Materia Medica

Efgartigimod Alfa-fcab (Vyvgart™): First in A New Class of Medications for Myasthenia Gravis

aRDen Kalsey, PhaRmD CanDiDate tuCKeR FReeDy, PhaRmD, BCPs

Myasthenia gravis is a rare autoimmune disease of the neuromuscular junction marked by painless, fatigable weakness of striated muscles. The pattern of muscle involvement varies between patients, but most commonly patients present with eyelid drooping or double vision. Other symptoms like weakness of the facial muscles, respiratory muscles, limbs, difficulty speaking, swallowing, and chewing can occur. This can lead to further complications like respiratory failure, aspiration pneumonia, falls, and muscle atrophy. Currently, the prevalence in the US is estimated at 14.2 cases per 100,000 people.1 The highest incidence of generalized myasthenia gravis (gMG) occurs in men > 50 years old, with a peak incidence at age 70. Women have a peak at ages 20-40, then another peak at age 70.1

In generalized myasthenia gravis the majority of patients (about 80-90%) will have antibodies against skeletal muscle postsynaptic acetylcholine receptors (AChRs).1,2 These antibodies alter the function of AChRs, promote degradation of the receptors, which then leads to destruction of the postsynaptic surface through complement activation. Because of this, muscle action potentials are unable to be generated because of the decreased number of functioning AChRs. It is thought that when the number of receptors is reduced to ≤ 30 percent from baseline, this is when the symptomatic effects of gMG are seen.1

Currently, there is no cure for gMG, however, the goal of therapy in gMG is to render patients minimally symptomatic or better while minimizing side effects from treatment. The initial therapy for most patients with mild to moderate MG is an acetylcholinesterase (AChE) inhibitor, usually pyridostigmine, which can be used long term. However, acetylcholinesterase inhibitors provide only symptomatic control and are usually not sufficient alone in gMG. Importantly, no single pyridostigmine dosing schedule fits all patients. Some patients require dosing as frequently as every 3–4 hours while awake.3 When a patient has significant persistent weakness despite the use of pyridostigmine in sufficient doses, or the side effects preclude effective dosing, then immunotherapy is generally warranted. Glucocorticoids are typically the first-line immunotherapy. Many patients with gMG require addition of a nonsteroidal immunotherapeutic agent, such as azathioprine, for maintenance therapy if they are unable to tolerate or to limit long-term steroid toxicities. Alternative immunosuppressive agents like mycophenolate mofetil, methotrexate, or cyclosporine, can also be used. It is important to note that ~10 percent of patients with gMG are refractory to these immunosuppressive agents or are limited by their specific toxicities.1

In these refractory gMG patients, treatment strategies may include monoclonal antibody therapies, such as rituximab and eculizumab. The last type of treatment for gMG is intravenous immune globulin (IVIG) or plasma exchange. These therapies are generally reserved for either severe gMG or for patients experiencing a myasthenic crisis.1

However, as of December 17, 2021, a new drug, efgartigimod alfa-fcab (Vyvgart™) hit the market. This medication is the first FDA-approved neonatal Fc receptor (FcRn) blocker - a new class of medication, for adults with gMG who test positive for the anti-AChR antibody. Efgartigimod alfa is a human IgG1 derived antibody fragment that binds to the neonatal Fc receptor, to reduce the circulating IgG and abnormal number of antibodies that attack acetylcholine receptors at the neuromuscular junction and cause weakness in skeletal muscles.3,4

The ADAPT trial5 tested the efficacy of efgartigimod alfa for the treatment gMG in adults who are AChR antibody positive in a 26-week, multicenter, randomized, double-blind, placebo-controlled trial.3 The trial enrolled 167 patients (≥18 yo) with gMG with or without AChR antibodies. Patients had Myasthenia Gravis Foundation of America (MGFA) class II to IV disease; a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of at least 5 (with > 50 percent of the score due to non-ocular symptoms) and were receiving a stable dose of at least 1 treatment for gMG (ie., AChE inhibitor, corticosteroid, nonsteroidal immunosuppressant therapy) before screening and throughout the trial. Exclusion criteria included treatment with rituximab or eculizumab within the previous 6 months; thymectomy within the previous 3 months; treatment with IVIG or plasma exchange within the previous month; hepatitis B, hepatitis C, or HIV; serum IgG level less than 6 g/L; or pregnancy. Of the 167 patients enrolled, 129 (77 percent) were AChR antibody positive.5

