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AAN 2021 | ADAPT analysis: efgartigimod for generalized myasthenia gravis

Efgartigimod is an investigational antibody fragment that binds to the neonatal Fc receptor (FcRn). Blocking FcRn reduces disease-causing immunoglobulin G (IgG) antibodies. James F. Howard, Jr., MD, FAAN, University of North Carolina School of Medicine, Chapel Hill, NC, discusses the findings of the Phase III ADAPT trial (NCT03669588) evaluating the efficacy, safety, and tolerability of efgartigimod in patients with generalized myasthenia gravis. Efgartigimod demonstrated that it is well-tolerated and showed a rapid, durable, and clinically meaningful response. This interview took place during the American Academy of Neurology (AAN) 2021 Annual Meeting.

Transcript (edited for clarity)

Efgartigimod belongs to a first-in-class drug that blocks the neonatal Fc receptor. But it’s not a neonatal receptor, it’s ubiquitous throughout life. Its primary purpose is to function as a salvage pathway for IgG immunoglobulin and, as such, pathogenic autoantibodies that are of the IgG subclasses.

By blocking the Fc receptor, we’re able to more rapidly clear circulating autoantibodies...

Efgartigimod belongs to a first-in-class drug that blocks the neonatal Fc receptor. But it’s not a neonatal receptor, it’s ubiquitous throughout life. Its primary purpose is to function as a salvage pathway for IgG immunoglobulin and, as such, pathogenic autoantibodies that are of the IgG subclasses.

By blocking the Fc receptor, we’re able to more rapidly clear circulating autoantibodies. Typically, IgG antibody, if you will, is taken into the cell and then recycled back to the circulation. It thus extends its half-life some four times over other immunoglobulin subclasses like IgM, IgA. By blocking the Fc receptor, we’re able to alter that pathway and shunt these antibodies into a lysosome for destruction.

It was tried in myasthenia gravis, underwent a successful Phase II trial, and we’re presenting the Phase III trials at the AAN meeting. Patients with myasthenia gravis, 80% of them which had antibodies to the acetylcholine receptor and 20% of the population had non-AChR-positive disease. They were given four weekly doses and a matched placebo to a one-to-one randomization and then followed sequentially over several weeks. We’re able to demonstrate that by inhibiting the Fc receptor, there is a very rapid decline in circulating IgG, as well as acetylcholine receptor antibody that reached its nadir around four to five weeks. With this was associated a clear improvement in the myasthenic outcome scores that we used.

The primary outcome measure was the MG-ADL. Unlike other clinical trials, we utilized what we call an MG-ADL responder, such that these individuals had at least a two-point change in their score, but sustained it for four consecutive weeks and that improvement began within one week of their last infusion. The majority, nearly 70%, achieved this MG-ADL responder response versus some 27% in the placebo arm of the study. Likewise, the non-AChR-positive group, and they could include patients with MuSK antibodies, LRP4 antibodies, or were seronegative, had a very similar response.

We’re able to demonstrate in this first cycle that a similar response was seen in the MG QMG score as well, highly favoring the active drug. We were also able to demonstrate that we could repeat the cycles, and they had a similar response as to the first cycle response. About 89% of the patients who achieved this MG-ADL responder analysis response did so within the first two weeks of treatment. So unlike the overwhelming majority of the treatments we currently use, this response was seen quite quickly, which was very gratifying.

The other thing of note was that the durability of the response was quite favorable. While we had an operational definition as to when we could re-treat the patients, more than half had sustained responses in excess of eight weeks, and about a third of them went beyond three months, and a number of them never required re-treatment during this 26-week observation period.

So in summary, a relatively safe drug, the AE profile was very nominal. In fact, it’s very similar between placebo and active drug arms. It was a very durable response, it was a very rapid response, as well as a very clinical meaningful response.

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