Erenumab Discontinuation After 12-Month Treatment

Abstract

Objective

To assess migraine outcome after 12-month treatment with erenumab and compare patients who underwent 3-month erenumab discontinuation following the first treatment cycle with those who continued monthly administrations.

Methods

This is a multicentric observational study in patients with migraine in treatment with erenumab. After a full 12-month treatment cycle (T¹²), patients could either continue or discontinue erenumab for at least 3 months. Patients who underwent treatment discontinuation were assessed after 3 months (T¹⁵) to decide whether to start retreatment. Patients were then assessed following at T¹⁶ and T¹⁸.

Results

Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T¹² up to T¹⁵, whereas 11 continued prophylaxis. At T¹⁵, patients who discontinued treatment documented significantly more migraine days (17.06 ± 6.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (14.8 ± 9.2 vs 4.6 ± 2.5; p = 0.002), compared with those who continued treatment. After retreatment, at T¹⁶, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01 ± 4.4 vs 17.06 ± 6.5; p < 0.0001) and analgesics consumption (9.6 ± 7.3 vs 14.8 ± 9.2; p = 0.004). Such improvement was even greater at T¹⁸, comparable with T¹².

Conclusion

After treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at retreatment, which might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention. Although clinical improvement was documented after retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible—even ethical—to re-evaluate current timing of discontinuation.

Classification of Evidence

This study provides Class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in nonresponder status and migraine days than those who continued treatment.

Erenumab is a fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor,¹ recently approved for migraine prevention. Randomized clinical trials and real-life studies proved erenumab efficacy in both episodic migraine (EM) and chronic migraine (CM) prevention.^2-5 Moreover, erenumab safety has been proven in both short-term^2-5 and long-term clinical trials, even after 3 years of continuous treatment.⁶ Current guidelines⁷ and national regulations regarding erenumab prescription suggest a continuous 12-month treatment cycle, followed by discontinuation for at least 3 months.

The aim of this study was to assess patients' response after a 12-month treatment cycle, comparing patients who continued vs those who discontinued erenumab for 3 months. Moreover, we aimed to assess migraine outcome after retreatment in those patients who, following discontinuation, documented a significant clinical worsening.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

This study received approval from the ethics standards committee on human experimentation (local ethics committee of the ASST Spedali Civili Hospital, Brescia: NP 3949, approved August 10, 2020). Full written informed consent was required for all participants.

Study Design and Participants

This observational retrospective multicentric study was conducted from December 2018 to March 2021 at 4 centers across Northern Italy. The study included all adult patients with a diagnosis of migraine⁸ in prophylactic treatment with erenumab, who had completed at least 12 months of treatment. Inclusion criteria were documented history of migraine for at least 12 months, ≥8 migraine days per month for at least 3 months, and ≥3 previous prophylactic failures. Exclusion criteria were latex allergy, documented history of cerebrovascular disease and/or myocardial infarction, and systemic hypertension. According to the neurologist choice, after a 12-month treatment cycle, patients could continue treatment or undergo a 3-month pause. In the latter case, if a significant clinical worsening was observed (>30% increase in headache frequency), the patient could attempt retreatment.

Outcome Measures

The objective of this analysis was to assess clinical outcome in patients with migraine in prophylaxis with erenumab after 12 months of treatment. This study provides Class III evidence that discontinuing erenumab migraine prophylaxis after 12 months is more likely to result in clinical worsening compared with continuous treatment.

At the end of the 12-month treatment cycle (T¹²) and after 3, 4, and 6 months (T¹⁵, T¹⁶, and T¹⁸, respectively), responder rates (<50% or ≥50% reduction in headache days/month compared with baseline), mean migraine days (MMDs), and analgesics consumption per month were collected. Baseline (T⁰) information regarding migraine severity, clinical history, comorbidities, and previous prophylaxis was also recorded.

The primary endpoints were (1) to compare clinical response at T¹⁵ between patients who did and those who did not discontinue erenumab prophylaxis at T¹² and (2) to assess clinical response after erenumab retreatment at T¹⁶ and T¹⁸.