Patients were randomized 1:1 to treatment with efgartigimod alfa 10 mg/ kg or placebo administered once weekly for 4 weeks (1 cycle). Randomization

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From Page 27 was stratified by AChR antibody status, nonsteroidal immunosuppressant therapy, and Japanese nationality. All patients received 1 treatment cycle; subsequent cycles were administered based on clinical response (ie., when MG-ADL score was ≥ 5 [with at least 50 percent of the score due to non-ocular symptoms]. Subsequent cycles could begin no sooner than 8 weeks from the start of the previous cycle, meaning a maximum of 3 cycles was possible during the 26-week study. At the end of the study, the number of treatment cycles received was 1 in 25 percent and 31.3 percent of the efgartigimod alfa and placebo groups, respectively; 2 in 66.7 percent and 65.1 percent, and 3 in 8.3 percent and 3.6 percent.5 In the 44 responders in the efgartigimod alfa group, onset of response occurred by week 2 in 37 (84 percent) patients; duration of response was 6 to 7 weeks in 14 (32 percent) patients, 8 to 11 weeks in 10 (23 percent) patients, and 12 weeks or longer in 15 (34 percent) patients.5

The primary efficacy end point was to compare the proportion of patients who achieved MG-ADL response (defined as at least a 2-point reduction in total MGADL score compared to treatment cycle baseline that was sustained for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle) in cycle 1. 68 percent (44 of 65) of patients in the efgartigimod alfa group and 30 percent (19 of 64) in the placebo group responded (odds ratio [OR], 4.95 [95 percent CI, 2.21 to 11.53]; P<0.0001). The secondary endpoint focused on the proportion of patients who achieved a clinically meaningful improvement in the Quantitative Myasthenia Gravis scale (QMG) score (defined as at least a 3-point reduction) in cycle 1. 63 percent of patients in the efgartigimod alfa group and 14 percent in the placebo group achieved this response (OR, 10.84 [95 percent CI, 4.18 to 31.2]; P<0.0001). Additional secondary endpoints evaluated the proportion of patients who achieved early (onset by week 2) MG-ADL response in cycle 1, with 57 percent of patients in the efgartigimod alfa group and 25 percent patients in the placebo group seeing this response.5

A long-term, open-label extension study designed to evaluate the safety and tolerability of efgartigimod alfa in patients with gMG is ongoing, with an estimated study completion date of June 2023.3

Efgartigimod alfa is administered as a 1-hour IV infusion in treatment cycles. It should only be administered by a qualified healthcare professional. For adults weighing < 120 kg, administer 10 mg/ kg IV infusion once weekly for 4 weeks. For adults weighing > 120 kg, administer a maximum of 1200 mg IV infusion once weekly for 4 weeks. Administration of subsequent treatment cycles is based on clinical evaluation. Time between treatment cycles should be no sooner than 50 days. The average time between treatment cycles during clinical trials was approximately 10 weeks. If a scheduled infusion is missed, it may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed. Efgartigimod alfa must be diluted prior to administration. Dilute the withdrawn efgartigimod alfa solution in an infusion bag with sodium chloride 0.9 percent injection to make a total volume of 125 mL. Patients should be monitored during administration and for 1 hour after the infusion for signs and symptoms of hypersensitivity reactions.6

Efgartigimod alfa exhibits linear pharmacokinetics. Volume of distribution is 15-20 L and terminal half-life is 80-120 hours. Efgartigimod alfa is expected to undergo metabolism by proteolytic enzymes into small peptides and amino acids. Following administration of a single IV dose of efgartigimod alfa 10 mg/kg to healthy participants, less than 0.1 percent of the dose was recovered in urine.3,6

Pharmacokinetics of efgartigimod alfa have not been evaluated in patients with moderate to severe renal impairment. A population pharmacokinetics analysis of data from efgartigimod alfa clinical studies showed drug exposure was increased 22 percent in patients with mild renal impairment (estimated glomerular filtration rate 60 to 89 mL/min/1.73 m²) compared to patients with normal renal function. Pharmacokinetics of efgartigimod alfa have not been evaluated in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa.3,6

