Welcome back for week two. This week we have two outstanding talks from leaders in the field. Our first session is Therapeutic Landscape and Novel Therapies for Myasthenia Gravis, presented by Dr. Gil Wolf. Dr. Wolf is a neuromuscular specialist with decades of clinical and research experience in the field of Myasthenia Gravis. He's the Irvin and Rosemary Smith Endowed Professor and Chair at the Department of Neurology at State University of New York, University of Buffalo, Jacobs School of Medicine and Biomedical Sciences. Please enjoy his wonderful talk. Hi, my name is Dr. Gil Wolf. I'm a professor at the University of Buffalo, and my talk today is on the Therapeutic Landscape and Novel Therapies for Myasthenia Gravis. I have the following relevant financial relationships to disclose, and as far as off-label use of medications, and there's going to be quite a bit in this discussion, but all agents except for the acetylcholinesterase inhibitors and ecolizumab are either not approved or investigational in the treatment of Myasthenia Gravis. This is a single slide summary of MG. The prevalence is around 1 in 10,000 in most series. It is our most common defined neuromuscular junction disorder. The clinical features of it involve fatigable muscle weakness involving specific muscle groups. It worsens with activity. It's kind of the classic fatiguing disease in neurology. It improves with rest. In fact, rest was the first treatment for Myasthenia Gravis. Ptosis and diplopia eventually in 90% of patients, about 50% present with those. Only 15% of patients, according to the old historical literature, remain purely ocular. It's probably higher than that now. If patients do generalize, they usually do so really in the first two years, first two to three years, and it has sort of a proximal presentation mostly, although there are case series. In fact, our group wrote one up a few years ago of distal predominant Myasthenia Gravis, respiratory weakness in about a third of patients. Respiratory weakness is more common in musk MG. It's twice that full, 50% to 60%. Then just a quick slide showing that we have improved the therapies over time in MG. This was David Grove's work. You can see over these different decades of time that he had patient records for, you can see the deaths from MG did decline significantly. The improvements, the patients that improved over these periods of time also went up significantly. What didn't change very much is this clear white bar of those who were actually in remission. Another point of the paper that was made, because I'm not going to discuss any new developments in thymectomy in this talk, it's all going to be pharmacologic agents, but if you look at a sort of secondary aspect of the paper, the impact of thymectomy on remission seemed to decline from the records that he had. I realize this was all retrospective and so forth. A large group that I helped direct along with several others did show the clear benefit of thymectomy in acetylcholine receptor antibody positive generalized MG. I'm going to show you a couple of slides here that kind of give you a pattern of how we develop therapies in MG and in other diseases. This was a case report from our colleague, Dr. Evely, in Rome. She had an MG patient who was diagnosed at age 13, poor periodostigmine tolerance, had a thymectomy at 25, deteriorated at a pregnancy at age 34. She actually worsened with periodostigmine again. She did have some benefit from prednisone. It was only found later when musc antibody testing became available that she was musc positive. What she found is that these persistent symptoms of ptosis, facial, neck extensor weakness, dysphonia, they did transiently improve with a plasma exchange. The 3,4-diaminopyridine 10 milligrams QID did improve much of these symptoms and signs with subjective improvement in breathing and speaking as well. The animal models, because there's been concern of a postsynaptic kind of end plate myopathy with too much stimulation in these types of patients, but that has not been shown with 3,4-diaminopyridine in the mouse model. There is potentially this presynaptic issue in musc MG specifically along with the postsynaptic impairment where 3,4-DAP might help. That led to this double blind placebo controlled trial that was published a couple years ago. Seven days per each treatment period. It wasn't a large study. They ended up having seven patients randomized. The typical mean dose was about 45 milligrams per day. The max allowed was 60 milligrams a day. The primary outcome, the QMG, went down significantly as did the MGADL with very significant P values in this small population with the strength of a crossover study on the 3,4-DAP versus placebo. The secondary outcomes, the MG composite, the Carlo Vesta neurologic impairment score, all those also favor the amifampridine as well. No significant adverse events, no severe ones, just some mild paresthesia, which is a well-known side effect. You can see where little small observations can lead to a trial in MG. What are the unmet needs in MG? We have 10% or so of patients who are refractory. 