Evolving Understanding of CIDP: Pathophysiology, Rationale for Targeting FcRn, and Results From ADHERE Trial

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) was the focal point of a symposium by three experts at the 2024 Peripheral Nerve System (PNS) Annual Meeting. Thomas Harbo, a neurologist at Aarhus University Hospital, discussed the CIDP Disease Overview and Current Treatment Landscape. Karissa Gable, an associate professor of neurology at Duke University, shared insights on the Potential Role of IgG in the Pathophysiology of CIDP and the Rationale for FcRn Targeting. Jeffery Allen, an associate professor of neurology at the University of Minnesota, presented the results of the ADHERE study in adult patients with CIDP.

Dr. Harbo explained that diagnosing CIDP is challenging due to symptom overlap with other neuropathies. He noted, "The reasons for misdiagnosing CIDP are mainly the variants. Typical CIDP does not cause much trouble for physicians, but we see it a lot in the variants." Diagnosis often requires a multifaceted approach involving clinical evaluations, electrophysiologic studies, and sometimes nerve biopsies. Studies reveal that 32-47% of patients diagnosed with CIDP are misdiagnosed, and 14% are underdiagnosed. The European Academy of Neurology and the Peripheral Nerve Society (EAN/PNS) updated their diagnostic guidelines in 2021 to address these issues. These revisions include specific clinical criteria for typical CIDP and its variants, comprehensive electrodiagnostic criteria requiring both motor and sensory conduction studies, and additional supportive diagnostic criteria. The guidelines also emphasize CIDP management, including dose adjustments and addressing the significant physical, emotional, and daily life impacts on patients.

Dr. Gable elaborated on the potential role of immunoglobulin G (IgG) in CIDP pathophysiology and the rationale for targeting the neonatal Fc receptor (FcRn) in treatment. FcRn is crucial for regulating and recycling IgG antibodies, significant drivers of autoimmune disorders like CIDP. Both humoral and cellular immunity are involved in CIDP, with FcRn receptors binding IgG in endosomes, initiating downstream signaling and IgG recycling processes. This reduction in pathogenic antibodies is expected to alleviate the autoimmune attack on peripheral nerves, thereby mitigating CIDP symptoms. VYVGART HYTRULO (coformulation of efgartigimod alfa and hyaluronidase-qvfc) works by binding to FcRn, blocking the recycling of IgG, and reducing pathogenic IgG levels.

Dr. Allen presented the safety and efficacy data of VYVGART HYTRULO, which was studied in the ADHERE trial in 322 adult patients with CIDP. Ensuring proper diagnosis was crucial, and the ADHERE study utilized a CIDP confirmation committee to address the high rates of misdiagnosis and underdiagnosis in clinical trials. The trial design involved several stages. Patients showing improvement in an initial open-label treatment phase, Stage A, were then randomized into Stage B, a withdrawal period where they received either the drug or a placebo for up to 48 weeks. The results showed that efgartigimod alfa significantly reduced the risk of CIDP relapse in Stage B by 61% (HR: 0.39; 95% CI: 0.25–0.61). The safety profile of VYVGART HYTRULO was consistent with prior studies, showing common side effects such as respiratory tract infections, headaches, urinary tract infections, and injection site reactions.

The ADHERE trial highlights the potential of targeting FcRn as a therapeutic strategy in CIDP, offering new hope for better disease management and patient quality of life.