Article In Brief
Satralizumab was effective in controlling relapses in patients with neuromyelitis optica spectrum who continued to take other immunosuppressant therapies during the trial.
Newly published phase 3 trial results for satralizumab add to growing excitement over the expanding treatment options for neuromyelitis optica spectrum disorder (NMOSD), a rare and debilitating autoimmune disorder for which there were no approved drugs until several months ago.
Eculizumab was cleared for marketing by the US Food and Drug Administration (FDA) in June for treatment of NMOSD, while satralizumab and another drug, inebilizumab are expected to get FDA approval in 2020.
The new study, published November 28, 2019, in The New England Journal of Medicine (NEJM), assessed satralizumab in NMOSD patients who continued to take other immunosuppressant therapies during the trial.
Results of another clinical trial that compared satralizumab alone to placebo were presented this past summer at the European Committee for Treatment and Research in Multiple Sclerosis, and both sets of trial findings have been submitted to the FDA as part of an application by Genentech to market the drug for NMOSD.
NMOSD, which is characterized by inflammatory lesions that mostly affect the optic nerve and spinal cord, can lead to mobility problems, paralysis and blindness, as well as death.
Satralizumab, eculizumab, and inebilizumab all are monoclonal antibody therapies, but they have different mechanisms of action.
Satralizumab, which is administered subcutaneously, targets the receptor for interleukin-6, an inflammatory factor that is believed to be key in NMOSD and is found to be elevated in the spinal fluid of persons with the disorder.
“The more medications we have that effectively target different aspects of the of the pathologic autoimmunity in NMOSD, the better it is for patients,” said Stacey Clardy, MD, PhD, assistant professor of neurology at University of Utah and staff neurologist at the Salt Lake City VA, who was not involved with the current study.
“As more medications are approved, even a patient who may have contraindications or intolerable side effects from one therapy will have more choices for an effective treatment that is right for them,” Dr. Clardy said.
Up until now, various immunotherapies, including rituximab, have been used off-label to prevent and treat the recurrent attacks associated with NMOSD, though up to 50 percent or more of patients continue to have attacks despite taking medication. Disability can result from one attack and worsen with each relapse, the authors of the study noted.
About two-thirds of NMOSD patients have antibodies against the water channel protein, aquaporin-4 (AQP4-IgG) that is involved in the inflammatory cascade. A positive AQP4 status is associated with more severe disease and also seems to be a favorable factor in whether patient benefit from the new targeted therapies.
Study Design, Findings
The new study, led by researchers in Japan and involving patients in multiple countries, included both APQ4-positive and APQ4-negative patients, ages 12 to 74. Patients were eligible to participate if they had had at least two relapses in the two years prior to screening, including one relapse in the previous 12 months.
The trial, known as SAkuraSky, assigned 83 participants to either satralizumab at a dose of 120 mg or placebo as add-on therapy. The drugs were administered subcutaneously at the start and again at weeks two and four and every four weeks after that. Patients kept taking their usual immunosuppressant treatment. (The two most common were oral glucocorticoids and azathioprine.)
The primary endpoint was protocol-defined relapse. Secondary endpoints included change from baseline to week 24 in the visual-analogue scale for pain—scores range 0 to 100, with higher scores indicating more pain—and the Functional Assessment of Chronic Illness Therapy-Fatigue score, which has a range of 0 to 52, with higher scores indicating more fatigue.
Relapse occurred in eight patients receiving satralizumab (20 percent) compared with 18 patients on placebo (43 percent). That amounted to a 62 percent reduction in risk of relapse for those on satralizumab, the researchers reported.
The percentage of patients who were free of relapse at 48 weeks was 89 percent in the satralizumab group and 66 percent in the placebo group. At 96 weeks, those numbers were 78 percent and 59 percent, respectively, the report said. The median treatment duration with satralizumab was 107.4 weeks.
The drug was most effective in patients who tested positive for the APQ4-IgG antibody; that group had a 79 percent reduction in risk of relapse compared with those taking placebo. In patients who were APQ4-IgG negative, risk reduction was lower, 34 percent, compared with placebo.
