Alexion: ICER Releases Draft Evidence Report on Therapies for Myasthenia Gravis

 Executive Summary 

Myasthenia Gravis (MG) is an autoimmune disease that affects the neuromuscular junction. The prevalence in the United States is estimated to be between 14 and 20 per 100,000 people1,2 and the annual incidence is approximately 2.2 per 100,000.3 The characteristic finding of MG is muscle weakness that worsens with repeated use (“fatigable weakness”).4 With progressive disease, treatment typically includes high-dose corticosteroids combined with or followed by “steroid-sparing” immunosuppressive drugs (most commonly azathioprine and mycophenolate mofetil [MMF]). The goal of therapy is to maintain the patient with minimal manifestations (MM) of disease (no symptoms or functional limitations from MG despite minimal weakness on examination) or better.5 Currently, about 20,000 patients with generalized MG are intolerant or have an inadequate response to conventional treatment options.6

 In this Report, ICER reviews eculizumab, a monoclonal antibody, and efgartigimod, an immunoglobulin fragment that targets the neonatal Fc receptor. Eculizumab received US Food and Drug Administration (FDA) approval in October 2017 for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-AChR antibody positive, 7 and an FDA decision on efgartigimod is expected on December 17, 2021.8 We identified one Phase III trial each for eculizumab (REGAIN) and efgartigimod (ADAPT) but found insufficient data to compare these drugs to maintenance intravenous immunoglobulin IVIG and rituximab (RTX). In the Phase III REGAIN trial, patients with anti-AChR antibody positive, treatmentresistant gMG who received eculizumab had significantly better improvement in the myasthenia gravis activities of daily living (MG-ADL) and quantitative myasthenia gravis (QMG) scores than those on placebo at four weeks and eight weeks (Table ES1), and the improvements were sustained at 26 weeks. In addition, at week 26, the proportion of patients with minimal symptom expression (MG-ADL score of 0 or 1) was much greater in the eculizumab group (21.4% vs. 1.7%, p=0.0007).9 In the open label extension through 130 weeks of follow up, the benefits were maintained, and may have increased compared with 26 weeks.10 There were no excess adverse events (AEs) in the trials, although more patients in the eculizumab group stopped treatment due to AEs, and it carries a black box warning for meningococcal infections. 

The Phase III ADAPT trial was conducted in gMG patients with or without anti-AChR-antibody; however, the primary outcome was in the subgroup of anti-AChR antibody positive patients. The proportion of patients with clinically meaningful improvement (≥2-point MG-ADL improvement sustained for ≥4 weeks) was much greater in the efgartigimod group compared to the placebo group. Anti-AChR antibody positive gMG patients who received efgartigimod did significantly better on MG-ADL and QMG than those who received placebo (Table ES1). However, the improvements were greater at four weeks than at eight weeks, reflecting the unusual dosing schedule in the trial.

Patients received their second treatment cycle only when they no longer had a clinically meaningful improvement on the MG-ADL. Thus, many patients were back near baseline at eight weeks. The anti-AChR antibody negative patients randomized to efgartigimod were only slightly more likely to respond based on the MG-ADL (68% vs. 63% in placebo group, p=NR). AEs did not appear to be more common with efgartigimod, but there are long term concerns about infections with lowering of IgG levels. 

One important area of uncertainty is that it is not clear if or when to stop either of the drugs in patients who are responding to them. For efgartigimod, the primary uncertainty is the appropriate dosing regimen. In the ADAPT trial, subsequent cycles were started once patients lost clinical benefits. It seems likely that in routine practice, patients and clinicians will not want to wait until the benefits have receded before starting another round of therapy. Also, despite their use in clinical practice, there is a lack of comparative efficacy data for both rituximab and IVIG used as maintenance therapy for gMG. Taking into consideration the above information on the benefits and AEs of eculizumab, we believe there is moderate certainty of a small or substantial net health benefit with high certainty of at least a small benefit for eculizumab added to conventional therapy (B+) in adults with gMG positive for anti-AChR antibodies “refractory” to conventional therapy. For efgartigimod, given the uncertainties about dosing and consistent long-term benefits of therapy, we concluded that there is moderate certainty of a comparable, small, or substantial net health benefit of efgartigimod added to conventional therapy with high certainty of at least comparable net health benefit (C++) in adults with gMG positive for anti-AChR antibodies. While there is evidence for efgartigimod in adults with gMG negative for anti-AChR antibodies, it is sparse and of uncertain clinical and statistical significance. Thus, we concluded that the evidence was insufficient (I) to distinguish the net health benefit of efgartigimod added to conventional therapy from conventional therapy alone in patients who test negative for anti-AChR antibodies. In addition, the evidence is insufficient (I) to distinguish the net health benefits of rituximab and IVIG from placebo, eculizumab, and efgartigimod. In economic modeling, we evaluated the cost-effectiveness of (1) eculizumab plus conventional therapy versus conventional therapy alone in patients with refractory anti-AChR antibody positive gMG as defined in the REGAIN trial and (2) efgartigimod plus conventional therapy versus  conventional therapy alone in the patients with gMG including those with or without anti-AChRantibody. 

The analyses were conducted over a two-year time horizon, taking a health system perspective. Based on an annual cost of $470,200, the incremental cost/QALY and incremental cost/evLYG for eculizumab were estimated to be $3,746,000. For efgartigimod, using a placeholder price of $286,100, the incremental cost/QALY and incremental cost/evLYG were estimated to be $1,426,000. The model was sensitive to several inputs, including the utility values assigned to improved and unimproved MG and the proportion of patients achieving at least a 3-point reduction in the QMG for efgartigimod or its comparator, or eculizumab and its comparator. However, despite the large impact of changing these inputs on the results, the incremental cost-effectiveness ratio was never less than $2.5 million per QALY gained for eculizumab and $1.14 million per QALY gained for efgartigimod. In addition, the results of the probabilistic sensitivity analysis and scenario analyses had similar cost/QALY estimates. There are other potential benefits and important contextual considerations not fully captured in the economic model. For example, MG is a serious, lifelong disease with life-threatening manifestations, and most patients do not achieve treatment goals with conventional therapy. Additionally, there is potential to improve childbearing and career opportunities for women who are often diagnosed early in their lives. This is particularly relevant for Black women who typically present at younger ages and may have a more severe disease course than other patient groups. In conclusion, both eculizumab and efgartigimod significantly improve function and quality of life for patients with gMG. However, at the current price for eculizumab the estimated costeffectiveness is well above typical thresholds; the cost-effectiveness of efgartigimod will depend on its actual price.

https://icer.org/wp-content/uploads/2021/03/ICER_Myasthenia-Gravis_Draft-Evidence-Report_072221.pdf