20% of patients have problematic adverse events is the estimation from my experience and others. MUSC-MG patients can be more refractory. MG during pregnancy would be nice to have further therapies. MG crisis when IVIG or plasma exchange are not effective. Many medical centers now don't even have plasma exchange. Perhaps something that is more persistent. Also, another unmet need that we're talking about now is this bridge period where we're often having to use higher doses of prednisone than we would like before, say, a non-steroid immunosuppressant starts taking effect, which can be months to even a year or so, as you know. Hopefully, over time, this unnamed variable, this is straight out of the International Treatment Guideline that I was involved with, that the use of a specific newer agent as maintenance therapy should be considered for patients with refractory MG and those where immunosuppressant medications are contraindicated because of comorbidity or pregnancy. Then we'll have more things plugged in there for maintenance therapy or for this bridging period of time, as I mentioned before. So now let's go to the therapies. And we're going to start with the B-cell therapies. I am not going to talk about bolimumab, but the two starred agents here actually have had formal studies behind them. The bolimumab study failed on the QMG, the MGC, the MGADL. It did not show a significant impact. It included must patients as well as receptor antibody-positive patients. But I'll go through the rituximab literature. And obviously, these are drugs that are having effects on the B-cell and its descendants, plasma cells, and so forth, that make antibodies. And so the rituximab story, it didn't start right here, but it's been going on for quite a while. But this was one of the first larger series of both receptor antibody-positive and musk antibody-positive patients who really were not doing well on conventional therapy. And they used the typical dose, which is stated here. And they found that basically all these patients, except for one with receptor antibodies, improved. And they didn't have to have any reinfusions after the initial three months of therapies in the musk patients. They needed in about half of the receptor antibody-positive reinfusions. They had long follow-up, two to three years. Patients did well. One of the other larger retrospective looks that was published in Muscle & Nerve a few years ago by Riptandin's group, what you found here was an accumulation of a large number of patients, from single case reports and from small series. And getting to the crux of the matter here, as far as patients who were having relapses before versus after the rituximab therapy, you can see that the numbers went down dramatically, from 93% of receptor antibody-positive patients to just 33%. All musk patients were having relapses only 14% after the rituximab therapy. The fatal response predictors were if you're musk antibody-positive. That's been seen in quite a few pieces of the literature that musk patients, where it's an IgG4 antibody, particularly seem responsive to anti-B cell therapies. A younger age, more moderate disease, neither antibody levels were predictive of whether you responded or not. It was tolerated quite well. Flushing was seen in three patients. All others of these 15, there was an adverse event that appeared only once in that population. There was a reactive herpes zoster infection in one patient. So here we are seeing a very, very nice true retrospective, but a nice response to rituximab. Another study, this was a prospective review where they actually had blinded evaluators look at charts on patients who got rituximab. This was only in musk MG patients. It included 55 patients who were treated over this decade of time. 24 of those 55 received the rituximab, so there were 31 controls, and the baseline characteristics were similar between these two groups. The primary endpoint in Michael Harer's paper was this MG status and treatment intensity. What he was looking for is a level of 2, 1, or 0 is considered favorable. What is a level 2? It requires patients to be in minimal manifestation status from MG, which is a well-defined preferred outcome measure. On relatively low doses of these different medications that you can see here, for instance, prednisone less than 20 a day, mycophenolate less than 2,000 a day, and so forth. So two or less. This is what they found. This was the baseline up here. The final visit on this outcome measure, everything in green to the left is good. That's a score of 2, 1, or 0. You could see there was a significantly larger proportion of patients who got the rituximab with those scores than there was in the control. These are the actual numbers here. That was a significant p-value. The number needed to treat to hit that outcome was 2.4. That's a pretty low number needed to treat. As far as prednisone at the last visit, only 29 percent of rituximab patients versus 74 percent of controls were on prednisone. There wasn't a lot of adverse event data published in this paper, but there