MONTREAL — An investigational targeted immunotherapy for Guillain-Barré syndrome (GBS) more than doubled disability improvement after eight weeks compared to a placebo, with sustained benefits after 26 weeks. Researchers say the new findings mark the first advance in GBS treatment in 40 years.
The phase 3 trial investigated ANX005, a fully humanized recombinant immunoglobulin (Ig) G4 monoclonal antibody that has been granted fast track and orphan drug designations by the U.S. Food and Drug Administration (FDA) and the European Medicines Association (EMA).
“Because of the rapid complement inhibition and concomitant reduction in neuroinflammation, we expect patients treated with ANX005 to begin seeing rapid improvements,” said Henk-Andre Krohn, MD, PhD, research investigator and head of translational medicine at drug development company Anexon.
“In this study, this translated into increased speed of independent walking, shorter duration of mechanical ventilation for patients requiring mechanical assistance, fewer days in the intensive care unit during the acute phase of the illness, and ultimately, an increased likelihood that patients would return to their pre-illness health state,” Krohn told Medscape Medical News.
The study findings were presented at the Peripheral Nerve Society (PNS) 2024 Annual Meeting on June 25, 2024.
Reduced nerve damage
GBS is an acute inflammatory peripheral neuropathy characterized by rapid onset of ascending muscle paralysis with a limited window for therapeutic intervention. There is no FDA-approved treatment for the disease, but intravenous immunoglobulin (IVIG) and plasma exchange are used as supportive care.
The disease is estimated to result in more than 22,000 hospitalizations each year in the United States and Europe, causing significant long-term disease burden.
ANX005, an anti-C1q antibody, is administered as a single infusion and reduces complement-mediated neuronal damage by blocking the classical complement pathway, Krohn explained.
Researchers randomly assigned 241 patients with severe GBS to receive either placebo or one of two doses of ANX005 (75 mg/kg or 30 mg/kg). Baseline characteristics were generally well balanced across groups.
The majority of participants were male (63%-70%), 70%-80% had a baseline GBS Disability Score (GBSDS) score of 4, indicating difficulty staying in bed or a chair, and participants waited an average of approximately 6 days from the onset of muscle weakness to random assignment.
Approximately half of the participants scored between 0 and 20 on the Medical Research Council (MRC) muscle strength scale, indicating severe muscle weakness.
The study achieved its primary endpoint at the lower dose, with ANX005 30 mg/kg achieving a highly statistically significant 2.4-fold improvement in GBSDS at week 8 compared with placebo ( P = .0058).
The treatment was also superior to placebo on key secondary endpoints, including early increases in MRC scores at day 8 ( P < .0001) and week 8 ( P = .0351), and a median reduction of 28 days on mechanical ventilation by week 26 ( P = .0356).
Real World Evidence
Patients receiving active treatment had a 31-day reduction in median time to independent walking compared with placebo ( P = .0211) and an earlier reduction in serum levels of neurofilament light chain, a biomarker of nerve damage (11.2% reduction compared with placebo between weeks 2 and 4, P = .03).
The drug appears to be safe and well tolerated. The majority of adverse events were mild (grade 1) to moderate (grade 2) in severity. The most common treatment-related adverse events were infusion-related reactions (30.4%), most of which were mild and transient rashes.
As stated in the press release, the 75 mg/kg dose of the drug “demonstrated superiority over placebo on multiple endpoints,” but the results were not statistically significant for the primary endpoint of the GBSDS at week 8.
“For patients and caregivers, GBS is a traumatic experience. Clinicians understand that the path to recovery is uncertain and there are no specific treatment goals other than the expectation that patients will get better. Patients call this the ‘new normal,'” Krohn said.
A treatment like ANX005 could give GBS patients an early sign that the disease is under control and they are on the road to recovery. Importantly, it could give patients confidence that they will recover and reduce the anxiety that comes with the disease, he added.
This study was conducted in Bangladesh and the Philippines, where the prevalence of GBS is high and access to IVIG is limited, and therefore the study population may not be fully representative of the GBS patient population in Europe and the United States, where different phenotypes of the disease are more prevalent.
To address this, Anexon has initiated a real-world evidence protocol in conjunction with the International Guillain-Barré Syndrome Outcomes Study (IGOS) to establish comparability between study participants and Western patients.
“IGOS data show that many patients in the U.S. have muscle strength of 21 or greater (using the MRC total score), and we evaluated these patients in a prespecified subgroup analysis.
“In the overall population, patients who received ANX005 had an odds ratio of better health compared with patients who received placebo of 2.4, whereas in patients typically seen in the United States the odds ratio was 3.0, suggesting that treatment with ANX005 may be more effective than observed across the full spectrum of the disease,” Crohn said.
Game changer?
Michael Lunn, MD, Consultant Professor of Clinical Neurology and Clinical Lead in Neuroimmunology at the National Hospital of Neurology in London, UK, called the findings “potentially game-changing” in a statement to Medscape Medical News.
“The effect sizes cited are quite large in terms of disability and speed of recovery. These are not insignificant effects,” said Lunn, who was not involved in the study.
“GBS is one of the best-understood autoimmune neurological diseases, yet the field has not seen any real therapeutic advances in 40 years,” said Lunn.
Although plasma exchange and IVIG are clearly effective in speeding recovery, they are not necessarily effective in preventing damage after recovery, Dr. Lunn said.
He noted that results from two previous C5 complement inhibitor studies using eculizumab (the ICA-GBS and JET-GBS trials) have shown that the drug is safe and has offered “some enticing hints of therapeutic efficacy.”
“C1q inhibition is potentially safer and offers broader complement correction. By the time patients arrive at the emergency department, most of the remaining immunopathogenesis has already occurred, so manipulating complement is likely one of the few ways to alter neurological damage in GBS,” he said.
This study was funded by Anexon, Inc. Kroon is an employee of Anexon, Inc. Kroon disclosed that he previously served on Anexon’s Clinical Trials Advisory Board.