UCB made public that the Journal of Neurology has disclosed data originating from an after-the-fact examination of the pivotal Phase 3 RAISE study and the continuous Phase 3 RAISE-XT open-label extension (OLE) study assessing the enduring impact of zilucoplan on exhaustion in adult patients with mild to severe anti-acetylcholine receptor antibody positive (AChR-Ab+) gMG.
The publication indicates that treatment with zilucoplan indicated statistical and substantial enhancements in fatigue scores and intensity compared to placebo by Week 12 during RAISE, which persisted until Week 60 in RAISE-XT.
These discoveries make zilucoplan the first C5 inhibitor to exhibit a significant reduction in fatigue, encompassing severe fatigue, which is notably incapacitating for patients.
Zilucoplan stands out as the primary once-daily subcutaneous (SC), targeted complement component 5 (C5) inhibitor for generalized myasthenia gravis (gMG), freshly sanctioned in the UK, Europe, the U.S., and Japan for adult patients with anti-acetylcholine receptor antibody positive (AChR-Ab+) gMG.
The findings revealed that patients with gMG treated with daily subcutaneous injections of the complement C5 inhibitor zilucoplan underwent meaningful enhancements in fatigue, preserved for over a year.
Clinically significant enhancement from baseline was characterized by a change of −3.5.
The post hoc analysis unveiled that mean Neuro-QoL Short Form Fatigue T-scores ameliorated from double-blind baseline to Week 12 in the zilucoplan group (n=86) with a clinically substantial disparity versus placebo (n=88; least squares mean difference: −3.61, and these enhancements were preserved up to Week 60 mean [SE] CFB −9.15 [1.80]. By Week 12, more patients on zilucoplan witnessed improvements in ≥1 fatigue severity level from baseline versus placebo.
The enhancements in fatigue discerned in the zilucoplan group during the double-blind phase of RAISE extended further into RAISE-XT, the ongoing OLE study, and were sustained up to Week 60, signifying that zilucoplan ameliorated fatigue in MG patients for up to 60 weeks. Among patients who shifted from placebo to zilucoplan in the OLE (placebo-switch group), enhancements were evident at the initial week after transitioning to zilucoplan 0.3mg/kg (Week 13).
Assessing fatigue severity scores, at double-blind baseline, most patients grappled with “severe” or “moderate” fatigue. Overall, by Week 60, the majority of patients observed an improvement to “mild” or no fatigue (n=55, 65.5%). These findings remained consistent across the zilucoplan group and in the placebo-switch group (data not exhibited).
In general, zilucoplan was well received and demonstrated a favorable long-term safety profile. Out of 200 enrolled patients, 188 (94.0%) patients reported a TEAE, and 64 (32.0%) patients reported serious TEAEs. The most frequent TEAEs comprised (worsening of) MG (26.0%), COVID-19 (24.5%), headache (17.5%), diarrhea (15.0%), and nasopharyngitis (15.0%). Seventeen (8.5%) patients experienced a TEAE resulting in permanent cessation of treatment.
gMG is an uncommon, persistent, heterogeneous, erratic autoimmune ailment characterized by dysfunction and damage at the neuromuscular junction (NMJ).
Several factors contribute to gMG disease pathology, including the complement cascade, immune cells, and pathogenic immunoglobulin G (IgG) autoantibodies.
In AChR antibody positive gMG, pathogenic AChR autoantibodies (IgG1 and IgG3) trigger the classical complement pathway, which, together with the alternative and lectin complement pathways, converge at C5, leading to MAC (membrane attack complex) deposition, NMJ damage, loss of AChRs, and subsequent impaired synaptic transmission. Preventing MAC formation diminishes damage to the post-synaptic membrane, reduces disruption of ionic channel conductance, and aids in preserving neuromuscular transmission.
MG has a worldwide prevalence of 100–350 cases per every 1 million individuals.
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