was one non-responder who had an adverse event after initial dose of rituximab. This excitement about rituximab obviously led to the Neuronext trial, the BEAT-MG trial. This recruited MGFA MG grades two through five, so mild generalized or worse MG. Prednisone was greater than 15 milligrams a day or equivalent on alternate days with a stable dose for 30 days. They were allowed to stay on their immunosuppressants as long as they were on a stable dose for six months. Those were continued during the trial. They couldn't have platelet exchange or IVIG for four weeks. The primary outcome was a steroid sparing effect requiring at least a 75 percent drop in prednisone at the end of basically the year. They also looked at safety. The prednisone tapering here was as long as patients were felt to be stable by the investigator, they were on this regimen of prednisone tapering, and that may have had something to do with the non-significant findings, which are here. They recruited 52 patients. The mean prednisone dose at the end was 24 milligrams of rituximab and 22 milligrams on placebo. Sorry, that was at the beginning of the study. The primary outcome response rate, that 75 percent prednisone reduction was basically the same between the two groups. This showed futility for rituximab and its ability over a year to lowering prednisone more than just a prednisone alone regimen. You can see the secondary outcomes. They looked a little bit better on rituximab, but these were not of significant differences. Again, the lower, the greater the drop, the lower the number on the MGC or the QMG, the better you're doing as far as MG is concerned. No significant safety issues. That's where we are with the B-cell therapies. I know rituximab is off-label. It is still used in MG. I think a lot of us feel it is helpful in musk MG in particular. That paper has not been published formally yet from the Neuronext trial, but it should be fairly soon. We're going to turn now, since we've talked about these, to the complement-mediated agents. Echolizumab is now approved in MG. It is a humanized monoclonal antibody that binds to C5. It prevents the cleavage to C5a and C5b that have pro-inflammatory, pro-thrombotic effects respectively. C5b is that first component that makes the MAC, the membrane attack complex, or what's now also called the TCC, the terminal complement component. It's already indicated for PNH, paroxysmal nocturnal hematuria, and hemolytic uremic syndrome. A Phase II study that was small, double-blind, crossovered, enrolled 14 patients. This was published in Muscle & Nerve now seven years ago. These patients were some of the toughest patients we ever recruited into an MG trial. That was also true of the Phase III study that we'll look at in a second. They had to have moderate to severe weakness despite two immunosuppressive regimens, including primosome, for at least a year. In Period I, before the crossover in this Phase II study, there was a signal of Echolizumab having an effect. This is the drop in the MGADL. It was greater for Echolizumab than placebo in Period I. Period II was harder to interpret because there seemed to be a carryover from the initial period of treatment to the second period. Part of this also led to the MGADL being used as a primary outcome in the Phase III study, which is here. This was a 26-week duration study. It had somewhat looser entry criteria than the Phase II regarding plasma exchange and IVIG. It used a slightly higher dose, 900 milligrams a day, initially weekly, and then it went to 1,200 milligrams every other week. That's actually how it is labeled. It is, over time, still an every-other-week medication, according to the label. The MGADL was the primary outcome. It didn't miss by much, but it missed on the worst-rank analysis a certain statistical model that had not been evidently utilized in neuromuscular trials until that point. 18 out of 22 pre-specified endpoints had a p-value of less than .05 based on a primary and five secondary outcomes. That included the worst-rank analysis for the QMG was at a p of less than .05 and responder analyses for MGADL and QMG that I'll show you on this slide. This is showing you the proportion of patients who had this amount of point drop on the MGADL or the QMG with placebo in red, ecolizumab in blue. You can see the bars are wider for ecolizumab than they were for placebo, showing a greater response as far as these different point reductions in these scales for the active medication. This was of significant p-values as shown here. And then there was a longer-term open label study, although realize these initial here, so patients who were on placebo were then crossed over after that six-month period of time, and just like you saw initially a pretty rapid drop with blue again being the active meds, here when they crossed over from placebo again you saw a very rapid drop and realize these assessments were done blindly. The evaluator didn't know what the patient's treatment experience had been in that initial 26-week period of time. And again, this was showing significant impact