Investigational Drugs for Chronic Inflammatory Demyelinating Polyneuropathy

Investigational therapies may soon change the treatment landscape for chronic inflammatory demyelinating polyneuropathy (CIDP).

"Despite the fact that we have some good standard-of-care therapies -- IVIG [intravenous immunoglobulin], corticosteroids, and plasma exchange -- there's still a significant need to develop new treatments, partly due to suboptimal efficacy, high administration burden, and undesirable side effects," said Richard Lewis, MD, of Cedars Sinai Medical Center in Los Angeles.

At the 2024 American Academy of Neurology (AAN) meeting in Denver, researchers presented phase II data for two novel CIDP treatment approaches: the neonatal Fc inhibitor efgartigimod (approved as Vyvgart for generalized myasthenia gravis), and the complement inhibitor riliprubart.

Efgartigimod

Efgartigimod is a neonatal Fc receptor blocker shown to reduce immunoglobulin G (IgG) levels by promoting degradation and inhibiting recycling without affecting production. It can be given intravenously or, using a formulation with added hyaluronidase, in a rapid, high-volume subcutaneous infusion (efgartigimod PH20 SC; also approved for myasthenia gravis as Vyvgart Hytrulo) as used in ADHERE, a phase II trial of 322 CIDP patients.

"ADHERE is now the largest randomized controlled trial of any CIDP treatment to date. It supports the role of pathogenic autoantibodies in CIDP pathology," said Jeffrey Allen, MD, of the University of Minnesota in Minneapolis, who presented the findings at a clinical trials plenary session at AAN.

"A single rapid 30- to 90-second injection of weekly efgartigimod may provide a new therapeutic option to reduce the treatment burden in patients with CIDP," Allen added.

In ADHERE, CIDP patients with prior treatment in the last 6 months went through a run-in period of up to 12 weeks, followed by open-label stage A treatment with weekly 1,000 mg subcutaneous infusion, then a randomized stage B double-blind period of treatment versus placebo. A total of 221 CIDP patients were in stage B; half were randomized to efgartigimod and half to placebo.

The run-in phase aimed to identify patients who had active CIDP, Allen explained. "Patients on standard-of-care were asked to suspend their treatment for a period of up to 12 weeks and those patients were evaluated for evidence of clinical deterioration," he said.

During up to 12 weeks of follow-up, 66.5% showed clinical improvement in stage A, defined as improvement in scores on the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, Inflammatory Rasch-built Overall Disability Scale (I-RODS), or grip strength.

In stage B, only participants who improved in stage A were randomized to efgartigimod or placebo and followed for up to 48 weeks for the primary outcome measure, deterioration on the adjusted INCAT disability scale score (range 0-10, with higher scores indicating worse symptoms).

In stage B, relapse occurred in 27.9% of efgartigimod and 53.6% of the placebo group. Efgartigimod reduced the risk of relapse by 61% compared with placebo (HR 0.39, P=0.000039).

"Importantly, the prior treatment history was similar in all groups: IVIG or subcutaneous IG was used in about half of patients in stage A and roughly 43% of patients in stage B," Allen pointed out. Prior corticosteroid treatment was about 20% in both groups, and the degree of disability and strength impairment was similar in the stage B treatment groups, he added.

Safety data showed treatment-emergent side effect rates of about 63% in stage A (serious in 6.5%), Allen said. In stage B, treatment-emergent adverse events were 64% for efgartigimod and 56% for placebo (serious in 5.4% and 5.5%, respectively).

Discontinuations with efgartigimod occurred in 6.8% and 2.7% in stage A and B, respectively. Of two deaths in stage A, one was due to cardiac arrest and the other attributed to CIDP; neither were considered to be related to efgartigimod. One death in the placebo arm of stage B was attributed to pneumonia and was considered treatment-related by the investigator.

An open-label extension, ADHERE+, is ongoing. In February, the FDA accepted a supplemental biologics license application for efgartigimod with hyaluronidase for CIDP. The FDA's decision is expected in June.

Riliprubart

At the AAN meeting, Lewis presented preliminary efficacy and safety data for a phase II study of investigational riliprubart (formerly known as SAR445088).

Riliprubart is a humanized monoclonal antibody that inhibits complement C1s and subsequent membrane attack complex formation. The open-label trial started with study intervention for 24 weeks (stage A), followed by 52 weeks of treatment (stage B). Participants could continue 22 more weeks, to 98 weeks (stage C).

Three groups were studied: 25 CIDP patients who showed objective response to standard of care and discontinued IVIG and rapidly tapered corticosteroids for the trial; 18 patients who did not respond (refractory) who also discontinued IVIG and tapered corticosteroids; and 12 patients who were either treatment-naive or untreated for 6 months.

The primary endpoint was percentage of patients who relapsed, assessed again by INCAT scores.

In the standard-of-care group that subsequently received riliprubart, 12% relapsed and 44% improved versus baseline. Among refractory patients, 11% relapsed and 50% improved. The naive group "improved or remained stable in almost every patient," Lewis said.

"In particular, the 44% improvement in the standard-of-care treated group was a surprising result and encouraging," he pointed out. "The refractory patients' 50% improvement is impressive for a refractory group. This level of improvement exceeds what would be expected for a placebo response." There was strong inhibition of complement activity and neurofilament light chain levels suggested there may be less neuroaxonal damage in CIDP when treated with riliprubart, he added.

"Adverse events were relatively mild in all groups," Lewis said. There were two deaths, neither of which were thought to be treatment-related, he noted.

Two phase III riliprubart trials are underway: the MOBILIZE study in refractory patients and the VITALIZE study in patients with residual disability, he added.

The CIDP drug pipeline has agents that are being investigated in other autoimmune disorders. Riliprubart, for example, is being evaluated in cold agglutinin disease. The neonatal Fc receptor blocker nipocalimab is being studied in both CIDP and myasthenia gravis, as is batoclimab.

A 2023 proposal suggested repurposing immunotherapies tested in multiple sclerosis (MS) -- like B-cell therapies or Bruton's tyrosine kinase inhibitors -- to treat CIDP and other autoimmune neuropathies, as their effects are in the periphery. "This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation," the researchers wrote.

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