Myasthenia Gravis Learning Zone
Transcript: Efgartigimod: A targeted therapy
Dr Elena Cortés-Vicente
Interview recorded June 2024. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Well, I'm very happy to be here today. Thank you to the organisers for inviting me. I'm going to talk mainly about the efgartigimod trials, ADAPT and ADAPT-SC. But before, well, these are my disclosures. I would like to do a brief introduction about myasthenia gravis. As you know, it's a chronic autoimmune disease produced by antibodies immunoglobulin G that bind to postsynaptic antigens at the neuromuscular junction, and they lead to a neuromuscular transmission problem that produce, obviously, symptoms. The most frequent antigen is the acetylcholine receptor, which we can found antibodies against this antigen in 80, 85% of the patients. And these antibodies produce, damage the neuromuscular junction through three mechanisms. The first one, they just block the function of the receptor. The second one, they produce cross-linking. This means that one antibody combined to two antigen molecules and produce a signal of internalisation and destruction of the receptors. So, we have less receptors and less functioning receptors. And also because they are of the subclass, mainly IgG1 and IgG3, they can activate complement and they can destroy completely the postsynaptic membrane. So, to understand how efgartigimod works, I think we need to understand this FcRn-mediated recycling IgG mechanism that is happening in the endothelial cells. Immunoglobulin G will be endosighted inside of the endothelial cell. Some of these IgGs will bind to the FcRn receptor, and others will not.
The ones that will bind, they will go back to the blood. But the ones that are free, that have not been binded, they will go to the lysosome and will be destroyed. So, this is a physiological mechanism that is taking place. And efgartigimod is a human IgG1-Fc fragment that has a high affinity for this FcRn receptor. So, they are going to block this receptor. And the majority of the immunoglobulin G that is endocyted are not going to be binded and they're going to be destroyed. So, many less immunoglobulin G is going to be back the into the blood. Important is that efgartigimod targets only IgG, no IgA, IgD, E, or M. And also it does not produce an alteration in albumin or in cholesterol levels. And this is because it binds to the FcRn in the same way the endogenous immunoglobulin G. So, they are not going to produce any problem in the albumin and cholesterol metabolism.
However, a full-length FcRn inhibitor that binds in a different way could produce an decrease in albumin and increase in cholesterol. That may be a safety issue. Now, I'm going to start explaining the trials, and this is the design of the ADAPT trial. It was a randomised double-blind, placebo-controlled trial in which patients were randomised to receive four, once weekly, infusions of intravenous of efgartigimod or placebo. 167 patients participated in this trial. And once it was finished, they could be included in the open label extension study in which all patients received this fixed cycles of efgartigimod. In ADAPT-SC, it's the same molecule, but it's administered subcutaneously what we want to test here. So, it's a randomised trial, but it's an open label, non-inferiority study. In this case, patients weren't randomised to receive efgartigimod subcutaneously or intravenously in fixed cycles the same way for once weekly infusions or injections. In this case, 110 patients participated. And once it finished, all patients could be included in ADAPT-SC+, the open label extension study in which all patients received subcutaneous efgartigimod.
Let's move to the results. In ADAPT trial, the primary outcome was the percentage of responders, MG-ADL responders. That means patients needed to improve at least two points in the MG-ADL, and this improvement needed to be maintained for at least four weeks. And in this trial, the primary outcome was achieved. It was positive. 67.7 of patients receiving the treatment were MG-ADL responders compared to 29% of placebo. Exploratory endpoint was to test the response within the first two weeks because as you know, the immunosuppressive drugs we are using now, it take weeks or even months to be effective. So, we need fast treatments. And in this case, 84% of the MG-ADL responders, they produce, this improvement appear in the first two weeks of treatment. So, that was very good news. Also, when we look for the results of a clinical trial, of course, we want patients to improve clinically, but it's very important also to see how this clinical improvement impacts quality of life. And in this case, we can see that in the MG-QoL15R score, a score just to assess health-related quality of life, patients receiving efgartigimod, this scale improved. So, their quality of life improved compared to patients who were receiving placebo and in other scales like the EQ-5D-5L, also the same results were shown.
