James F. Howard Jr., MD, and Nicholas J. Silvestri MD, FAAN, review the role of complement inhibitors and FcRn inhibitors in the management of myasthenia gravis.
Dr. James F. Howard: Well, the last four years we've seen the development of new therapeutic strategies. Both in the two main drug classes have been complement inhibition and FcRn inhibition. I'd like to spend a few moments talking about those. But to preface it to get an understanding of what are the underlying mechanisms of synaptic failure in myasthenia. We talked about the antibody and the antibody is critically important because it can block the receptor and it binds to some determinant. And then because of the immunoglobulin molecule size, hysterically hinders transmitter, getting into the docking site. Rarely does it bind to the docking site itself. But the second mechanism is that as antibodies bind, they crosslink with each other and then actually accelerate a normal turnover process for the acetylcholine receptor. Typically, it turns over somewhere between seven to ten days, muscle-dependent species-dependent, and that gets accelerated. We get a net loss of receptors. And in both instances, we lose density of acetylcholine receptors. The endplate is a highly organized, highly architecturally defined piece of organ, if you will, with peaks and valleys. And on the tops of the mountain peaks, lie all the receptors and that was designed to increase surface area for receptor occupancy. But the third in what's now recognized as the primary pathogenic process is that binding of antibody activates complement cascade. And so, we said in motion, a very aggressive compliment attack to the neuromuscular junction. And latest therapeutics have been targeting C5. And C5 is cleaved by convertase into C5A, C5D. C5D then combines with C6, 7, 8, multiple copies of C9 inform a ring-like pour that attaches to the surface of the muscle, literally drills a hole through the tissue, leaks its contents, and we have muscle fiber death. And if enough that occurs, we then get muscle weakness. And so, the push started back in the early 2000s. Once there was a monoclonal antibody to C5 to see if it could be applied therapeutically to myasthenia originally to PNH and then to aHUS and those trials were very successful, ultimately approved for those diseases. And the start was a monoclonal antibody two C5 in myasthenia. The original trial was with a drug called eculizumab or Soliris. That's now the trade nine, and it's actually the first of three ever approved drugs to treat MG since 2017. Administered intravenously. And the beauty of the complement inhibitors has been the rapid, robust, and persistent therapeutic effects that we've seen. Ravulizumab was a cousin of eculizumab. And it was specifically engineered to alter in every two-week dosing cycle every eight weeks. It was just recently approved, and data was presented about a month and a half ago at the academy of neurology meeting demonstrating its efficacy, which was very similar to eculizumab its parent, if you will. And now will be available for use. The third kid on the block is one called zilucoplan, and it's a little different. It's still an investigational product, but rather than intravenous administration, this is subcutaneously administered on a daily basis. It's not a full-size monoclonal antibody, which has some theoretical advantages I believe. And it's administered daily, small aqueous solution. And the data that has been reported at meetings most recently at the myasthenia gravis international conference in May 2022 was that it looked as good as eculizumab, ravulizumab with a very rapid onset of action within days. Max improvement occurring somewhere around week 4, 6, 8 in that range, same as the other two, and then long-term efficacy over time. Though, that aspect of the trial is still ongoing. One of the issues with complement inhibition is that blocking C5 increases the risk for encapsulated bacterial infections. The worst of which is meningococcal meningitis. And so, patients have to be immunized and the immunization pattern is different depending upon what country you're in. In the US, we're fortunate to have two vaccines. And their particular paradigms that have to be followed to achieve proper immunization. In some countries, they only have the quadrivalent available, and in some countries, they co-administer antibiotics as long as you're on a complement inhibitor. In the US, typically, we do not though I have some colleagues who have used chronic antibiotic therapy while they're on a complement inhibitor. And we'll come back after we talk about the next class of drugs and where their role is and what we've seen in our own experience. But the second class or what we call FcRn inhibitors, the neonatal FC receptor, and you Nick have had experience with a couple of them. Give me your thoughts on those.
Dr. Nicholas J. Silvestri: Yeah, sure. Thanks, Dr. Howard. Unlike a complement inhibitor, an FcRn antagonist works a little bit differently. Just to level set for a minute. All of our IgG immunoglobulins are recycled naturally in the body. They're not made over and over again. There is a natural recycling process before they're eventually broken down. And what happens is, is that antibodies traveling in the bloodstream are brought into endothelial cells and they're brought into endosomes. And some of the IgG both pathogenic in the case of myasthenia, but non-pathogenic, normal “IgG,” some of it is bound to FcRn, the receptor in the endosome, which allows then the IgG to be recycled back out into the bloodstream. It basically prolongs the half-life, allows it to survive a little bit longer. Any IgG in the endosome that's not bound to the FcRn receptor then goes into the lysosome and is degraded. By blocking the FcRn within the endosome, it basically competitively inhibits the IgG from being bound, both pathogenic and non-pathogenic, shunting more towards degradation in the lysosome, thus reducing IgG levels both pathogenic and non-pathogenic. But for the importance of treating an antibody-mediated disorders like myasthenia or reducing the acetone receptor antibody levels. And so, one medication was recently approved to treat generalized myasthenia, and those patients that acetylcholine receptor-positive; that's efgartigimod, or Vyvgart is the trade name. And that's been on the market now for about six months, and there are at least three other FcRn antagonists in development right now in phase three trials that probably will be approved in the next year or so.
Transcript Edited for Clarity