Erenumab Dosage for Migraine Prevention

An Evidence-Based Narrative Review With Recommendations

Stewart J. Tepper MD; Huma U. Sheikh MD; Carrie O. Dougherty MD; Stephanie J. Nahas MD MSEd; Paul K. Winner DO; Ananda Krishna Karanam PhD; Andrew M. Blumenfeld MD; Ahmad Abdrabboh PharmD MPH; Soeren Rasmussen MD; Jamie L. Weiss PhD; Jessica Ailani MD

Disclosures

Headache. 2022;62(4):420-435. 

In This Article

Efficacy Data

EM and CM: Core studies

Clinical studies demonstrated that treatment with erenumab (70 and 140 mg vs. placebo) is effective in reducing monthly migraine days (MMD) frequency, number of acute monthly migraine-specific medication treatment days (MSMD), and in increasing the probability of achieving ≥50% reduction in MMD from baseline across the migraine spectrum of EM and CM.[10,11] Most endpoints were numerically higher for erenumab 140 mg than 70 mg (Table 5). The mean MMD at the STRIVE study[10] baseline was 8.3 days; over the last 3 months (Months 4–6) of the DBTP, the mean MMD was reduced by 3.7 (to 4.6) with erenumab 140 mg and by 3.2 (to 5.1) with 70 mg. The proportion of participants who achieved ≥50% reduction in MMD from baseline was numerically greater among those treated with erenumab 140 mg (50.0%) versus 70 mg (43.3%). The mean MSMD was reduced by 1.6 (to 1.8) from a baseline of 3.4 with erenumab 140 mg and by 1.1 (to 2.1) from a baseline of 3.2 with 70 mg.

As with the STRIVE study,[10] the Phase 2 EM study in participants from Japan demonstrated superiority of the two erenumab doses across a range of outcomes.[28] The mean MMD was reduced by 1.8 (to 6.3) from a baseline of 8.1 and by 2.3 (to 5.5) from a baseline of 7.8 with 70 mg over the last 3 months of the DBTP. A ≥50% reduction in MMD from baseline was observed in 27.2% (140 mg) and 28.9% (70 mg) of participants. The mean MSMD was reduced by 1.2 (to 4.7) from a baseline of 5.9 with erenumab 140 mg and by 1.2 (to 4.2) from a baseline of 5.4 with 70 mg. Unlike the STRIVE study,[10] where numerically greater efficacy was observed with erenumab 140 mg, the 70 mg dose in this Japanese population appeared to have numerical benefit. The difference in results between this study and the global STRIVE study could be due to genetic factors or a lower body mass index in the Japanese participants (22.0 kg/m2) versus participants in the global STRIVE study (27.2 kg/m2), causing differences in exposure to erenumab between the two populations.[28]

In addition to the proven efficacy of erenumab in EM, the results from the pivotal Phase 2 CM study[11] demonstrate efficacy versus placebo in the population with a greater disease burden. The mean MMD was reduced by 6.6 (to 11.2) from a baseline of 17.8 with erenumab 140 mg and by 6.6 (to 11.3) from a baseline of 17.9 with 70 mg over the last 4 weeks of the DBTP (Weeks 9–12). The proportion of participants who achieved ≥50% reduction in MMD from baseline was similar between the two doses (41% [140 mg] and 40% [70 mg]). The mean MSMD was reduced by 4.1 (to 5.6) from a baseline of 9.7 with erenumab 140 mg and by 3.5 (to 5.3) from a baseline of 8.8 with 70 mg. The mean reduction in cumulative monthly headache hours from baseline was in favor of erenumab 140 mg (−74.5) versus 70 mg (−64.8).

EM and CM: Extension Studies

Importantly, benefits observed in DBTP of the STRIVE were confirmed in the STRIVE active treatment phase (ATP).[24] Again, most endpoints were numerically higher for erenumab 140 mg than 70 mg (Table 6). At Week 52 of the ATP, the mean change in MMD was −4.6/−1.8 (to 3.6/3.5) from the pre-DBTP/pre-ATP baseline of 8.2/5.3 with erenumab 140 mg and −4.2/−1.1 (to 4.1/4.1) from a pre-DBTP/pre-ATP baseline of 8.3/5.2 with 70 mg. The proportion of participants who achieved a ≥50% reduction in MMD from the pre-DBTP baseline at Week 52 was numerically greater among those treated with erenumab 140 mg (64.9%) versus 70 mg (61.0%). The mean change in MSMD was −2.0/−1.0 (to 1.5/1.5) from a pre-DBTP/pre-ATP baseline of 3.5/2.5 with erenumab 140 mg and −1.8/−0.7 (1.8/1.9) from a pre-DBTP/pre-ATP baseline of 3.6/2.6 with 70 mg. Additionally, the efficacy of erenumab in the STRIVE ATP study[24] was assessed by comparing the mean change in MMD from pre-ATP baseline at Week 52 in participants continuing on the same erenumab dose (70 or 140 mg), participants increasing to 140 mg, or those decreasing to 70 mg. The mean change in MMD among participants who switched from erenumab 140 to 70 mg was −0.1 day and those who switched from erenumab 70 to 140 mg was −1.8 days, and the mean change in MMD among those who remained on the same dose was −0.6 (140 mg) and −1.1 (70 mg) days. The mean change in MMD among participants who switched from placebo to erenumab 70 mg was −2.2 days and among those who switched from placebo to erenumab 140 mg was −2.9 days. These results reflect the numerically greater efficacy of erenumab 140 versus 70 mg in DBTP of the STRIVE study and demonstrate that while the efficacy was maintained for the two doses of erenumab during the ATP, a numerically greater benefit is observed when switching from erenumab 70 to 140 mg.