of ecolizumab. And on the right here is showing MG exacerbations, crises, worsening of disease measured in 100 patient years, pre-study in dark blue, and then placebo versus ecolizumab in red and light blue respectively. And you can see nice drops with significant p-values and lowering the need, lowering the amounts of exacerbations and worsenings of disease measured in 100 patient years. These were the long-term study adverse events. And you could see here headache and nasopharyngitis were the two most common. You can see headache with this agent. I've seen it in clinical practice. But it has been pretty well tolerated. We'll get to the meningococcal vaccination in just a second, okay? But there was one case in this paper of meningococcal meningitis after the data lock. It resolved with antibiotic therapy, stopping the ecolizumab, obviously. The company is looking at Revolizumab, which was approved in late 2018 for a typical HUS, hemolytic uremic syndrome. This offers every eight-week administration instead of every two-week administration, and a phase three trial in MG is underway. So we have something that's given intravenously to Block C5. There's also an agent that's subcutaneous, the LeucoPlan, which is a macrocyclic peptide. And a phase two study has been completed, and a phase three study is underway. This is the phase two study. It was placebo versus 0.1 versus 0.3 milligrams per kilogram. Again, double-blinded. You can see the entry criteria. This trial did not restrict patients to refractory generalized MG like the ecolizumab studies did, but they were still pretty bad MG patients, as I'll show you. The primary outcome was a change in QMG to week 12 with the typical secondary outcomes as mentioned here. Here, the baseline QMG was very similar to the ecolizumab studies, 18. That's pretty high. I can tell you it was 12, 13 or so in the thymectomy trial. That's typically where you are in most trials for MG, but this was up in the high teens, worst disease status basically, and a long-term disease durations, eight years. I'm only showing the 0.3 milligrams per kilogram dosing responses. 0.1, there was trends largely, but you can actually see significant p-value reductions in just a few weeks on active versus placebo, both on the QMG and the MGADL from this phase two study. Here again is this responder, a Christmas tree analysis. Again, maybe not quite as obvious as what I showed you with the ecolizumab. Again, this is a smaller study, but you can see somewhat wider bars for these different point reductions of QMG and the MGADL. Obviously, every patient above here is included in these lower bars too. This is cumulative. This is looking at minimal symptom expression, which would be an MGADL score that's perfect at zero or one. It's a score that goes from zero to 24. It's an eight item scale. It takes 90 seconds to do. I do it routinely in my clinic. You can see here a higher proportion of patients hitting that minimal symptom expression by week 12 with both of the doses of Zolucoplan versus placebo. Again, an open label extension, just like we saw earlier. You can see once patients on placebo are switched over to the active drug, which occurred at week 12 here. Again, you see these quick reductions in their QMG or MGADL score with significant p-value. As far as side effects, this subcutaneous single injection agent has been pretty well tolerated. You can notice here, patients requiring rescue with IVG or plasma exchange, three needed it in the placebo arm, one at the low dose and none at the higher dose. You can see the rest of the adverse events, some bruising, some contusions, headache. Again, headache can be seen with a lot of injected or infused medications. Okay, so this is the Advisory Committee on Immunization Practices for Neisseria meningitides. Complement is crucial for fighting off encapsulated bacterial infections that includes Neisseria species. So there is the ACWY, the quadrivalent, two forms of that. You can see the dosing is the same for the two different brands. Initial two doses separated by two months with a booster five years later. For meningitis B, you cannot substitute one for the other. For the Bexsero, it's initial two doses separated by one month. For Trumenba, it's three doses at zero, one, and two months. And then another, sorry, at zero, one to two months, and then another at six months. So those are the three doses and then a booster at a year to cover these five different variants of Neisseria meningitides. Okay, so that's the end of the complement discussion. Now we're going to move on to anti-FCRN, neodatal FCR receptor strategy. So, the FCR, needle FCR receptor is crucial for recirculating IgG. It comes into these endosomes and in an acidic environment, IgG binds very tightly to FCRN and then the endosome releases it back, which is why IgG lasts in our systems quite a while, longer than other immunoglobulin species, in fact. Now, if it doesn't bind to this FCRN receptor, then the unbound protein, the IgG gets degraded in the lysosome, okay? So, if you can block this binding, then you may send