There was no difference between the treatment and placebo groups when it came to pain and fatigue as measured by the two assessment tools. Rates of serious adverse events and infections also did not differ between the active drug and placebo group, the report said.
The trial had limitations, including the fact that it was relatively small and there was no active comparator, the researchers noted. Without a head-to-head comparison, it is impossible to say, for instance, which of the three new targeted drugs is most beneficial. The trial also was unable to say whether there was a difference between the two groups at any given week of treatment, the report said.
“Longer and larger trials are necessary to determine the efficacy, durability, and safety of satralizumab and to investigate its effect in comparison with other treatments for NMOSD,” the study concluded.
The study's lead author Takashi Yamamura, MD, PhD, director of the National Institute of Neuroscience in Japan, said in an email to Neurology Today that while head-to-head comparisons are needed, there could be a practical advantage for satralizumab, “which allows patients to stay at home for continuous treatments, without going to hospital to receive intravenous infusions.”
He added, however, that whether a patient gets the drug at home or in a health-care setting could vary from country to country.
Dr. Clardy agreed with the potential for a convenience factor. “For patients to be able to avoid traveling to infusion centers—or even the planning and hours spent on home infusion visits—the option for a subcutaneous injection will potentially be a significant improvement in quality of life, especially when compared to therapies that require frequent intravenous infusions,” she said.
Dr. Clardy said the much better results for satralizumab in APQ4- positive patients suggest “we still have a lot of research to do to determine the ideal treatment for the patients who are either positive for the MOG antibody or double negative for AQP4 and MOG.” MOG is another antibody associated with NMOSD.
Steven L. Galetta, MD, FAAN, professor and chair of neurology at NYU Langone Health, said the newly published study on satralizumab is “incredibly exciting...because now we have three emerging therapies for NMOSD in one year. There was a time we thought it would be impossible to do a study in NMOSD because the number of patients with it is very small and we thought enrollment would fail.”
But he cautioned that the new study results in NEJM are somewhat muddied by the fact that patients in the current trial continued to take their standard immunosuppressants. He also questioned predictions that doctors and patients will quickly embrace the new monoclonal therapy drugs in a big way.
“I still think most doctors are going to go with rituximab first. It is going to be relatively cheaper for one thing,” Dr. Galetta said, noting that “small studies have shown that 70-80 percent of people can be relapse free on that drug.”
“If someone is doing really well on a current therapy, doctors are not going to be switching them out,” Dr. Galetta said, though he said having more options is always a good thing since patients may fail one therapy but respond to another.
Michael Levy, MD, PhD, FAAN, associate professor of neurology at Harvard Medical School and director of the Neuromyelitis Optica Clinic and Research Laboratory at Massachusetts General Hospital, said it remains to be seen how the three new drugs “are going to be incorporated into our routine. Are we going to take stable patients and convert them to an FDA-approved drug?”
Dr. Levy said, “My approach tends to be if a patient is stable for at least three years, I don't rock the boat. The truth is the drugs we use off-label are fairly effective and all are relatively well tolerated.”
Dr. Levy said he was initially an investigator for the satralizumab study reported in NEJM but his site failed to recruit any patients. He helped in the design of the trial and served on the scientific advisory board for Genentech. He also was an investigator for clinical trials involving eculizumab (PREVENT study) and inebilizumab (NMOmentum) in NMOSD.
He said studies on all three new drugs “demonstrated that [AQP4] seropositive patients are different from seronegative patients,” he said, which indicates that more work remains to be done to find treatments that benefit antibody-negative patients.
Dr. Levy said it is nonetheless encouraging that evidence continues to build that “we took a disease that causes disabling attacks and now can prevent a large number of relapses.”
Dr. Takashi served on scientific advisory boards for and has received speaker honoraria from Novartis, Takeda, and Sumitomo Dainippon. He has received fees for speaking for Chiome Biosciencem Mitsubishi Tanabe, Bayer, Japan Blood Products Organization, Otsuka, Kissei, Daiichi Sankyo, and Miraca Holdings.