Data were also available to assess the relative efficacy of erenumab doses in the extension studies[23,29] of the Phase 2 EM study[20] and the Phase 2 pivotal CM study.[11] Data from an interim analysis of 4+ years of the 5-year OLE of the EM study[23] provides evidence that switching from erenumab 70 to 140 mg is associated with a further therapeutic gain. The mean MMD at baseline was 8.7 days and the mean MSMD at baseline was 6.1 days; at the time of interim analysis (representing a time on erenumab of 4+ years), the mean change from baseline after switching to erenumab 140 mg was −5.8 (to 2.9) MMD and −4.6 (to 1.5) MSMD. Overall, 77%, 56%, and 33% participants achieved ≥50%, ≥75%, and 100% reduction in MMD from baseline.

Similarly, results of post-hoc analyses based on the last dose received from the 1-year OLE[29] of the Phase 2 registration CM study[11] of erenumab showed that while the efficacy of the two doses was sustained, greater clinical benefits were observed with erenumab 140 versus 70 mg across the MMD and responder rate outcomes (≥50%, 75%, and 100% response thresholds). At Week 52, the mean change in MMD was −10.5 (to 7.3) from the parent study baseline of 17.8 with erenumab 140 mg and −8.5 (to 9.4) from the parent study baseline of 17.9 with 70 mg. The proportion of participants who achieved ≥50% (67.3% vs. 53.3%), ≥75% (41.8% vs. 27.1%), and 100% (12.7% vs. 6.1%) reductions in MMD from the parent baseline was greater with erenumab 140 versus 70 mg. The mean change in MSMD was −6.7 (to 4.6) from the parent study baseline of 11.3 with erenumab 140 mg and −6.2 (to 6.2) from the parent study baseline of 12.4 with 70 mg. A numerically greater efficacy observed with erenumab 140 versus 70 mg on a majority of efficacy endpoints suggests that erenumab 140 mg may provide better long-term efficacy in participants with CM than erenumab 70 mg.

Efficacy in Difficult-to-treat Migraine

The studies identified in our search suggest that treatment with erenumab is effective across the migraine spectrum (EM and CM) in specific participant populations who have difficult-to-treat disease. These include participants with prior preventive treatment failure (TF),[13,14] and those with acute medication overuse.[15] Results from these studies further suggest that the efficacy associated with erenumab 140 mg is again numerically greater than with 70 mg.[13,14]

A prespecified post-hoc analysis[13] over Months 4–6 of the STRIVE study,[10] reported a mean change in MMD and MSMD from baseline that was numerically greater with erenumab 140 versus 70 mg for all TF subgroups (0, ≥1, and ≥2 TF; Table 7). The proportion of participants achieving ≥50%, ≥75%, and 100% response thresholds was higher with erenumab 140 versus 70 mg across all three TF subgroups (Table 7).

Erenumab 140 mg appears to be particularly more effective than 70 mg in reducing MSMD in participants with EM and TF. Results from a prespecified post-hoc analysis[14] of the Phase 2 pivotal CM study[11] support the premise that the 140 mg may have greater efficacy against MSMD in the population of those with even more difficult-to-treat CM and TF. At Month 3, the mean change in MMD and MSMD from baseline was numerically greater with erenumab 140 versus 70 mg (Table 7) among participants with ≥1 and ≥2 TF, but was similar between the two erenumab doses for MSMD and greater for MMD in the erenumab 70 mg dose group among those with no history of TF. The proportion of participants achieving ≥50% and ≥75% response thresholds was also numerically greater with erenumab 140 versus 70 mg among participants who experienced ≥1 and ≥2 TF (but not in those with no history of TF; Table 7). Similar to the STRIVE post-hoc analysis of participants with TF,[13] these results in a participant population with more severe disease (CM) show that erenumab 140 mg was also numerically better than erenumab 70 mg in reducing MMD and in increasing the probability of reaching the ≥50% MMD response threshold.

