efgartigimod or placebo. By measure of the Myasthenia Gravis Activities of Daily Living (MG-ADL), the study, reported in Lancet Neurology in July 2021, found that 68 percent of patients with AChR antibodies responded to treatment during the first cycle of efgartigimod, compared with 30 percent of the placebo group. More patients receiving the active drug also demonstrated response on a measure of muscle weaknessthe Quantified Myasthenia Gravis Score (QMG)compared with placebo, according to the FDA. The most common side effects experienced by participants on efgartigimod were respiratory tract infections, headache, and urinary tract infections.

Dr. Howard said the drug is continuing to be evaluated in an open-label study, and is also being formulated for subcutaneous injection, and that approach is also being studied.

Dr. Howard said that until recently the goal of MG therapy has been mostly to reduce the burden of symptoms, which include weakness in the arms and legs, trouble swallowing, impaired speech, eyelid dropping and double or blurred vision. He said the focus is now shifting to include reducing treatment burden, which he said is problematic for many MG patients. He said that registry data on patients in different countries around the world show that a significant number of patients report being unemployed and having to miss work, or they meet other measures indicative of a low quality of life.

Another study of more than 1,000 MG patients from Sweden, for example, found that 47 percent of patients reported symptoms that measured 3 or more on the MG-ADL score, signaling they are not satisfied with their current disease state. An editorial that accompanied the study in Neurology in October 2021 was titled People with Myasthenia Are Getting Better, but Are They Doing Well?

While neurologists have been able to reduce mortality from MG by generally improving muscle strength, we now know that up to half of patients with MG continue to live without the adequate vigor and stamina to properly enjoy life, the editorial said.

Much of the current thinking on how to treat MG is contained in a 2020 document, International Consensus Guidance for Management of Myasthenia Gravis, which was written by an international panel of 15 experts convened by the Myasthenia Gravis Foundation.

The document, which updates one from 2016, noted that evidence-based recommendations for the treatment of myasthenia gravis have historically been difficult to develop because of limited evidence from studies with a low risk of bias such as large, well-designed randomized controlled trial studies.

The document, which predates the approval of efgartigimod, updated previous recommendations for thymectomy and also included new recommendations for the use of rituximab, eculizumab and methotrexate.

Vera Bril, MD, professor of neurology at the University of Toronto, said any treatment plan for MG has to begin with an accurate diagnosis.

One of the first steps is to decide if they have a thymoma or not because if there is, the patient may need surgery, she said. In general, thymectomy is done in patients who are AChR antibody positive and under the age of 50. Dr. Bril said research has shown that older patients do not show benefits and they are more prone to surgical complications than younger patients.

The consensus guideline recommends that for patients without thymoma who have generalized disease and are antibody positive, thymectomy should be considered early in the disease to improve clinical outcomes and to minimize immunotherapy requirements and the need for hospitalization for disease exacerbations.

Dr. Bril said that in spite of newer therapies, we still use a lot of prednisone in our patients because it is extremely effective for this disease, despite potential side effects such as weight gain, osteoporosis, and diabetes. She said options such as azathioprine and mycophenolate take a minimum of 12 months to tell if they are working. If you are waiting that long for these drugs to take effect, it takes a long time out of a patient's life.

Dr. Bril, who was an investigator for the clinical testing of efgartigimod, said the drug could one day replace the use of rapid, short-acting intravenous immunoglobulin therapy for MG. While the drug was primarily tested in patients with positive AChR antibody status, she said there is some evidence to suggest it could help those with a negative antibody status.

Gil Wolfe, MD, the Irvin and Rosemary Smith Professor and Chairman of Neurology at University at Buffalo. SUNY, and coauthor of the 2020 consensus guidance, said he sees several treatment trends emerging for MG.

The approach of many of us has changed in the last few years, whereby we try to be more aggressive with treatment earlier based on data suggesting that being aggressive at the time of disease diagnosis pays off dividends over time in terms of more favorable patient outcomes, he said.

He said there also is growing data that patients who reach certain favorable milestones earlier, such as within the first year or two after diagnosis, tend to have a more stable course long term, perhaps for decades, he said.

He predicts that another treatment approach that will become more common is the use of the newer drugs, such as eculizumab and efgartigimod, as bridge therapies.

These newer agents that work relatively quickly will be used to bridge patients while we await conventional oral therapies such as corticosteroids and the so-called steroid-sparing immunosuppressants, to take hold, he said.

He said a treatment plan that still does rely on less expensive conventional agents that have been used for several decades in MG could spare patients from some of the unique risks posed by newer therapies such as the complement inhibitors in regard to infection from encapsulated bacteria; lower overall treatment costs to the healthcare delivery system since conventional oral agents are far less expensive; and also relieve some of the provider and patient burden that is inherent for new agents that require intravenous or subcutaneous delivery.

Dr. Guidon said that as treatment options for MG continue to expand, it is going to become easier and easier to escalate treatment and we want to make sure the diagnosis is correct. She said that patients may be experiencing some symptoms not necessarily caused by MG, and it is important to establish what's in the myasthenia bucket and what is outside of it.

Dr. Guidon said understanding where a patient is in terms of disease severity and other comorbidities is also key to treatment planning. She said there also may be cost and access issues to consider because a patient's insurance may not cover a given treatment, which may reach into the hundreds of thousands of dollars.

Deciding on treatment for MG is really a collaborative effort and evolves over time, she said.

Dr. Bril has received honoraria for consulting with UCB, Momenta, Janssen, Roche, Octapharma, Grifols, Alnylam, Akcea, CSL, Ionis, Immunovant, Sanofi, Takeda, Alexion. Dr. Wolfe has been a consultant for Grifols, Alexion, ArgenX, Takeda, BPL, and UCB; has served on the speaker's bureau for Grifols and Alexion; and has received grant/research support from ArgenX, Ra/UCB, Immunovant, Roche, Alexion, Sanofi, NINDS/NIH, and the Myasthenia Gravis Foundation of America. Dr. Howard has received honoraria for serving on the advisory board of Alexion Pharmaceutics, argenx BVBA, Ra Pharmaceuticals (now UCB), Immunovant, Regeneron Pharmaceuticals, Sanofi, USA, Toleranzia AB, and Viela Bio Inc. (now Horizon Therapeutics). He has research support paid to his institution from Alexion Pharmaceuticals, argenx BVBA, The Centers for Disease Control and Prevention, Millenium Pharmaceuticals, NIH, PCORI, and Ra Pharmaceuticals (now UCB).

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Expanding Treatment Options for Myasthenia Gravis: Why... : Neurology Today - LWW Journals