Inebilizumab demonstrated favorable long-term safety and efficacy outcomes for patients with neuromyelitis optica spectrum disorder (NMOSD). The 5.5-year follow up results of the open-label extension (OLE) period of the randomized controlled phase 2/phase 3 N-MOmentum trial [NCT02200770] showed that the risk of attack in NMOSD subjects treated with inebilizumab remained low. Moreover, long-term use of inebilizumab did not result in the occurrence of unexpected serious adverse events. Physician’s Weekly spoke with Bruce Cree, MD, PhD, clinical research director at the UCSF Multiple Sclerosis Center, CA, who presented the final efficacy and safety data of the N-MOmentum trial at the European Committee for Treatment and Research In Multiple Sclerosis Virtual Congress, which was held 13-15 October, 2021 (1).
Inebilizumab is a humanized anti-CD 19 monoclonal antibody depleting B cells, that is approved in the USA for the treatment of NMOSD patients who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG+). The initiation period of the N-MOmentum trial, randomized NMOSD AQP4+ patients (n=230) 3:1 to inebilizumab (300mg, intravenous, administered at day 1 and 15) or placebo. After 6 months, patients could enter the Open Label Extension (OLE) period, during which all enrolled subjects received inebilizumab every 6 months. In total, 174 patients completed the OLE period. Primary outcome was the time to the first attack.
The results of the randomised controlled period showed that inebilizumab outperformed placebo: 87.0% of the patients on inebilizumab was attack-free, compared with 59.9% of the placebo receivers (risk reduction 72.8%, P<0.001). After completion of the OLE period, 87.7% of the patients continuing inebilizumab, and 83.4% of patients switching from placebo, were attack-free. The mean treatment duration was 3.2 years, with a reported annualized attack rate of 0.092. Treatment-emergent adverse events occurred in 39.6% of the patients. Urinary tract infections (26.2%), nasopharyngitis (20.9%), and arthralgia (17.3%) were the most frequently reported AEs. The rate of infections did not increase with continued treatment (116.3 per 100 person-years in year 1 vs. 55.1 in year 4). Transient low IgG levels (<700 mg/dL were) were reported in 105 subjects. However, no association between IgG levels and the occurrence of infections was observed. One patient had died from complications of a NMOSD-attack after 9 days of inebilizumab treatment. Two other patients died after 224 and 1,225 days of inebilizumab therapy, due to a CNS event of unclear etiology and following a SARS-CoV-2 infection, respectively.
Physician’s Weekly interviewed Prof. Cree to discuss the implications of these findings.
Physician’s Weekly: Can you put the long-term results of the N-MOmentum trial in perspective?
NMOSD is a disease in which clinical attacks are often associated with residual disability, including the loss of vision in one or both eyes, or the inability to walk or provide self-care. If you can prevent attacks that drive disability by administration of inebilizumab, you have an indirect effect on disability. Moreover, the data is very robust, and the results display a trend of increasing improvement over the years. Patients who have been treated with inebilizumab for several years show an annualized attack rate of 0.05 or lower. This means that a patient has an attack once every 20 years. These are very striking results, especially given how difficult it has been to find an adequate therapy for NMOSD.
Physician’s Weekly: We know that blocking the IL-6 receptor pathway is important in NMOSD. How do the current results add to our understanding of the pathophysiology of this disease?
Blocking the interleukin-6 pathway is important indeed. We know that complement deposition is critical for mediating CNS injury as well. Therefore, we have learned that an agent targeting a complement terminal complex is effective. In fact, both strategies can effectively prevent tissue injury and attacks in NMOSD. However, these drug types have to be administered frequently. Eculizumab has to be administered biweekly, and satralizumab once a month .
With inebilizumab, the distinguishing feature is that it depletes B cells. It is not a blocking effect. The drug does not have to be in the system to execute its pharmacodynamic effect.
Therefore, it can be administered far less frequently, only once every 6 months.
Inebilizumab is reprogramming the immune system through the elimination of B cells. How this ultimately translates into therapeutic benefits for NMOSD patients remains to be determined, but it is plausible that we are interfering with the fundamental pathophysiology. I suspect that the primary mechanism of action is the elimination of memory B-cells that are driving immunological response against aquaporin-4. This would explain why we see improving efficacy with treatment duration. With each round of treatment, inebilizumab is potentially eliminating more memory B-cells, allowing the immune system to reset and reconstitute with naive B-cells, that have not been programmed for tissue destruction.
Physician’s Weekly: One would suspect that a B cell depleting approach would result in increased bacterial infections. However, this was not reflected in the results, was it?
B-cell depletion does not necessarily result in increased rates of bacterial infections, because you are leaving the innate immune system mostly unperturbed. Unless you are causing neutropenia by B-cell depletion, this approach is not going to increase the risk for bacterial infections. The types of infections that we see with the B-cell depleting monoclonal antibodies include reactivation of herpes virus and, hypothetically possible, severe opportunistic infections such as progressive multifocal leukoencephalopathy. When interfering with the adaptive immune system, the occurrence of viral infections , but not bacterial infections, is likely to increase. In contrast, interfering with the complement cascade will result in an increased risk of bacterial infections.
Physician’s Weekly: Did you observe equal efficacy of inebilizumab in individuals with African or east Asian ancestry, who are perhaps more likely to develop NMOSD?
There was a significant proportion of participants in this trial who were of Asian origin. A smaller proportion was of African ancestry. No differences in therapeutical efficacy of inebilizumab were observed across these groups. In addition, other baseline factors, such as age, EDSS scores did not seem to have an influence on the primary outcomes. However, the study was not powered to find clinically meaningful effects in each of these different subgroups.
Physician’s Weekly: Were there any other outcomes associated with prior treatments, such as rituximab?
There is data to suggest that patients who were previously treated with rituximab – and had disease activity on rituximab – might benefit from treatment with inebilizumab. This is remarkable, because rituximab is a B-cell depleting therapy as well. The small subgroup of patients who failed on rituximab showed low annualized attack rates. However, this observed trend needs further investigation, since the subpopulation of prior rituximab users was small.
