Use of Biologics in Myasthenia Gravis
Nicholas Silvestri, MD, FAAN, shares clinical results with eculizumab and ravulizumab, as well as which patients should use biologics and when during the treatment journey.
Nicholas Silvestri, MD, FAAN: In terms of data regarding eculizumab and ravulizumab, for eculizumab, the phase 3 trial was REGAIN. That study was published, I believe, in 2017. The drug was approved [for generalized myasthenia gravis] in 2017 and I believe the paper was published around that time as well. They looked at a group of patients with fairly severe myasthenia gravis—patients who had disease for quite some time that was not fairly well controlled. Thankfully, in the trial, there was a statistically significant difference in QMG [quantitative myasthenia gravis] score and a trend toward significance in the MG-ADL [myasthenia gravis activities of daily living] score. The medication was safe, it was well tolerated, and patients responded quite well—the majority of them, compared with placebo. In the open-label extension portion of that trial, which was subsequently published, those on placebo were given eculizumab and also responded quite nicely over time. Regarding ravulizumab, their phase 3 trial was CHAMPION MG. That was published, I believe, last year. I recall that ravulizumab is essentially the same medicine as eculizumab except it is slightly chemically altered to have a half-life of 8 weeks as opposed to 2 weeks. So, it’s an every-8-week infusion as opposed to eculizumab, which is an every-2-week infusion. The CHAMPION MG trial looked at patients that had more moderate to mild myasthenia gravis rather than severe disease, unlike the REGAIN trial. Thankfully, it also showed a benefit in that particular population. Again, those patients who were treated with ravulizumab vs placebo had statistically significant changes for the better in the MG-ADL and QMG scores. Then, in the open-label extension portion of the trial when patients initially on placebo were given ravulizumab, they thankfully also improved, similar to the patients in the first portion of the trial who initially received ravulizumab.
In terms of the modes of administration of the recently approved therapies, they’re all intravenous. Eculizumab is given as 4 initial doses every week, followed by every-other-week dosing thereafter—so, every 2 weeks thereafter. Ravulizumab is given as 2 doses 2 weeks apart, and then after that it’s given every 8 weeks by intravenous infusion because of its prolonged half-life. The dosing of efgartigimod is a bit different. It’s intravenous, but every round of therapy is 4 weekly infusions. Following that, reinfusions are done as clinically indicated per the package insert. Most of us prescribing efgartigimod are prescribing it in more of a set manner. I will typically prescribe it 4 weeks on and then 4 weeks off for 3 cycles or 3 rounds of infusions. After that, I’m trying to adjust the interval between the doses to find out what that particular patient might need on their own personalized basis. Some of the medications in the pipeline have a slightly different route of administration. I had mentioned that efgartigimod will probably be coming out as a subcutaneous formulation soon. There are other medications in the pipeline, including a subcutaneous complement inhibitor called zilucoplan, which is up for FDA approval at some point this year as well.
In terms of when to use a biologic in a patient, I think that it depends on a lot of different factors, as I mentioned before. In that mild to moderate patient with myasthenia gravis, I’m typically using a steroid bridge to an oral immunosuppressant. And should a patient fail that line of therapy, then I move on to a biologic, likely after efgartigimod or following ravulizumab. If a patient has a more severe disease course and I want to get better control of their disease early on to mitigate risk, I may use a biologic earlier on in that patient’s therapy, again, either after efgartigimod or ravulizumab.
In terms of nonresponders to the available agents that we have today, if you look at the trials, you’ll see there are nonresponders in the trials. So, it makes sense that you’re going to see those in clinical practice as well. In my own personal experience, thankfully, I’ve had a small number of nonresponders to treatment with efgartigimod. I’ve also had a small number of nonresponders to ravulizumab. In those cases, if a patient hasn’t responded to one of those, they may respond to another. I haven’t yet run into a patient who’s not responsive to either efgartigimod or ravulizumab/eculizumab. If I were to run into those patients, I may start to think about using chronic plasma exchange, which is inconvenient for patients. I could also consider using chronic intravenous immunoglobulin, though I don’t think it’s as effective as efgartigimod or ravulizumab. I could consider use of rituximab, but that’s effective mostly for patients with MuSK [muscle-specific tyrosine kinase] myasthenia gravis, or I might consider trying to stabilize patients with one of those agents while they await something in the pipeline.
Transcript edited for clarity.