more IgG this way into the lysosome to be degraded. That is the goal of anti-FCRN therapy and there's several of these agents that are available being tested now and I'll go through that data, but it's somewhat akin to plasma exchange. It lowers IgG subtypes by 70 percent. The agents are available intravenously or subcutaneously, those are that are being tested. It offers greater convenience and availability than plasma exchange, potentially with fewer complications, and it could have efficacy across various Mg antibody subpopulations as well. So, the one with the most data out, in fact, with the only formally published data to this point, is F-gartigamide, which is an IgG1-FC fragment. So, in this phase 2 study, 24 receptor antibody positive generalized Mg patients with impaired ADLs were randomized. They got four weekly, 10 milligram per kilogram, infusions versus placebo. They were continued on their prior therapy at stable dosing. The primary assessment here was safety and you can see the secondary outcomes and this has now been published as of last year in neurology. It was well tolerated, no significant adverse events, all eight E's were basically mild except for a couple. They did see headaches at 33 percent versus 25 percent and a few other side effects that were less than 10 percent. Again, a case of herpes zoster on the active arm. That patient was also on prednisone and mycophenolate, by the way. So, as far as secondary outcomes, and you'll see this a lot, at least a two-point drop in Mg ADL is what is looked for and they look for this as an efficacy outcome in this study. 75 percent of F-gartigamide patients versus 25 percent on placebo hit it for at least six consecutive weeks and that was a significant p-value difference. The clinical benefit at one week correlated with rapid IgG level drops. Again, you can see responses seemingly in one or two weeks with these agents. The largest IgG level drop was at five weeks. Remember, they got four weekly infusions for the first four weeks. Receptor antibody levels went down significantly except for one subject, 40 to 70 percent down, and all the Mg scales showed improvement over placebo at certain week periods, and you'll see that on the asterisks on this slide for the QMG here, for the Mg ADL here, and for the quality of life 15 are here. So, not every one of them hit a significant p-value at each of the time points, but quite a few of them did, and here you can see the responder analyses again for Mg ADL day 29 and day 36 with F-gartigamide in the light green. Okay, so a phase three ADAPT trial has now been publicized through a press release. This again was 10 milligrams per kilogram IV QE for four weeks versus placebo, and here you can see the outcomes which were just publicized in May. The Mg ADL greater than two point drop in 68 percent versus 30 percent of placebo. QMG at least a three point drop was looked at, 63 versus 14 percent. This was a secondary outcome, and again that minimal symptom expression that I mentioned before, 40 percent versus 11 percent. All the different Mg antibody subgroups responded. This included not just receptor antibody positive patients. Onset in the first two weeks was 57 percent versus 25 percent based on that Mg ADL outcome, and it was well tolerated. 28 percent with headache in both groups. There were actually fewer significant serious adverse events on the active treatment, and here you can actually see now another agent that's being tested, rosanolixizumab, often called rosamab for short. This was a phase two UCB trial that was publicized in 2018 and presented at the academy meeting last year. It's a humanized IgG4 monoclonal antibody. These are sub-q infusions. Period one was seven milligrams per kilogram versus every week for three weeks every week for three weeks versus placebo, and then they changed the dosing after a crossover to active agent, either four milligrams per kilogram or seven milligrams per kilogram. They did see headaches quite often versus placebo in period one before everybody ended up on active drug. You can see the QMG, the primary, they missed the p-value. They also did on the Mg composite. Mg ADL, however, hit a significant p-value. The responder rates of at least three point drops were significant only for the Mg ADL. You can see for the QMG, the responder rate of at least a three point drop was 38.1 percent with active versus 22.8 percent placebo, but that did not hit a significant p-value, and here you can actually see in the first basically four weeks of the trial, this was active versus placebo, and yeah, you can sort of sense a separation after two weeks, and this is all the different arms with the first month scrunched here, okay, all right, but then again switching over to either four or seven milligrams after. If they continued on seven Mg, it was in light green. Orange was when they went to four Mg, but here they actually got seven milligrams per kilogram. These are small numbers in each of these different treatment arms, only about 10 patients, but for whatever reason you didn't see this drop even at the