The primary outcome of the study, 50% reduction in corticosteroid dosing, was achieved by 60% of patients on IGIV-C and 63.3% of those randomly assigned to placebo.
Vera Bril, MD, FRCPC
Recently published findings from a phase 2, randomized, double-blind, placebo-controlled trial (NCT02473965) showed that immunoglobulin 10% caprylate/chromatography purified (IGIV-C; Gamunex; Grifols Therapeutics) therapy did not show a significant difference from placebo in reducing the corticosteroid (CS) dose in CS-dependent patients with myasthenia gravis (MG). These results suggest that effects of IGIV-C and CS are not synergistic and may be mechanistically different.1
Led by Vera Bril, MD, FRCPC, professor of medicine/neurology, University of Toronto, the study assessed percentage of patients on either IGIV-C or placebo who achieved a 50% reduction in CS dose at the end of a 39-week treatment period. All told, 60.0% of the patients on IGIV-C reached this benchmark compared with 63.3% of those in the placebo group. "This result may have been influenced by one of the selection criterion: eligible patients must have completed at least one prior attempt to taper CS. This assured that patients were on the lowest possible CS dose and that CS dose reduction was possible in these patients," Bril et al noted.
A total of 60 patients, aged 18 to 85 years, positive for antiacetylcholine (AChR) antibody and with a confirmed diagnosis of generalized MG were eligible and enrolled in the trial. At screening, potential patients were required to have MG symptoms controlled by CS and historical Myasthenia Gravis Foundation Association (MGFA) Class II-Iva. Systemic CS for at least 3 months was required with a stable CS dose of between at least 15 mg and 60 mg per day for 1 month prior to screening.
At baseline, patients received a loading dose of 2 g/kg IGIV-C over 2 days or placebo, followed by maintenance doses of 1 g/kg administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened, defined by Quantitative Myasthenia Gravis (QMG) score changes of at least 4 from baseline. CS doses were increased for those whose condition worsened; however, by week 6, patients were withdrawn if they failed to improve or if a second CS increase was needed. In total, 38 (63.3%) patients completed the study, with similar numbers of completion from either the IGIV-C (n = 18; 60.0%) or placebo (n = 20; 66.7%) groups.
Because there were a small number of patients in the higher CS dose stratum (41 mg-60 mg prednisone equivalent per day), no valid statistical analysis stratifying baseline CS doses could be conducted. Therefore, an additional analysis was conducted based on the median baseline CS doses prescribed at study entry, which was 20 mg/day prednisone or equivalent. Here, the data showed that 50% reduction of CS dose was more likely to occur in those with higher CS doses. This finding was seen in both the IGIV-C (70.0% vs 55.0%) and placebo (66.7% vs 60.0%) groups, with no meaningful between-arm difference in either subgroup (P = 1.00).
Percent reduction in CS dose, a secondary end point, was not statistically significantly different between the treatment groups (IGIV-C: 52.04% [±44.49]; placebo: 54.69 [±51.36]). Similarly, there were no between-group differences on 25th percentile of time to first worsening, as demonstrated by at least a 4-point increase in QMG score (IGIV-C: 33.10 weeks; placebo: 30.10 weeks). Using Kaplan-Meier methods, there were no difference in the probability of MG worsening between the treatment groups (P = .744), as well as no difference in exploratory end points except for immunoglobulin trough levels, which were significantly large in the IGIV-C group.
On safety analyses, IGIV-C was shown to be well-tolerated. In total, 90% of those on IGIV-C had at least 1 treatment-emergent adverse event (TEAE), which was similar to rates reported in the placebo arm (93.3%). Headache, MG worsening, upper respiratory tract infection, and nausea, were the most common TEAEs (>15%) in the IGIV-C group. Severe TEAEs, although rare, were found in 4.5% of those on IGIV-C and 13.4% on placebo. Additionally, there was 1 death in the IGIV-C group and 2 deaths in the placebo group. The deaths were attributed to a MG exacerbation, sepsis, and cardiac arrest in the setting of MG crisis, staphylococcal pneumonia, and acute respiratory failure. AEs leading to withdrawal occurred in 7 (23.3%) of the 30 subjects in the IGIV-C group and 4 (13.3%) of the 30 individuals in the placebo group.