Highlights from AAN 2022: Complement Inhibitors and Neurology Pipeline Assessment


The complement cascade has been implicated in the pathology of a number of different neurological diseases, from autoimmune diseases like myasthenia gravis (MG) to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). At the 2022 Annual Meeting of the American Academy of Neurology (AAN), new data were presented for several complement-targeting therapies that highlight the powerful efficacy of this approach both in controlled trials and in the real world. The agents presented at AAN 2022 show promise and represent only a fraction of the growing list of complement-targeting agents in development for neurological indications.

The first complement-targeting therapy approved for the treatment of neurological diseases was Soliris (eculizumab) from AstraZeneca/Alexion, approved in 2017 in the United States for generalized GD positive for anti-acetylcholine receptor (AchR+) antibodies. and in 2019 for the antibody positive aquaporin-4 (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Soliris is an intravenously (IV) delivered monoclonal antibody (mAb) that binds to complement component 5 (C5), preventing its cleavage into C5a and C5b; C5a acts as a chemotactic agent and anaphylatoxin while C5b is part of the membrane attack complex, by which cytotoxic pores are formed across cell membranes. Although this innate immune pathway is useful in killing bacterial cells, when directed at the self, it can cause cytotoxic damage and associated pathology.

New data presented on Soliris at AAN 2022 included three presentations on real world experiences in patients with MG and two studies focusing on NMOSD. For MG, data were presented from a US MG registry, a US retrospective chart review study (Project ELEVATE), and a post-surveillance study in Japan, all of which were sponsored by AstraZeneca. All of the studies demonstrated that patients initiating Soliris in a real-world setting demonstrated strong improvement over time. For example, in the presentation of data from the ELEVATE project, the mean MG Activities of Daily Living (MG-ADL) score dropped significantly from 8.0 before the start of Soliris to 3.7 after just six months and was maintained for 24 months. Additionally, among patients receiving prednisone at the start of Soliris, 77% were able to either stop or reduce their dose.

For NMOSD, interim data were presented from a Japanese post-marketing surveillance study which showed a marked decrease in the incidence of relapses in patients with NMOSD after starting Soliris: over the two years preceding the start of treatment, 36 patients presented 76 relapses against zero. relapse over an average of 36 weeks of treatment. This finding on relapse prevention was supported by another presentation including an indirect analysis of published data from randomized controlled studies of FDA-approved treatments for AQP4+ NMOSD. Specifically, Soliris was found to be more effective at preventing relapses than Roche’s Enspryng (satralizumab) or Horizon Therapeutics’ Uplinza (inebilizumab).

In 2021, AstraZeneca filed for FDA approval of a second-generation mAb targeting C5, Ultomiris (ravulizumab) in generalized AchR+ MG. On April 28, 2022, the drug was approved. Although it uses the same mode of action as Soliris, Ultomiris benefits from less frequent administration (once every eight weeks rather than every two weeks) due to slower clearance from the body. Pharmacokinetic and pharmacodynamic data presented at AAN 2022 support the enduring potency of Ultomiris, which hopefully means the drug will be able to address an important unmet need in MG – burden and frequency of the treatment. Ultomiris in an IV formulation was recently approved, but preliminary studies for a subcutaneous formulation are underway, which may provide patients with an additional treatment option in the future.

Topline results from Ultomiris’ Phase III study in MG, CHAMPION MG (NCT03920293), were announced in July 2021, suggesting the drug met key primary and secondary endpoints. Results presented at AAN 2022 reinforced these claims by providing more detailed efficacy and safety data during the placebo-controlled portion of the trial as well as data from the open-label extension study ( OLE) associated. During the placebo-controlled portion of the trial, significant improvements in MG-ADL scores were observed within one week and were maintained through week 26; data from the OLE study showed that these improvements persisted through the end of the 60-week study period. Similar patterns of efficacy were observed for several secondary endpoints, including the total quantitative myasthenia gravis score and two measures of quality of life, during the placebo- and OLE-controlled portions of the study. In both arms of the CHAMPION study, no new safety issues were reported, with only five patients (3.0%) experiencing a serious adverse event deemed to be related to Ultomiris.

In addition to the two approved complement-targeting agents described above, GlobalData has identified 28 additional agents in clinical or preclinical development for neurological conditions. These are three products in phase III, four in phase II, five in phase I and 16 in the preclinical or discovery phase. Figure 1 illustrates the complement-targeting pipeline products in development across all neurological indications.

MG is the neurological indication with the highest number of complement-targeting agents in development with nine agents, followed by AD with five in development, although mostly in preclinical/discovery stages. In terms of specific complement pathways targeted, 23.3% of products in the development pipeline use the classical complement pathway (C1s/C1q and C2), 66.7% use the alternative pathway (C5, C6, C9 and factor D) and 10.0% target C3, which plays a role in both the classical and alternative complement cascade. Phase III products currently in development include UCB’s zilucoplan for ALS, Regeneron Pharmaceutical’s pozelimab for MG, both targeting C5 agents, and Annexon Inc’s C1q inhibitor, ANX-005, for the SGB. ANX-005 was the only one of these three to present data at AAN 2022; presentations included data on a small trial exploring ANX-005 in combination with IVIG (NCT04035135) while another explored the impact of ANX-005 on classical complement activation in cerebrospinal fluid collected from patients participating in a phase Ib placebo-controlled study.

With promising data presented at AAN 2022 and an ever-expanding pipeline, targeting the complement cascade is a neuroimmunological strategy of growing importance across a wide range of neurological conditions. GlobalData expects these agents to have a significant impact on the market in the future.

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