seven Mg per kg versus placebo in that particular group, but you know, we need larger studies basically. There's another agent, Nipah Calamab, which is a human IgG1 that again binds to FCRM, and this was an eight-week study using again either Q4 weeks or Q2 week infusions, and the dosing here was different across the different arms versus placebo, and again this has only been by press release so far, but what they found is the MgADL of a greater than two point decline was seen in 52% across these active arms versus only 15% on placebo. That was a significant p-value. The MgADL reduction seemingly like with the other agents was, you saw a response within two weeks. There were no significant, sorry, no serious adverse events, okay, so that's the end of the FCRM antagonism story for now, okay. There's some other agents where no data has been released so far that are still being tested. I want to just talk about a couple of other things very, very quickly. JAK-STAT blockers, okay, which allow for CD4 stimulation and also IL-6 blockers. IL-6 does a variety of things on the B cell and the T cell side of things, but one thing that it does is it stimulates B cells via CD4, a release of interleukin-6, so that could reduce potentially antibody production from the B cell family. Tokalizumab is a IL-6 receptor blocker. Again, it can reduce autoantibodies. It's been approved for several arthritic disorders. It's being tested in NMO. Adverse events, the bad ones, perforated diverticulitis and nasopharyngitis can occur, so two women with receptor antibody positive MG who had failed just about everything, steroids, azathioprine, had had thymectomy, mycophenolate, IVIG. They even got rituximab, although it was fairly low dose. They got tokalizumab, IV, six to eight milligrams per kilogram, monthly times three, followed by the sub-Q injection every one to two weeks. Their QMG scores fell either seven points or 50 points. Those are big drops in tough patients. There was uncomplicated nasopharyngitis. That was published a few years ago. As far as the JAK-STAT pathway story, again, this dry CD4 positive T cell differentiation. It's been approved for myelofibrosis, which is how the case report came about. It's had some promising data in alopecia areata and rheumatoid arthritis, but this was a 70-year-old woman with musc antibody positive MG, stable dysphagia, facial and neck weakness. Her QMG, it wasn't a terrible score. It was seven, but she had this stable weakness. It just didn't get better, but she also had myelofibrosis and papirazine and aspirin was stopped. She had no response to hydroxyurea for the myelofibrosis, so they gave her ruxolitinib since it's labeled for that. It's a PO drug. She got 10 milligrams BID. It improved her blood parameters, but it also resolved all her MG weakness. Her musc antibody became undetectable. Her single fiber EMG, her JITR normalized as well. Just a food for thought of other pathways that may come into play in the next few years in MG. This is a summary of different agents being looked at in MG and even in some other neuromuscular disorders like CIDP, immune-mediated necrotizing myopathy, or dermatopoly. Tocilizumab is actually being looked at in a phase three study, the IL-6 receptor antagonist that I mentioned before. So here are the different anti-FCRNs. We did discuss specifically three of those. RVT-1401, the phase two is still underway for that, and the different C5 inhibitors as well that are still under investigation. I'm going to finish just informing everyone of an update for the International Consensus Conference for MG Treatment Guidelines. We started this in 2014 at Duke University. Don Sanders and I have co-directed this with a facilitator, Dr. Narayana Swamy. We have a very stable, enthusiastic group of panelists. We did add a South American representative, Gabrielle Sayah from University of Chile, in this last rendition for the update that hopefully will be out soon in 2020. And we did have a MGFA, Myosin Gravis Foundation America representative involved as well. So the first treatment guidance came out in 2016. We covered all these different categories, and this is what we're going to cover for the 2020 update. Ocular MG, bimectomy update, methotrexate, rituximab, ecolizumab, physical training. There was hope to do that, but it looks like it's going to be removed. And we are talking about checkpoint inhibitors precipitating or worsening MG as well. So I think everyone can hear me, but I typed in some notes just to explain part of the talk and also to update things because this talk was recorded half a year ago now. For instance, the Bexsero, one of the two meningitis B vaccines, it also needs a booster. There's this organization, which is mostly infectious disease docs, I think it's called the ACIP, and they make recommendations about immunization. And so now you have to do a booster for that too. So all of them need a booster if patients are going to continue with complement with complement blocking therapies. And if it's not clear, the complement system is very important in fighting off encapsulated