The following secondary endpoints were also assessed: (1) the number of MMDs and analgesics consumption at T¹⁵, T¹⁶, and T¹⁸, (2) the proportion of patients who maintained a headache frequency consistent with a diagnosis of EM at T¹⁵, T¹⁶, and T¹⁸, and (3) the proportion of patients with medication overuse (MO) at T¹⁵, T¹⁶, and T¹⁸.

Clinical variables potentially affecting clinical worsening after T¹² were assessed (baseline diagnosis, age, disease duration, add-on prophylactic treatments, allodynia, comorbidities, and MO).

Statistical Analysis

Continuous and categorical variables are reported as mean (SD) and number (percent), respectively. Differences between patients who did and did not discontinue erenumab were compared using the independent samples t test, within-subjects t test, χ² test, or Fisher exact test as appropriate.

To explore factors associated with clinical worsening after the 12-month treatment cycle, a multivariable logistic regression model was implemented.

Statistical significance was set at p < 0.05. Data analyses were performed with SPSS software (version 22.0; Armonk, NY).

Data Availability

All study data and materials will be available from the corresponding author on reasonable request.

Results

Of 94 patients in treatment with erenumab, 52 had completed a full 12-month treatment cycle, of which 30 had an available follow-up up to T¹⁸ and were enrolled in this study. Nineteen patients underwent treatment suspension, whereas 11 continued prophylaxis. Baseline clinical and demographical characteristics of the study population are presented in Table 1.

Table 1.

Baseline Clinical and Demographic Characteristics

At T¹⁵, all patients who discontinued erenumab treatment restarted erenumab prevention treatment.

At T¹², 26 patients (86.7%) were considered responders, whereas 4 presented a headache frequency reduction of <50% compared with baseline (Table 1). The number of responders decreased to 11 (36.7%) at T¹⁵, with a significant highest frequency of responders in those who had continued erenumab treatment during the 3-month follow-up (81.8% vs 10.5%; χ² = 15.2; p < 0.001) compared with those who did not, as presented in Figure. Of 19 patients who underwent treatment discontinuation, only 2 could still be qualified as responders. At T¹⁶, after reintroduction of erenumab (1 administration), there still was a significant higher frequency of responders in patients who had not discontinued treatment compared with those who had, although smaller (90.9% vs 57.99%; χ² = 3.6; p = 0.05). At T¹⁸, no significant difference was found between the 2 groups (90.9% vs 94.7%; χ² = 0.1; p = 0.68). Overall, responder rates at T¹⁶ and T¹⁸ were, respectively, 70% and 93.3%.

Figure. Percentage of Responders at T¹², T¹⁵, T¹⁶, and T¹⁸ in Patients Who Underwent Treatment Discontinuation at T12 and Patients Who Continued Treatment.

T¹² = end of the 12-month treatment cycle; T¹⁵ = 3-month follow-up after discontinuation; T¹⁶ = retreatment, first month; T¹⁸ = retreatment, 3 months.

At T¹⁵, patients who discontinued treatment for 3 months documented significantly more MMDs (16.4 ± 5.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (15.1 ± 7.2 vs 4.6 ± 2.5; p = 0.007), compared with those who continued erenumab after the 12-month cycle. At T¹⁶, compared with T¹⁵, patients who had previously undergone discontinuation documented a significant improvement in terms of MMD (7.2 ± 4.2 vs 16.4 ± 5.5; p < 0.0001) and analgesics consumption (7.3 ± 5.4 vs 15.1 ± 7.2; p = 0.001). However, when comparing patients who underwent treatment discontinuation and those who did not, at T¹⁶, the formers documented significantly more MMDs and analgesics consumption (respectively, 8.7 ± 4.3 vs 4.7 ± 2.5, p = 0.01 and 8.9 ± 6.1 vs 4.5 ± 2.5, p = 0.03).

At T¹⁸, no difference was to be found in terms of MMD (6.4 ± 3.4 vs 4.7 ± 2.5; p = 0.1) and analgesics consumption (6.5 ± 3.7 vs 4.5 ± 2.5; p = 0.09) between the 2 groups. Moreover, when comparing MMD (6.2 ± 3.9 vs 5.8 ± 3.2; p = 0.1) and analgesics consumption (6.9 ± 4.1 vs 5.9 ± 3.5; p = 0.06) between T¹⁸ and T¹², no significant difference was found.

