A 2024 systematic review and network meta analysis (NMA) of 18 randomized controlled trials (RCTs) including 22,429 patients compared Lasmiditan, Rimegepant, Ubrogepant, and Zavegepant for acute migraine treatment. All agents were superior to placebo. For pain freedom at 2 hours, lasmiditan 100 mg (risk ratio [RR] 1.54; 95% confidence interval [CI] 1.21 to 1.99), lasmiditan 200 mg (RR 1.85; CI 1.46 to 2.40), rimegepant 75 mg (RR 1.82; CI 1.30 to 2.55), and ubrogepant 25 to 100 mg were all effective, with ubrogepant 100 mg ranking highest. For pain relief at 2 hours, lasmiditan 100 mg (RR 1.44; CI 1.34 to 1.55) and 200 mg (RR 1.43; CI 1.33 to 1.54) ranked highest and were superior to lower dose ubrogepant and zavegepant. For most bothersome symptom freedom at 2 hours, rimegepant 75 mg (RR 1.40, CI 1.17 to 1.68) and ubrogepant 50 mg (RR 1.40; CI 1.11 to 1.78) ranked highest. For sustained pain relief at 24 hours, all gepants were effective, including rimegepant, ubrogepant 25 to 100 mg, and zavegepant 5 to 20 mg. For photophobia freedom at 2 hours, rimegepant 75 mg showed strong efficacy (RR 1.53; CI 1.31 to 1.79), and for phonophobia freedom, rimegepant (RR 1.51; CI 1.20 to 1.90) and ubrogepant 50 mg (RR 1.30; CI 1.07 to 1.60) were significant. [1]
In terms of safety, Lasmiditan had the highest risk of adverse events, with dose-related increases in dizziness, paresthesia, and fatigue. In contrast, Rimegepant showed no significant increase in adverse events compared with placebo, and Ubrogepant had generally similar safety across doses, although nasopharyngitis was increased with 50 mg (RR 11.25; CI 1.46 to 86.79). Zavegepant was associated with dysgeusia and dose-related nasal discomfort. Overall, rimegepant 75 mg and ubrogepant 100 mg demonstrated a favorable balance of efficacy and safety, while lasmiditan showed strong efficacy but worse tolerability; however, conclusions are limited by indirect comparisons and variable certainty of evidence. [1]
A 2024 Bayesian NMA evaluated the efficacy and safety of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) for the prevention of chronic migraine, incorporating data from 10 RCTs identified through systematic searches of PubMed, MEDLINE, Cochrane, and ICTRP databases. The analysis compared multiple mAbs, including eptinezumab, fremanezumab, galcanezumab, and erenumab, across outcomes of mean monthly migraine days (MMD), ≥50% responder rates, and treatment-emergent adverse events over a 12-week follow-up period. Results demonstrated that galcanezumab 120 mg was associated with the greatest reduction in MMD (mean difference [MD] −2.7; 95% credible interval [CrI] −4.8 to −0.83), while fremanezumab quarterly dosing showed the highest responder rate (odds ratio [OR] 2.9; 95%CrI 1.9 to 4.6). In terms of safety, eptinezumab was associated with the lowest rate of adverse events (OR 0.88; 95%CrI 0.61 to 1.3) compared with other mAbs. Surface under the cumulative ranking (SUCRA) analysis further supported these findings, ranking fremanezumab highest for response rate and eptinezumab as the safest option, while galcanezumab ranked highest for reduction in migraine days. The study concluded that, although all evaluated anti-CGRP mAbs demonstrated broadly similar efficacy and safety profiles, differences in relative performance were observed across specific endpoints; however, the absence of head-to-head trials and the need for long-term data were noted as limitations. [2]
A 2023 meta-analysis of RCTs evaluated the “wearing-off” efficacy of CGRP monoclonal antibodies for migraine prevention, incorporating four phase 3 trials (EVOLVE-1, EVOLVE-2, REGAIN, and CONQUER) with a total of 2,409 patients. The analysis focused exclusively on galcanezumab and assessed changes in migraine frequency between earlier and later weeks within a dosing cycle. Overall, there was no statistically significant difference in wearing-off effect between galcanezumab and placebo (pooled risk ratio [RR] 1.29; 95% CI 0.73 to 2.28; I²= 58.18%). However, subgroup analysis demonstrated a statistically significant increased wearing-off effect in patients with chronic migraine (RR 1.91; 95% CI 1.11 to 3.28), while no significant effect was observed in high-frequency episodic migraine. No significant differences were identified between galcanezumab doses (120 mg vs 240 mg). The analysis did not include other CGRP-targeting therapies such as fremanezumab, erenumab, or eptinezumab due to lack of available RCT data for this specific outcome, and therefore did not provide direct comparative efficacy or safety data across different CGRP receptor antagonists or monoclonal antibodies. [3]