Also the ADAPT-SC trial met its primary outcome. As I said before, it was a non-inferiority study. And the primary outcome was the reduction from baseline in total IgG levels, day 29. And they were pretty similar between both groups of patients treated either with intravenous or subcutaneous efgartigimod. A secondary endpoint was also the proportion of MG-ADL responders, and they were pretty similar independently of the route of administration. And also this exploratory endpoint, the response in the first two weeks, we could see that 88% of MG-ADL responders did it within the first two weeks. Another important thing for me, very important is the minimal symptom expression, because this means patients achieve an MG-ADL of zero or one. So, they are asymptomatic or nearly asymptomatic, and this is what we want when we treat myasthenia gravis patients. We want patients that are fine, that are okay.
So, this is very important to check when we read the clinical trial about myasthenia gravis. And in the ADAPT study, we saw that 40% of patients treated with efgartigimod reached minimal symptom expression compared to 11% of placebo. And in ADAPT-SC, this percentages were pretty similar, around 40, 45%. And what about safety? This is also important when a new drug comes to our lives. In fact, they were pretty similar between placebo and efgartigimod in the ADAPT study. The majority of them were mild to moderate. And in the ADAPT-SC, of course, we saw more frequently rash injection site related because, obviously, about the route, the route of administration, but the majority, mild to moderate. And also important, we have data from the extension studies. We are very interested in this double-blinded studies, but we really want to know how a drug is effective in the long term. And in ADAPT+, the open level extension study of ADAPT, we could see that this clinically meaningful improvement in MG-ADL and QMG, they were consistent of a multiple cycles. And also in ADAPT-SC+, the open label extension study for ADAPT-SC, we could see very similar results. With also over multiple cycles, the efficacy was consistent. And this, there's going to be a poster, I think, about minimal symptom expressions and quality of life data that will be presented during the congress. So, keep an eye on that. And about safety in the long term. This is also very important, but both ADAPT+ and ADAPT-SC+ study didn't raise any new safety issue.
Again, the majority of side effects were mild to moderate. And in general, it's a very well-tolerated disease in both formulations. So, just to finish, well, treatment in both IV and subcutaneous formulations of efgartigimod can be individualised to address patient's needs. And this is a very good new because, well, we have patients with different characteristics, myasthenia is heterogeneous in many ways. And it's important that we can check, choose the best way to treat each of our patients. In routine practise, a time to subsequent cycles of efgartigimod needs to be individualised and should be based on the clinical evaluation. And also important, patients who are receiving intravenous efgartigimod can switch to the SC formulation just at the start of a new cycle. And the study, ADAPT-SC+, showed that patients that have received previously intravenously, when they changed to subcutaneous, it was effective the same.
So, this, we have data about that. And important thing about the subcutaneous drug is that it can be self-administering home. So, this is important for patients because they don't need to be so hospital-dependent, and also for us, because they are not going to be in the hospital, they're not going to need staff. So, I think it's useful for them and for us. And this is just to finish, a question for you. Which factors are the most important when considering initiation patients on a Sub-Q formulation? You can choose more than one because there may be more than one that are useful. You have the patient preference, institution factors, route of administration convenience, ability to self-administer, possibility of home administration, patient disease activity/symptoms, patient early in disease course, or potential for reduction in side effects. All of them are important, I think the majority of them, but, of course, patient preference, it's important. Self-administration, I think that's a very big advantage of the drug. Well, good, home administration. Yeah, I agree that this is the most important [Indistinct]. Okay, so just to, as a summary. As you know, in generalised myasthenia gravis, muscle weakness result from impaired transmission at the neuromuscular junction mediated by IgG antibodies via three distinct mechanisms.
Efgartigimod and antibody Fc fragment blocks FcRn-mediated recycling of IgG by binding in the same formation, thereby inhibiting the mechanisms associated with acetylcholine receptor pathogenicity without impacting albumin binding. The safety and efficacy of efgartigimod in both formulations, intravenous and subcutaneous, has been assessed across a broad population of patients in generalised MG in the ADAPT clinical programme. Efgartigimod intravenously achieve its primary endpoint in ADAPT, demonstrating a significantly higher MG-ADL responder rate than placebo, significant quality of life benefits over placebo, and a tolerable safety profile. ADAPT-SC trial met its primary endpoint. And efgartigimod subcutaneous demonstrated not inferior efficacy and safety compared with the IV formulation. And across trials, more than 40% of patients treated with efgartigimod consistently achieve minimal symptom expression. In the ADAPT+ and ADAPT-SC+ open label extensions, efgartigimod show long-term efficacy across multiple cycles, with no new safety signals observed. And treatment with both IV and subcutaneous formulations of efgartigimod can be individualised to address patient's needs.
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