At T¹², only 1 of the baseline 25 patients still had a migraine frequency compatible with a diagnosis of CM. At T¹⁵, the number of patients with a monthly migraine frequency of ≥15 days had increased to 12, all belonging to the group who had discontinued treatment (χ² = 11.5; p = 0.001). At T¹⁶, only 2 patients still documented a monthly migraine frequency of ≥15 days, both belonging to the group who had discontinued treatment. At T¹⁸, all patients documented a migraine frequency compatible with a diagnosis of EM. Regarding MO, at T¹², 4 of the baseline 23 patients presented with this condition, who became 13 at T¹⁵, all belonging to the group who had discontinued treatment (χ² = 13.2; p = 0.001). At T¹⁶, still 6 patients documented an analgesics intake compatible with MO, all who had undergone erenumab discontinuation between T¹² and T¹⁵ (χ² = 4.3; p = 0.03). At T¹⁸, no patient documented MO. All data are presented in Table 2.

Table 2.

Persistence of Chronic Migraine and Medication Overuse at T¹², T¹⁵, T¹⁶, and T¹⁸

In the multivariable logistic regression model, treatment discontinuation (odds ratio [OR] 8.93, 95% confidence interval [CI] 1.3–58.7, p = 0.002) and baseline CM diagnosis (OR 2.87, 95% CI 0.86–10.8, p = 0.03) were the only variables associated with clinical worsening between T¹² and T¹⁵.

Discussion

This study documented a significant migraine worsening following erenumab discontinuation after 12 months of treatment. In particular, a higher migraine burden was found in patients who underwent erenumab discontinuation compared with those who continued treatment. Similar results were recently published,⁹ documenting a slight clinical worsening following the first month after treatment discontinuation. Following the first month of retreatment, patients who underwent deterioration during discontinuation did benefit from reintroduction of erenumab, yet displaying more migraine days and analgesics consumption compared with those who never discontinued treatment. Such temporary worsening was no longer found at further follow-up (T¹⁸).

Moreover, the only variables found to be associated with clinical worsening during the end of the first 12-month treatment cycle and further follow-up were baseline diagnosis (CM) and treatment discontinuation.

Regardless of current guidelines, no disease-modifying treatment has ever been available for migraine. Previously, the only prophylactic treatment specifically targeted for chronic migraine was onabotulinumtoxin A,^10,11 for which discontinuation, in responder patients, is recommended only when clinical improvement remains stable over at least 3 months.¹²

The rapid deterioration in patients undergoing erenumab discontinuation, despite good response during treatment and at retreatment, might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention, which, possibly, might take longer to demonstrate its full effect. Thus, it might be reasonable to extend erenumab treatment over 12 months, especially in patients with CM. Further research will be needed to confirm our results and extend retreatment follow-up.

TAKE-HOME POINTS

• → Current guidelines regarding erenumab prescription in migraine prophylaxis suggest a continuous 12-month treatment cycle, followed by discontinuation for at least 3 months.

• → After erenumab discontinuation, a significant clinical worsening was found in terms of responder rates, migraine days, and analgesics consumption per month.

• → Erenumab retreatment proved to be effective, with data after 3-month follow-up being comparable with those at the end of the 12-month treatment cycle.

• → Variables associated with clinical worsening after 12-month treatment were erenumab discontinuation and a baseline diagnosis of chronic migraine.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

F. Schiano di Cola, S. Caratozzolo, E. Venturelli, U. Balducci, V. Sidotti, E. Pari, C. Costanzi, A. di Summa, G.J. Sixt, E. D'Adda, P. Liberini, and R. Rao report no disclosures relevant to the manuscript. A. Padovani is a consultant and served on the scientific advisory board of GE Healthcare, Eli-Lilly, and Actelion Ltd. Pharmaceuticals and received speaker honoraria from Nutricia, PIAM, Langstone Technology, GE Healthcare, Lilly, UCB Pharma, and Chiesi Pharmaceuticals. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.