How FcRn Blockade Targets Myasthenia Gravis Autoantibodies

We kicked off our conversation with Katie Abouzahr, MD, vice president, Autoantibody Diseases, and Maternal-Fetal Immunology Disease Area Leader, Johnson & Johnson Innovative Medicine, by learning about the clinical features of generalized myasthenia gravis and how this life-long autoantibody-driven chronic disease affects patient quality of life.

You can revisit part 1 of our interview here.

In part 2, we discuss the challenge inherent in treating adolescents who have the disease and how nipocalimab—for which a biologics license application received a priority review designation from the FDA and currently has an expected Prescription Drug User Fee Act date in Q2 of this year—works via FcRn blockade to reduce the circulating autoantibodies that drive myasthenia gravis.

This transcript has been lightly edited for clarity; captioning was auto generated.

Transcript

Are there unique challenges that adolescents and adults with myasthenia gravis face?

Maybe 10%, 15% of patients are diagnosed as adolescents. Interestingly, in the adolescent population, you do see a preponderance of females diagnosed with myasthenia gravis. These diseases share a lot of common features. There are a few differences, but by and large, there are a lot of common features as well.

The challenge with adolescence is that actually it represents an area of immense unmet medical need. There are almost no approved therapies; certainly none of the advanced therapies have been approved for use in adolescence. So that really is a unique challenge—so something that we think is really important to address for these patients.

How does the FcRn blockade mechanism of nipocalimab compare with current standard treatments for myasthenia gravis?

So traditionally in myasthenia gravis, like the majority of immune-mediated diseases, the sort of typical standard-of-care was broad immunosuppressants; think steroids, for example. Those carry a number of challenges around their safety and tolerability profile, and they're often not studied specifically for use in these diseases.

Excitingly, in myasthenia [gravis], we have entered the advanced therapy era with the approval of the complement inhibitors starting in 2017, and now, more recently, the FcRn [neonatal Fc receptor] blockers. That said, even though it's exciting, a lot of unmet need remains. But let me take FcRn blockade and the mechanism of action of nipocalimab and how is it applicable to this disease.

As I mentioned earlier, myasthenia gravis is autoantibody driven, with autoantibodies causing damage that then impact your ability to use your skeletal muscles. Nipocalimab is an FcRn blocker; it binds to and inhibits the FcRn receptor, crystallizable fragment neonatal receptor. It's a mouthful, FcRn.

So what does that do? Actually, it does a couple of things. By blocking the FcRn, the first thing you do is you prevent the FcRn receptor from recycling IgG [immunoglobulin G], and therefore IgG reduces out of circulation. IgG includes pathogenic IgG and autoantibodies as I mentioned earlier, like, for example, the IgG1 [immunoglobulin G1], AChR [acetylcholine receptor], or the [IgG4 immunoglobulin G4] muscle-specific kinase autoantibodies that we find in myasthenia gravis.

It does have a second mechanism of action. By inhibiting the FcRn receptor, you prevent it from transferring IgG across the FC neonatal receptor—clues in the name—from mom to baby during pregnancy, which is a mechanism of action that we leverage in some of the other maternal-fetal programs that nipocalimab is being studied in, the alloimmune diseases of pregnancy. So with FcRn blockade, you therefore have the ability to selectively target one of the underlying causes of myasthenia gravis: by reducing from circulation these autoantibodies. And you'll hear us talk about IgG reduction as a sort of PD [pharmacodynamic] biomarker for reducing these antibodies and therefore being able to think about efficacy in this space.

Nipocalimab binds to very tightly the FcRn, reduces IgG, and in fact, in our Vivacity-phase 3 data [NCT04951622], we saw IgG reduction of around up to 75%, 77%, including, therefore, these pathogenic autoantibodies underlying the disease.