bacterial infections, and that includes Neisseria meningitis, which obviously can be fatal. When you hear about kids dying on college campuses from meningitis, it's usually Neisseria, it's usually that organism. And fortunately, now we have vaccines. And some college campuses most, I think, require the students to be vaccinated. But the older population like me, I was never vaccinated for any of the meningococcal strains. I still haven't been, but my kids have. All right. You know, one question that came up that Connie actually asked, which I think is important for everyone to hear too, is I think some of you will follow patients who are quite stable and they're still on immunosuppressive therapy and how quickly to reduce, for instance, azathioprine or mycophenolate or cyclosporine or tacrolimus or methotrexate, depending on what they're on. And, you know, my approach to that's large. Now we don't have great studies for most of those, but we do have some studies with mycophenolate on this from the Duke group, which I think are very informative. And it seems if we, first of all, you can't do it as fast as we reduce steroids and we shouldn't reduce steroids really, really fast anyway. But I'll talk about steroids in a second. But if you reduce things like mycophenolate every year by a single pill, so like 500 milligrams of mycophenolate or 50 milligrams of methotrexate, sorry, 50 milligrams of azathioprine or one or two milligrams of tacrolimus, those types of reductions every year, it's less likely the patients are going to relapse than if you do it faster than that. Sometimes you could push it to every six month reductions, but in my practice, I really try to stick to the every year reduction. During the pandemic, some patients were worried about being on immunosuppressive therapy because of their ability to fight off, you know, God forbid, COVID-19, the SARS-CoV-2 virus. So I sped it up if the patients were really worried, but not any faster than every six months. On steroids, you can't do it that slowly. But one mistake is dropping steroids too fast, like every week or something. Once patients are stabilized, you really shouldn't be lowering prednisone doses any faster than every, maybe every two weeks, but usually it's every four weeks. And when patients get to a lower dose of prednisone, which is safer, say below 20 milligrams every other day or 10 milligrams a day, the reduction should be even slower than that. You know, every month or two, maybe go down by two and a half or five milligrams. I hope that gives you an idea of how quickly you can reduce it as long as patients stay stable. So there's a question. I'll go ahead and do, I type very fast. I used to be a journalist, but I'll go ahead and answer these verbally. Are we providing vaccines in your neuromuscular clinic? We aren't right in our clinic, but the internal medicine group on the same floor, you can get a vaccine over there and the family medicine. But at least in my state, in New York state, we've saturated pretty well, at least those people who want the vaccine. So, so there hasn't been as much of a demand for the office-based vaccine giving, even though it is available, as opposed to these mass vaccination sites. Our university on their South campus, they had a big vaccination site and a parking lot that was, you know, through the state of New York. So most people have already gotten it who've wanted it, but no, we did not give up directly in our neuromuscular clinic, but we're encouraging people to get it. Really, no matter what they're on, they need to get the vaccine. Most of the time we can convince patients of that. All right. Do you foresee any of these therapies being used in patients as a first or second line therapy? Excellent question. In patient with milder disease or will they be used for refractory patients only? Well, I can tell you Ecolizumab, you know, whether you like the idea or not is seemingly being used in milder patients earlier in their disease state. You know, one thing we've talked about with FCRN antagonists and to some degree also with the complement five agents is there is this bridge that we have trouble with in patients with MG as we wait for non-steroid immunosuppressants like azathioprine or mycophenolate or cyclosporine or tacrolimus to work because it takes months for those to really have an impact. As far as we can tell, it could take a year, a year and a half. So what do we do now? Oftentimes we'll use IVIG. Rarely will we use maintenance plasma exchange because it's so hard to do plasma exchange on a regular basis. You know, you need big catheters usually. Patients have to come in. You can't do it at home. Maybe some of these newer agents will be introduced in that bridging period until we see how mycophenolate or azathioprine are going to work for our patients and stabilize them. So yes, it may be used somewhat in milder and earlier stages of the disease. We'll see where that goes. The other thing is in crisis, since they work fast, I showed you several slides where you can see an impact within a couple of weeks. Well, that's