The use of olamkicept (sgp130Fc) may be more beneficial for neuromyelitis optica spectrum disorder (NMOSD) patients than satralizumab (Enspryng®), a letter published in Multiple Sclerosis and Related Disorders argues.
Interleukin-6 (IL-6) has been shown to be involved in increasing the permeability of the blood-brain barrier (BBB), allowing anti-aquaporin-4 (anti-AQP-4) antibodies to attach to AQP-4 and cause an immune cascade resulting in the production of AQP-4-targeting immunoglobulin-Gs (AQP4-IgG). Satralizumab blocks the IL-6 receptor (IL-6R) and has been shown to reduce the risk of relapse in people with NMOSD.
IL-6 can play 2 different roles in the body, however, with a proinflammatory trans-signaling pathway mediated by the soluble form of IL-6R (sIL-6R) and an anti-inflammatory classic-signaling pathway mediated by membrane-bound forms of IL-6R (mIL-6R).
The trans-signaling pathway is believed to play a role in the neuronal degeneration of NMOSD, while the classic-signaling pathway has been hypothesized to play a protective role in the central nervous system through the acceleration of nerve regeneration following trauma.
Read more about satralizumab for NMOSD.
“Neutralizing antibodies against IL-6 or IL-6R (like satralizumab) globally block all IL-6 activities, both classic-signaling (anti-inflammatory) and trans-signaling (pro-inflammatory), determining profound immunosuppression and loss of the neuroprotective side of IL-6,” wrote the author, Giuseppe Magro, from Magna Græcia University of Catanzaro in Italy.
“Selective blockade of the pro-inflammatory pathway (trans-signaling) could lead to better outcomes in autoimmune disorders where IL-6 plays a major role,” he added.
Evidence points to the trans-signaling pathway being involved in the major issues in NMOSD, with in vitro models showing increased BBB permeability following pathway activation, and clinical investigation has shown increased levels of sIL-6R in patients.
No evidence of impairment of regeneration following treatment with satralizumab has been demonstrated in NMOSD patients but more investigation is needed.
“These results suggest the possibility that the detrimental role of IL-6 in NMOSD is mainly mediated by the trans-signaling, therefore specifically targeting this pathway represents a more reasonable approach,” the author concluded.
“Olamkicept (sgp130Fc) is a recently approved monoclonal antibody that prevents only the trans-signaling pathway of IL-6 to be activated,” he explained.
In a previous phase 2 clinical trial (FUTURE) in patients with irritable bowel disease, olamkicept was able to induce a clinical response in 44% of patients and clinical remission in 19%. No trials of olamkicept in NMOSD have been conducted yet, however.
Magro G. Satralizumab might not be enough. Olamkicept (sgp130Fc) in neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2022;65:104037. doi:10.1016/j.msard.2022.104037