Telitacicept following plasma exchange in the treatment of subjects with recurrent neuromyelitis optica spectrum disorders: A single‐center, single‐arm, open‐label study

Abstract Introduction Neuromyelitis optica spectrum disorders (NMOSD), mainly mediated by B cells and AQP4 antibody, has a high rate of recurrence. Telitacicept is a novel drug specifically targeting the upstream signaling for the activation of B cell with its following production of autoimmune antibodies. Thus, it may be a promising approach. Our study preliminarily explored the potential safety and effectiveness of Telitacicept following plasma exchange in the treatment of recurrent NMOSD. Methods This was a single‐center, single‐arm, open‐label study enrolling eight patients with recurrent NMOSD in China. All patients received plasma exchange three times, followed by Telitacicept 240 mg every week for 46 times. The primary endpoint was the time of first recurrence after enrollment. Secondary end points included: changes in Expanded Disability Status Scale score, Optic Spinal Impairment Scale score, Hauser Ambulation Index, number of lesions on MRI, retinal nerve fiber layer thickness measured by optical coherence tomography, latency and amplitude of visual evoked potential, titer of AQP4 antibody, and immune parameters of blood. Safety was also assessed. The study was registered with Chictr.org.cn (ChiCTR1800019427). Results Eight eligible patients were enrolled. Relapse occurred in two patients (25%) and five patients (63%) remained relapse free after 48 weeks of treatment. The time to first recurrence was prolonged and the number of recurrences was reduced (p < 0.001, power of test = 1). One patient withdrew from the study due to low neutrophil count. No serious adverse events occurred. Conclusions In this small, uncontrolled study, Telitacicept following plasma exchange has the potential to be a safe treatment for patients with recurrent NMOSD. It may prolong the recurrence interval and reduces the annual count of recurrences. A multicenter randomized controlled study with a larger sample is thus feasible and needed to further assess its safety and efficacy.


| INTRODUC TI ON
Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune disease of the central nervous system (CNS) mainly mediated by B cells and AQP4 antibody. 1 The prevalence rate is ∼0.5-4 per 100,000 and it can reach 10 per 100,000 in some ethnic groups. 2 It has a high rate of recurrence and disability. 3,4 The reported incidence of NMOSD in female is up to 10 times higher than in men. The median age of onset is around 40 years old, with a high incidence in young and middle-aged people. 5,6 NMOSD greatly impacts both individuals and society. Therefore, a safe and effective treatment targeting the pathogenesis of NMOSD is urgently needed.
Nowadays, the treatment of NMOSD varies according to the stage of the disease. In the acute stage of relapse, initial treatments involve high-dose intravenous methylprednisolone, intravenous immunoglobulin 7 and plasma exchange. 8,9 Plasma exchange has been proved to be effective in the treatment of acute-phase NMOSD. [9][10][11] It substantially filters the major pathogenic molecules, such as AQP4 antibody. In the remission phase, concomitant immunotherapy such as azathioprine and mycophenolate mofetil are used to prevent recurrence. Although there are some recent drug developments in phase III clinical trials in NMOSD, 12 current immunosuppressant medications are used off-label for the prevention and treatment in patients with NMOSD. 13 Stepwise deterioration due to recurrent attacks and accumulated disability remain an intractable problem in patients with NMOSD. The side effects of glucocorticoid and current immunotherapy, such as leukocytopenia and osteonecrosis of femoral head, lead to poor compliance and outcome. 14 19 Telitacicept was reported to be safe and effective in experimental autoimmune encephalomyelitis (EAE), an animal model of inflammatory demyelinating disease of the CNS. 20 BLyS and APRIL are members of Tumor Necrosis Factor (TNF) family, predominantly found in B cell-mediated autoimmune diseases such as SLE, RA and NMOSD rather than MS. [21][22][23][24][25] Thus, it is plausible that Telitacicept may be a promising drug regimen in NMOSD.
Telitacicept is a novel drug specifically targeting the upstream signaling for the activation of B cell with its following production of autoimmune antibodies. It is thus plausible to speculate upon the therapeutic potential of Telitacicept in prolonging the effectiveness of plasma exchange, which eliminate the existing autoimmune antibodies in the circulation. According to our knowledge, we are the first group to investigate the outcome in the treatment of recurrent NMOSD with Telitacicept following plasma exchange.
As the strict regulations and high-standard requirements for initiating clinical research in Shanghai, we are only allowed to conduct a single-center clinical study of Telitacicept in a small scale due to the registered indications of Telitacicept is limited to SLE only. Therefore, the objective of this study is to investigate preliminarily, for the first time, the potential safety and efficacy of Telitacicept following plasma exchange in treating recurrent NMOSD, providing insight for future large-scale multicenter randomized controlled trials.  severe mental illness symptoms, who were unable to collaborate; (9) patients unable to undergo MRI examination; (10) patients who had used rituximab or mitoxantrone during 3 months before enrollment.