what we need in crisis. And plasma exchange and IVIG, first of all, plasma exchange may not be available in every hospital system. I know it's not. In IVIG, there can be shortages and sometimes it just doesn't work that great as we would like in crisis or severe exacerbation scenarios of MG. So maybe these other agents, because they work fast, can be used. The problem with something like ecolizumab and Zolucoplan, though, is you've got to get them vaccinated and trying to figure out quickly, are people vaccinated or ready for meningitis? In a young person, likely, and people who are older, 30 or 40 or above, probably not. And you have to wait two weeks after the vaccination to safely give those agents, unless you're going to be really bold and put them on prophylactic antibiotics. But I feel uncomfortable doing that. I really want them to be vaccinated. So that's going to be the issue in crisis. The meningitis vaccines, are we giving those in the neuromuscular clinic? I thought you meant the COVID vaccine. No, we don't give them in the clinic, at least in New York State, and this is true in a lot of states. You can just write it on a prescription. They could take it to their pharmacy, just kind of like the same as a shingles vaccine, and they can give it to them. They give it to, actually, in my office, right below me is the pharmacy, and they've done it through there. They just take it by, you call it in, or they take it by, and they have the vaccine the next day, if they don't have it right then and there. So it's given out enough to these younger people, especially these college, these high schoolers are getting ready for college, and most of the colleges want them to be on it. If they haven't gotten it through their pediatrician already, it's a pretty commonly given vaccine. Both the tetravalent, which is for ACWY, is how I remember it, ACWY, that's those four serotypes, and then the B is the fifth one that's a separate vaccine. All right, so we don't give it, actually, right in our clinic. Any other questions? I put in some other comments. I don't see any more, and I think the AAM could monitor, maybe, maybe they can't, if you raise your hand, but if there's any other questions, I'd be happy to answer them, but just as a general comment, it's a very exciting time in MG, clinical trials, as busy as it's been ever in my career. More companies are interested in MG. It's a pretty well-understood disease. Obviously, there's been success with trials of late, as far as recruiting patients and showing efficacy with well-validated outcome measures. It was a drug approval for ecolizumab, so anyway, there's more steam ahead on the MG side, and I do anticipate we will have more agents approved in the near term, in the next year or two, for MG. Oh, somebody said, oh, thanks, Connie. All right. If there's any questions about things I didn't talk about, about standard therapies in MG, happy to answer those, or if you have questions about things that are not MG, CIDP, Guillain-Barre, I'm not sure how often you guys see Guillain-Barre, because I think most of you are on the outpatient side of Guillain-Barre, at least Achilles, handled in the hospital, obviously, or other neuromuscular conditions. I hope these courses are providing useful information. I think it's, my understanding, it's a fairly new educational program for the ANEM, and I'm just glad they have it, as the number of advanced practice providers, and we have several in my department, not, one is partially focused on neuromuscular, but, you know, we use APP, so you guys provide crucial access to patients, so we have them in stroke, child neurology, memory disorders in my department, and they help some with epilepsy as well, but they're crucial on the memory disorder side, on the stroke follow-ups, on MS, and you guys do great jobs for, in neurologic care, in academic centers, in community practices, and so forth, and so I hope this provides information that's useful in your practice. Well, either we answered all the questions or people are, I guess some people may be ready for lunch depending on your time setup. I wolf mine down earlier. Dr. Wolfe, thank you so much for your time. We really appreciate it. Thank you for everything. If there are no more questions, do you plan on sticking around for the next talk? Maybe answering questions in the chat? I could. Wonderful. Maybe a few more minutes and then we'll move on to the next video. Thank you so much for your time. Truly. Sure. I enjoy these things. Are you going to start at the top of the hour so people can take a bathroom break? We're going to get started here actually as right now. As a matter of fact, we're going to keep on moving so that they can enjoy the rest of their lunch break. If you have any more questions for Dr. Wolfe, hopefully he sticks around for a few more minutes and you can put those in the chat function. Thank you again so much for your time. Sure. Wonderful. Take care.

myasthenia gravis

muscle weakness

B-cell therapies

rituximab

complement-mediated agents

eculizumab

clinical trials

future directions