By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital
Dr. Perumal reports she is a consultant for Biogen and Genzyme.
In a randomized, placebo-controlled trial of neuromyelitis optica spectrum disorder patients, satralizumab monotherapy demonstrated a decrease in relapse rate when compared to placebo. In a randomized, open-label, multicenter trial of tocilizumab vs. azathioprine, treatment with tocilizumab demonstrated a decreased risk of a relapse compared to azathioprine.
Zhang C, Zhang M, Qiu W, et al. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): An open-label, multicentre, randomised phase 2 trial. Lancet Neurol 2020;19:391-401.
Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: A randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 2020;19:402-412.
Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that preferentially affects the optic nerves and spinal cord. Classic NMO, or Devic’s disease, is characterized by concurrent episodes of optic neuritis (ON) and transverse myelitis (TM). NMO spectrum disorder (NMOSD) is diagnosed in patients with isolated ON or TM who have the NMO IgG (aquaporin-4) antibody, which is potentially pathogenic and has high specificity for this group of diseases.
Currently, the only disease-modifying therapy that is a Food and Drug Administration (FDA)-approved treatment for NMOSD is eculizumab, a humanized monoclonal antibody that is a complement-5 inhibitor. It was approved in 2019. However, other medications that traditionally have been used include pulse corticosteroids, intravenous immunoglobulin (IVIG), azathioprine, mycophenolate mofetil, and rituximab. More recently, several medications with diverse mechanisms of action are being explored for the treatment of NMOSD, either as combination therapy or as monotherapy. There is a need for such therapies because NMOSD can be a devastating illness resulting in severe disability from relapses. In this review, we report on recently published results from clinical trials of satralizumab and tocilizumab.
Satralizumab is a humanized monoclonal antibody that is an interleukin-6 (IL-6) inhibitor. IL-6 is a pro-inflammatory cytokine that is believed to have multiple pathogenic effects in NMOSD. An earlier trial with satralizumab or placebo as an add-on therapy for patients already on immunosuppressive treatment for NMOSD showed that patients in the satralizumab arm had a decrease in risk of relapse. In the current study, researchers explored satralizumab monotherapy.
This was a phase 3, double-blind, placebo-controlled, multicenter study. The double-blind period was followed by an open-label extension. Both seropositive and seronegative NMOSD patients were included in the study. Ninety-five patients were randomized to either satralizumab (63) or placebo (32). Study medication was administered subcutaneously at weeks 0, 2, and 4, and then every four weeks for the duration of the study. The primary outcome was the time to first protocol-defined relapse. Secondary outcomes included visual analog scale (VAS) pain score, Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score, proportion of relapse-free patients, annualized relapse rate, and change in disability scores.
The median treatment duration in the double-blind phase was 92.3 weeks (range zero to 202 weeks). Thirty-five protocol-defined relapses were observed during the double-blind periods; 19/63 (30%) of patients in the satralizumab arm and 16/32 (50%) of patients in the placebo arm (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.23-89; P = 0.018). Patients in the placebo arm also had a shorter time to relapse. No significant change was observed between the groups on the VAS pain score or the FACIT fatigue score. During screening for the study, the number of aquaporin-4 immunoglobulin G (AQP4-IgG) seronegative patients was kept at 30% of the subjects. A subanalysis of the results by sero-status showed that satralizumab was effective in reducing the risk of relapse on AQP4-IgG seropositive patients. There was not enough evidence to demonstrate efficacy in the seronegative group. Regarding adverse events, the incidence was similar between the satralizumab and placebo groups. The most commonly reported adverse events were urinary tract and upper respiratory tract infections. No opportunistic infections were reported.
Although the patient numbers were small, satralizumab demonstrated efficacy in reducing the risk of relapse, predominantly in seropositive patients, and no unexpected serious adverse events were noted.
Tocilizumab also is an IL-6 inhibitor that currently is FDA-approved for several autoimmune diseases, including severe rheumatoid arthritis and giant cell arteritis. Prior reported case series demonstrated efficacy of tocilizumab in decreasing the risk of relapse in NMOSD. In this open-label, multicenter, randomized, phase 2 trial, tocilizumab was compared to azathioprine, a medication that is used in an off-label manner for the treatment of NMOSD.
One hundred eighteen NMOSD patients were randomized in a 1:1 manner to either tocilizumab or azathioprine. Each arm had 59 patients. Azathioprine was titrated up until a target dose of 2 mg/kg to 3 mg/kg per day was reached. This dosage was maintained. Tocilizumab was administered intravenously at a dose of 8 mg/kg every four weeks. The planned total duration of follow-up was 60 weeks after randomization. The primary outcome was time to first relapse. Secondary outcomes included proportion of patients with confirmed disability progression and change in serum AQP4-IgG levels at the end of the trial.
At the end of 60 weeks, the risk of a relapse was lower in the tocilizumab group when compared to the azathioprine group (HR, 0.24; 95% CI, 0.123-0.607; P = 0.0006). In the tocilizumab group, 8/59 patients (14%) had a relapse when compared to 28/50 patients (47%) in the azathioprine group. The median time to first relapse was longer in the tocilizumab group when compared to the azathioprine group (78.9 weeks vs. 56.7 weeks). The incidence of adverse events was similar between the two groups. Most were mild. The most common adverse events in both groups were elevated liver enzymes, upper respiratory tract infections, and urinary tract infections.
Two patients died, one in the azathioprine group and one in the tocilizumab group, but neither death was considered treatment-related. The patient who died in the azathioprine group had a relapse of thoracic myelitis, then developed a high fever and was diagnosed with meningoencephalitis caused by Listeria monocytogenes. The death in the tocilizumab group occurred in an individual with extensive transverse myelitis that ascended to the medulla oblongata and resulted in respiratory arrest and cardiopulmonary failure.
NMOSD is characterized by severe relapses with a significant risk of disability from the residual deficits from relapses that can be refractory to treatments used for acute relapses (i.e., steroids, IVIG, plasmapheresis). Hence, medications that decrease the risk of a relapse are vital in preventing disability. Although several medications have been used off-label for the treatment of this disease, there currently is just one medication that was FDA-approved in 2019 for NMOSD — eculizumab. There is an urgent need for further treatment options for those who fail existing medications or have tolerability issues. Based on these two studies, satralizumab and tocilizumab have demonstrated efficacy without any prohibitive adverse events and would expand the armamentarium of NMOSD treatment. They appear likely to be approved by the FDA in the near future.