A 2023 NMA of 19 phase 3 RCTs (n= 14,584) evaluated the efficacy of CGRP monoclonal antibodies (erenumab, eptinezumab, fremanezumab, galcanezumab) and gepants (atogepant, rimegepant) for migraine prevention. Across included studies, all agents demonstrated superiority to placebo in reducing mean monthly migraine days and improving ≥50% responder rates, although statistical significance for responder rates was primarily observed with subcutaneous and intravenous therapies and not consistently with oral agents. Indirect comparisons suggested that differences in efficacy between agents were generally small, with some variability by dose and route of administration; however, no direct head-to-head trials were identified. Importantly, the analysis was based on separate network meta-analyses by route of administration, limiting cross-class comparisons between monoclonal antibodies and gepants. Safety outcomes were not evaluated within this analysis and were reported separately. Overall, while the findings support class-wide efficacy versus placebo, the absence of direct comparative trials precludes definitive conclusions regarding relative efficacy or safety between CGRP receptor antagonists and other CGRP-targeting therapies. [4]
Another 2023 NMA of 19 RCTs including 14,584 patients compared the safety and tolerability of CGRP pathway therapies for migraine prevention, including monoclonal antibodies such as Erenumab, Eptinezumab, Fremanezumab, and Galcanezumab, as well as gepants Atogepant and Rimegepant. For treatment-emergent adverse events, atogepant 120 mg (odds ratio [OR] 2.22; 95% CI 1.26 to 3.91) and galcanezumab 240 mg (OR 1.63; CI 1.33 to 2.00) showed the highest odds compared with placebo. Eptinezumab 30 mg was associated with higher odds of adverse events leading to treatment discontinuation (OR 2.62; CI 1.03 to 6.66). No significant differences in serious adverse events were observed between any active treatments and placebo. Across treatments, Eptinezumab was associated with the lowest odds of treatment-emergent adverse events and serious adverse events, while Erenumab had the lowest odds of any adverse events overall, and quarterly Fremanezumab had the lowest odds of discontinuation due to adverse events. Overall, both monoclonal antibodies and gepants were well tolerated with no increased risk of serious adverse events, though some differences in non-serious adverse event rates were observed across individual agents. [5]
A 2022 systematic review and meta-analysis of 15 RCTs evaluated the safety of oral calcitonin gene-related peptide receptor antagonists for acute migraine, including BI44370TA , MK-3207 (both are abandoned developmental drugs), Rimegepant, telcagepant, and Ubrogepant. Across studies, CGRP receptor antagonists were associated with a modestly increased risk of any adverse events compared with placebo (RR 1.15; 95% CI 1.07 to 1.23), but there was no significant difference in treatment-related adverse events (RR 1.18; CI 1.00 to 1.38). Compared with triptans, CGRP receptor antagonists demonstrated a more favorable safety profile, with lower rates of any adverse events (RR 0.78; CI 0.63 to 0.98) and treatment-related adverse events (RR 0.68; CI 0.58 to 0.79). Overall, the analysis suggests that oral CGRP receptor antagonists have generally good tolerability in acute migraine treatment. While they may slightly increase non-serious adverse events compared with placebo, they appear safer than triptans with respect to overall adverse event burden, supporting their role as a better tolerated alternative option for acute migraine therapy. [6]
A 2021 network meta-analysis of 27 RCTs evaluated the efficacy of CGRP receptor antagonists, including erenumab, eptinezumab, fremanezumab, and galcanezumab, in reducing monthly migraine headache days (MHDs) in patients with episodic and chronic migraine. Across treatment durations of 6, 8, and 12 weeks, all evaluated agents demonstrated greater reductions in MHDs compared with placebo, with relative efficacy varying by time point and dose. At 6 weeks, fremanezumab (notably 900 mg) showed the greatest reduction in MHDs (SMD −0.55; 95% CI −0.97 to −0.12), whereas at 8 and 12 weeks, erenumab 140 mg demonstrated the highest efficacy (SMD −0.51 and −0.48, respectively). Subgroup analyses indicated that in chronic migraine populations, fremanezumab 900 mg, erenumab 140 mg, and erenumab 70 mg were most effective at 6, 8, and 12 weeks, respectively, while in episodic migraine, galcanezumab 300 mg was most effective at 6 weeks and erenumab 140 mg at later time points. When analyzed irrespective of dose, fremanezumab ranked highest at 6 weeks, whereas erenumab ranked highest at 8 and 12 weeks. The analysis provides indirect comparative efficacy data across CGRP receptor antagonists using network meta-analytic methods; however, the study primarily evaluated efficacy outcomes (MHD reduction), and no direct comparative conclusions regarding safety differences between agents were reported. [7]
A 2022 prospective single-center cohort study evaluated real-world use of erenumab, galcanezumab, and fremanezumab in 203 adults with resistant chronic migraine (84.7% with medication overuse) followed up to 12 months. The study was not designed to compare agents directly and reported descriptive findings only. Overall, all three anti-CGRP monoclonal antibodies were described as similarly effective, with improvements in monthly migraine days, MIDAS scores, HIT-6 scores, and analgesic use. ≥50% monthly migraine day responder rates ranged from 36.4% to 56.8%, while ≥50% MIDAS reduction ranged from 89.5% to 100%. No severe treatment-related adverse events were reported; adverse drug reactions occurred in 7.9% of patients, and 1.5% discontinued treatment due to persistent fatigue. [8]