Participants with migraine and acute medication overuse represent another population with difficult-to-treat disease. Here, the difference in the two doses is less clear. In a subgroup analysis[15] (of the Phase 2 registration CM study[11]) of participants with medication overuse, the least-squares mean change in MMD with the two erenumab doses was −6.6 (to 12.2) from baseline of 18.8 over the last month of DBTP (Month 3). The least-squares mean change in MSMD was −4.9 (to 8.2) from baseline of 13.1 with erenumab 140 mg and −5.4 (to 6.9) from baseline of 12.3 with 70 mg. The proportion of participants achieving a ≥50% reduction in MMD from baseline was similar between both groups (34.6% [140 mg] and 36.4% [70 mg]).

Exploratory Analysis of Phase 2 CM Study

A post-hoc analysis[16] of the Phase 2 study[11] was performed to contextualize the actual treatment benefit in participants with CM achieving or not achieving response thresholds (≥50%, ≥75%, and 100% reduction in MMD). At Month 3, the proportion of participants achieving ≥50% and ≥75% response threshold (but not 100% responder threshold) was numerically greater with erenumab 140 mg than 70 mg (Table 7). Moreover, for the efficacy outcome measures of MMD and MSMD at Month 3, the proportion of participants achieving spectrum of response thresholds (≥50%, ≥75%, and 100%) was numerically greater with erenumab 140 mg than 70 mg (Table 7).

Onset of Efficacy

Results from a post-hoc analysis[27] of the STRIVE study[10] and the Phase 2 CM study[11] showed the onset of efficacy as early as the first week with erenumab 70 and 140 mg in participants across the spectrum of migraine. The mean weekly migraine days (WMD) in the two studies was 2.1 for EM and 4.5 for CM. For EM, the least-squares mean change in WMD from baseline as early as Week 1 was −0.6 (to 1.5) with erenumab 140 mg and −0.3 (to 1.8) with 70 mg. For CM, the least-squares mean change in WMD from baseline as early as Week 1 was −0.8 (to 3.7) with erenumab 140 mg and −0.9 (to 3.6) with 70 mg. The odds of achieving ≥50% reduction from baseline in WMD at Week 1 and Week 4 was higher with erenumab 140 versus 70 mg in STRIVE, but similar in the Phase 2 CM study with the two erenumab doses (Table 7).

Conversion From CM to EM

Findings from a post-hoc analysis[19] of the Phase 2 registration CM study[11] followed by OLE showed that participants who had reversion to EM as assessed during Weeks 1–12 of the DBTP remained as EM over the longer-term erenumab treatment (i.e., DBTP plus OLTP). Over 12 weeks of the DBTP, 53.1% of the participants (n = 190/358) achieved EM reversion (53.9% [n = 96/178; 70 mg] and 52.2% [n = 94/180; 140 mg]). Overall, 66.3% (n = 120) of completers (i.e., participants who completed DBTP and OLTP; N = 181) achieved a long-term reversion to EM, irrespective of reversion status after 12 weeks DBTP. Conversely, 45.9% (n = 83/181) of completers remained in CM over 12 weeks of the DBTP, and 43.4% (n = 36/83) who had attained delayed reversion to EM (i.e., no reversion in the DBTP) remained in EM reversion (77.8%; n = 28/36) over 52 weeks of OLTP (i.e., delayed long-term reversion to EM).

At Weeks 40 and 52 of the OLTP (based on the last dose received), participants achieved higher EM reversion rates with erenumab 140 versus 70 mg dosage (Week 40: 75.9% [140 mg] and 64.5% [70 mg]; Week 52: 75.8% [140 mg] and 69.2% [70 mg]). About two-thirds of participants with CM who received erenumab had reversion to EM that persisted over 64 weeks, and the likelihood of this outcome was numerically higher with erenumab 140 mg than 70 mg.

Temporal Response Patterns

The AHS[4] and EHF[5] guidelines recommend mAbs against CGRP or its canonical receptor in adults with migraine in whom at least two available preventive treatments were unsuccessful. Given the half-life of erenumab and time-to-steady state, temporal response patterns are of clinical relevance, as those who may not respond initially to mAb treatment may respond during subsequent months (i.e., 4 weeks after each first, second, and third subcutaneous doses).[4] A post-hoc analyses of the STRIVE study[10] and the pivotal Phase 2 CM study[11] were performed to evaluate continuous responses to treatment with erenumab in participants with CM and EM.[30,31] After the first month of erenumab treatment, the proportion of participants with EM who subsequently achieved ≥50% response threshold increased over time, and this proportion was greater in those receiving 140 versus 70 mg (Month 1: 36% vs. 33%; Month 2: 31% vs. 24%; Month 3: 48% vs. 41%; Months 4–6: 68% vs. 61%).[31] Similarly the proportion of participants with CM who achieved the ≥50% response threshold increased over time, and the proportion was greater in those receiving erenumab 140 mg (28%) versus 70 mg (24%) after Month 1; however, when analyzed over 3 months (Months 1, 2, and 3), the proportion that achieved the ≥50% response threshold was 54% (140 mg) versus 57% (70 mg).[30] The results of these post-hoc analyses support the AHS[4] recommendations that the benefits of anti-CGRP mAbs should be assessed at least 3 months after initiation. This analysis is limited by the number of participants who dropped out over the assessment period.

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