Efgartigimod alfa’s safety and efficacy profile was established in the ADAPT trial.5 In this study, most adverse reactions were mild or moderate in severity. Severe adverse reactions occurred in 11 percent of patients who received efgartigimod alfa and 10 percent of patients who received placebo. Adverse reactions related to infection occurred in 46 percent of patients in the efgartigimod alfa group and 37 percent of patients in the placebo group. Three serious adverse events related to infection occurred, influenza and pharyngitis in the efgartigimod alfa group and upper respiratory tract infection in the placebo group. Infusion-related reactions occurred in 4 percent of the efgartigimod alfa group and 10 percent of the placebo group; all were mild in severity.5

During the ADAPT trial, 77 percent of patients who received efgartigimod alfa and 84 percent of patients who received placebo had a treatment-emergent adverse event. The most common adverse reactions in patients receiving efgartigimod alfa were respiratory tract infection, headache, urinary tract infection, paresthesia, and myalgia.5,6 Monitor for clinical signs and symptoms of infection during treatment with efgartigimod alfa.6

Studies evaluating immunization with vaccines during efgartigimod alfa treatment have not been conducted. The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Because efgartigimod alfa is associated with a decrease in IgG levels, administration of live or live-attenuated vaccines is not recommended during treatment. Clinicians should evaluate the need for administration of age-appropriate vaccines according to immunization guidelines prior to starting a new treatment cycle of efgartigimod alfa.6

Hypersensitivity reactions (e.g., rash, angioedema, dyspnea) have occurred with efgartigimod alfa. Reactions were mild or moderate in severity, occurred within 1 hour to 3 weeks of administration, and did not lead to discontinuation of efgartigimod alfa treatment. Patients should be monitored for 1 hour after administration for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs during administration, the efgartigimod alfa infusion should be stopped and appropriate supportive measures should be initiated.6

No formal drug interaction studies have been performed with efgartigimod alfa. It is not metabolized by CYP-450 enzymes; therefore, interactions with agents that are substrates, inducers, or inhibitors of CYP-450 enzymes are unlikely.6 Use of efgartigimod alfa with agents that bind to FcRn (e.g., immunoglobulins, monoclonal antibodies, antibody derivative containing the human Fc domain of IgG) may decrease systemic exposure of these medications and reduce effectiveness. Closely monitor for reduced effectiveness of these medications if efgartigimod alfa is used concomitantly. If concomitant long-term use of agents that bind to FcRn is unavoidable, consider discontinuing efgartigimod alfa and using alternative therapies.6

There is no data on the use of efgartigimod alfa during pregnancy in humans. However, when administering very high doses of efgartigimod alfa (100 mg/kg/day) to pregnant rabbits and rats in animal studies, no adverse outcomes were observed. Because there is limited data the risk vs benefits of use during pregnancy should be weighed. Also, efgartigimod alfa was not studied in lactating women and children while on efgartigimod alfa, but maternal IgG is known to be present in human breast milk.3,6

It is estimated that efgartigimod alfa IV solution (400 mg/20 mL) will cost around $7,140 per (400 mg/20 mL) vial.3 For an 80 kg patient, this means that for one infusion a patient would require 2 vials or approximately $14,280 per weekly infusion and $57,120 for 1 cycle.3

Conclusion

Generalized myasthenia gravis is a rare condition that is not fully understood and for which there is no cure. Current therapies should be individualized based on symptom control and other functional limitations but are often limited by unfavorable adverse effects. Efgartigimod alfa is indicated for the treatment of generalized myasthenia gravis in adults who are anti-AChR antibody positive. It has a novel mechanism of action involving selective IgG reduction through FcRn blocking and data from the phase 3 clinical trial suggest that it is an effective and well-tolerated treatment. Acetylcholinesterase inhibitors and other immunosuppressive agents will still be used as initial therapy but efgartigimod alfa can be a beneficial option for patients who do not respond adequately on these first-and second-line treatment options.

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Ms. Kalsey is a Doctor of Pharmacy candidate at Duquesne University School of Pharmacy. Dr. Freedy is a Clinical Pharmacy Specialist in Medicine and Drug Information at Allegheny Health Network, Allegheny General Hospital. For any questions concerning this article, please contact Dr. Freedy at the Allegheny Health Network, Allegheny General Hospital, Center for Pharmaceutical Care, Pittsburgh, PA. (412) 359-3192 or email tucker.freedy@ahn.org