| Procedures
Specific details regarding this study procedures, can be found in our study protocol published previously. 26 All patients received plasma exchange three times. Telitacicept was then administered subcutaneously 14 days after enrollment, with a dose of 240 mg once a week (at least 48 h apart) for 46 times in total. After registration, participants received no systemic corticosteroids or immunosuppressive agents such as azathioprine, mycophenolate mofetil, cyclosporine and methotrexate. Biological immunosuppressive agents, hematopoietic stem cell transplantation, lymphatic irradiation and immunoglobulin injection were also prohibited.
During the study, visits were conducted at 4th, 12th, 24th and 48th week after enrollment. Expanded Disability Status Scale (EDSS) score, Optic Spinal Impairment Scale (OSIS) score and Hauser Ambulation Index were evaluated by two senior neurologists.
Patients who had a protocol-defined recurrence were recorded and withdrawn from the study. A recurrence was defined by the following criteria: (1) the appearance of new nervous system abnormalities or deterioration of the original symptoms; (2) the symptoms last for at least 24 h; (3) more than 30 days from the last recurrence; (4) without fever, body temperature <37.5°C without infection. 27 Blood and urine tests were performed at the baseline, 4th, 12th, 24th and 48th week after enrollment or recurrence, including virological examination, pregnancy test, complete blood count, serum biochemicals, immunoglobulin, complement, lymphocyte subsets count and urine routine. Optical coherence tomography (OCT) was used to evaluate the changes in retinal nerve fiber layer (RNFL) thickness according to "Fast RNFL Thickness" protocol.
Visual evoked potential (VEP) was used to record the latency and amplitude of P100. Titers of AQP4 antibody, BLyS and APRIL were examined at baseline, 24th and 48th week after enrollment. The titer of AQP4 antibody was detected by cell-based transfection immunofluorescence assay (CBA), BLyS and April by enzyme-linked immunosorbent assay (ELISA). Brain, optic nerve and spinal cord MRIs were performed at baseline, 48th week or in case of recurrence. The number of low-signal lesions on T1 weighted images (T1WI), high-signal intensities on T2 weighted images (T2WI) and gadolinium enhanced

| Baseline characteristics
A total of ten patients were screened, of which eight met the inclusion criteria and were enrolled in the study (Figure 1). One patient was eliminated because of withdrawal of informed consent and the other one met the exclusion criteria of history of severe liver disease (more than twice the normal value of liver function test). Among eight patients, females accounted for 87.5% (n = 7) and males for 12.5% (n = 1). The age of the enrolled subjects ranged from 24 to 66 years with a median age of 53 years. All patients are seropositive to anti-AQP4. The patient characteristics are listed in Table 1. Three patients failed to receive or tolerate attack prevention therapies before enrollment.
Five patients received immunosuppressant treatments before enrollment. Regardless of prior drug regime, the recurrence rate remains high in all eight patients. The times of relapses prior to registration was 3 (2-7) and the duration of disease was 1.20 (0.14, 18.43) years ( Table 2).

F I G U R E 2
Attack frequency before and during Telitacicept treatment enrollment (p < 0.001, power of test = 1; Table 2; Figures 2 and 3). Two patients with relapse both had preceding fatigue followed by optic neuritis sparing spinal cord. The EDSS score increased by 2 points.
After 48-week treatment, EDSS score was ameliorated from 3.5   Table S1). The serum AQP4 antibody titer tended to be stable. It increased during the last visit in some patients. The level of BLys and APRIL generally decreased along the course in relapse-free participants, but increased at recurrence. Interestingly, Patient 5 had increased levels of both BLys and APRIL at 24 weeks, without recurrence during the study.  (Table S2).

| Characteristics of OCT and VEP
The thickness of RNFL in OCT tended to be stable. In the left eye of patient 2, it gradually became thinner since the visit at 4th week.
However, there was no significant change in the VEP examination and clinical symptoms.
The latency and amplitude of VEP P100 wave tended to be stable during the study. Due to the poor compliance of Patient 8, the P100 wave of VEP in binocular cortex was not recorded at 4th, 24th, 48th week (Table S2).

| Safety assessment
A total of 43 adverse events were registered (AE). Injected site swelling was the most frequent adverse event, which was ameliorated within 2-4 months ( Table 3). Patient 7 was affected by concomitant SLE and RA. She had a history of leukopenia and decreased neutrophil count and, during the study, her neutrophil count was less than 1.0 × 10 9 /L for two times. According to the protocol, the patient was removed from the study. The researchers considered that, for this patient, the decreased neutrophil and leukocyte count is likely attributable to either the administration of Telitacicept or concomitant SLE. Patient 3 and 4 were child-bearing age females and they had amenorrhea and menorrhagia, respectively. Patient 3 had late menarche and irregular menstruation prior to this study. Patient 4 had similar symptoms before enrollment. Further investigation is required to determine whether these episodes were related to the intervention of this study.

| DISCUSS ION
This is the first study to introduce Telitacicept following plasma exchange to recurrent NMOSD patients during acute phase.
Plasma exchange removes pro-inflammatory factors, providing a fresh start for Telitacicept to kick in. Telitacicept neutralizes the interaction between BLys and APRIL, resulting in inhibition of autoimmune humoral immunity and prolonged recurrent interval of NMOSD. In our study, the time of first recurrence was prolonged and the disability function score decreased, indicating a potiential effectiveness of Telitacicept in preventing the recurrence of NMOSD, avoiding the side effects of corticosteroid hormone.
Adverse events were mild and resolved quickly, and no serious

| CON CLUS ION
In conclusion, this is the first study of Telitacicept following plasma exchange, a novel therapeutic strategy, in recurrent NMOSD. This exploratory study showed that Telitacicept following plasma exchange has the potential to be generally well tolerated in patients

CO N FLI C T O F I NTE R E S T
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

I N FO R M ED CO N S ENT
Written informed consent was obtained from participants or their guardians.