A new analysis from the phase 3 HALO development program showed that Teva’s CGRP inhibitor fremanezumab (Ajovy) separated from placebo by Day 2 posttreatment, suggesting not only rapid clinical improvement, but the potential to positively impact treatment adherence.
Paul K. Winner, DO
A new analysis of the phase 3 HALO clinical trial program suggests that the early onset of treatment effect of fremanezumab (Ajovy; Teva Pharmaceuticals) may have the ability to improve not only clinical outcomes for patients with chronic migraine, but adherence to medication regimens as well.
The fully-humanized calcitonin gene-related peptide (CGRP) antibody was approved by the FDA in June 2019 for the prevention of migraine in adults. In this analysis, it was observed to have significantly separated from placebo by Day 2 of treatment (P = .003), with a treatment effect seen for all groups by Week 1 compared to placebo (P <.0001).
The study, which included 1130 patients randomized to quarterly (n = 376) or monthly (n = 379) fremanezumab, or placebo (n = 375), was led by Paul K. Winner, DO, FAAN, FAAP, FAHS, director, Premiere Research Institute and the Palm Beach Headache Center, attending neurologist, Palm Beach Neurology, and clinical professor of neurology, Nova Southeastern University.
Winner and colleagues wrote that “overall, this study demonstrates that the efficacy and safety profile of fremanezumab, combined with the lack of a need for dose titration, subcutaneous formulation, flexible dosing schedule, and consistent demonstration of early onset of efficacy, may have the potential to address key barriers to compliance and improve clinical outcomes.”
Over the 12-week study period, the mean number of monthly headache hours was reduced by 38.0 hours (95% CI, −44,8 to −31.2) hours in the quarterly group, 42.8 hours (95% CI, −49.4 to −36.1) in the monthly group, and 24.0 hours (95% CI, −30.8 to −17.2) in the placebo group (both P <.001). These significant effects were observed as early as the 4 weeks within the first dose, with a baseline reduction of 37.6 hours (95% CI, −44.3 to −30.9) and 41.2 hours (95% CI, −47.8 to −34.6) in the quarterly and monthly groups, respectively, compared to 17.6 hours (95% CI, −24.3 to −10.9) in the placebo group (both P <.0001).
Additionally, this effect was observed to be maintained in the 4-week periods following the second and third doses (P <.05) for both groups.
During the 4-week period following the first dose, the all-fremanezumab cohort displayed significant decreases in monthly headache hours of 39.4 hours (95% CI, −44.9 to −33.9) compared with placebo’s reduction of 17.6 hours (95% CI, −24.3 to −10.9; P <.0001).
As well, 1 week after the first dose, treatment with the study drug was associated with a significant reduction of the weekly number of headache hours, with an observed reduction of 8.8 hours (95% CI, −10.5 to −7.2) compared with placebo, which experienced a reduction of 1.8 hours (95% CI, −3.9 to −0.3; P <.0001). This effect was maintained at Week 2 (P <.0001), Week 3 (P <.0001), and Week 4 (P = .0001).
“Adherence to migraine preventive medications is generally poor, with many patients discontinuing treatment due to factors such as lack of efficacy and poor tolerability,” Winner and colleagues detailed. “Currently available oral preventive medications for migraine, such as topiramate, require a relatively long dose-titration period, with a tendency for treatment-limiting adverse events to occur during this period…Furthermore, given that most patients suffer [from] nausea or vomiting as symptoms of migraine, the use of oral daily medications may prove very difficult, thereby limiting the clinical impact of such interventions.”
Winner et al noted that medications such as topiramate and onabotulinumtoxinA, while capable of treating patients with chronic migraine, often result in the experience of either unwanted adverse events (AEs)—in the case of topiramate—or delayed efficacy—in the case of onabotulintoxinA. This, they wrote, points to the fact that “treatments that address the diverse patient needs around the efficacy, safety, tolerability, and overall patient experience (quality of life, convenience, etc.) remain an unmet need in migraine, especially for those with chronic disease.”
Safety in this study resulted in the treatment being deemed well-tolerated, with 64% (n = 240) of placebo patients reporting an AE compared to 70% (n = 265) and 71% (n = 270) in the quarterly and monthly groups, respectively. Most were mild to moderate. Serious AEs were infrequent and similar across groups.
The primary results of the study, which were published in 2017, showed that the average number of headache days per month was reduced by 4.3 ±0.3 for those taking fremanezumab quarterly and 4.6 ±0.3 for those taking fremanezumab monthly, compared with 2.5 ±0.3 with placebo (P <.001 for both). Meanwhile, 38% of those on the quarterly regimen and 41% of those on the monthly regimen achieved ≥50% reduction in monthly migraine days, compared to 18% of those given placebo (P <.0001 for both).2
Winner and co. did acknowledge some limitations of the work, most notably that “some analyses were not defined as a priori, and despite what the placebo-subtracted differences would suggest, the effect sizes at early time points are not confirmed as clinically meaningful.”
Additionally, the treatment also recently showed success in patients with refractory migraine who experience their attacks on both an episodic and chronic basis.
1. Winner PK, Spierings ELH, Yeungh PP, et al. Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine. Headache. Published online November 1, 2019. doi: 10.1111/head.13654.
2. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113-2122. doi:10.1056/NEJMoa1709038.