Long-term efficacy and safety of erenumab in Japanese patients with episodic and chronic migraine: results from a 28-week open-label treatment period of a randomised trial.

OBJECTIVES: To evaluate the 1-year efficacy and safety of once-monthly erenumab 70 mg following a 24-week double-blind treatment period (DBTP) of a phase III randomised study of Japanese patients with episodic migraine (EM) or chronic migraine (CM). DESIGN: Multicentre open-label study. SETTING: A total of 41 centres in Japan. PARTICIPANTS: Patients completing the DBTP continued into the 28-week open-label treatment period (OLTP). 254 of 261 (97.3%) randomised patients continued into the OLTP; 244 (93.5%) completed treatment. INTERVENTIONS: Once-monthly subcutaneous erenumab 70 mg. MAIN OUTCOME MEASURES: Changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication treatment days (MSMD) reported via patient eDiary; proportion of ≥50% and ≥75% responders in MMD reduction from baseline; incidence and exposure-adjusted incidence of treatment-emergent adverse events (TEAEs). RESULTS: At week 24 of the DBTP, the mean (SE) change from baseline in MMD for the erenumab group was -3.8 (0.4) days (EM, -3.0 (0.4); CM, -5.2 (0.8)); in MSMD, -2.6 (0.4) days (EM, -2.1 (0.4); CM, -3.4 (0.7)). At the end of the OLTP (52 weeks postbaseline), the mean (SE) change from baseline in MMD was -4.7 (0.3) days (EM, -3.4 (0.3); CM, -6.9 (0.6)); in MSMD, -3.3 (0.3) days (EM, -2.4 (0.3); CM, -4.6 (0.5)). The proportion of ≥50% responders for MMD reduction in the erenumab group was 34.1% at week 24; 44.4% at week 52. The exposure-adjusted incidence of TEAEs was 219.7 per 100 patient-years during the OLTP (DBTP, 251.0 for the erenumab group). The most common TEAEs during the OLTP were nasopharyngitis, constipation and influenza. No new safety concerns were identified. CONCLUSIONS: Erenumab treatment was associated with reduced migraine frequency in Japanese patients with EM or CM for up to 1 year. Overall safety results from the OLTP were consistent with DBTP results. TRIAL REGISTRATION NUMBER: NCT03812224.

Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis.

OBJECTIVE: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. BACKGROUND: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. METHODS: This 52-week open-label extension study followed a 12-week double-blind placebo-controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once-monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. RESULTS: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was -9.3 (95% confidence interval: -10.4, -8.1 days) in the medication overuse subgroup versus -9.3 (-10.1, -8.5 days) in the non-medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine-specific medication, the mean change in monthly migraine-specific medication days at Week 52 was -7.4 (-8.3, -6.4 days) in the medication overuse subgroup versus -5.4 (-6.1, -4.7 days) in the non-medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non-overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. CONCLUSION: Long-term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.

Etelcalcetide Versus Cinacalcet in Hemodialysis Patients in the United States: A Facility Calcimimetic Approach to Assess Real-World Effectiveness.

Rationale & Objective: Some US hemodialysis (HD) facilities switched from oral cinacalcet to intravenous etelcalcetide as the primary calcimimetic therapy to control parathyroid hormone (PTH) levels after the introduction of etelcalcetide in 2017. Although clinical trials have demonstrated the superior efficacy of etelcalcetide versus cinacalcet, evidence comparing real-world effectiveness is lacking. Study Design: Prospective cohort. Setting & Participants: Patients receiving HD enrolled in US Dialysis Outcomes and Practice Patterns Study facilities. Exposure: We classified HD facilities on the basis of whether >75% of calcimimetic users were prescribed etelcalcetide ("etelcalcetide-first") or cinacalcet ("cinacalcet-first") from March-August 2019. Outcomes: PTH, calcium, and phosphorus levels among calcimimetic users, all averaged in the 6 months after the exposure assessment period. Analytical Approach: We used adjusted linear regression to compare outcomes using 2 approaches: (1) cross-sectional comparison of etelcalcetide-first and cinacalcet-first HD facilities; (2) pre-post comparison of HD facilities that switched from cinacalcet-first to etelcalcetide-first using facilities that remained cinacalcet-first as a comparison group. Results: We identified 45 etelcalcetide-first and 67 cinacalcet-first HD facilities; etelcalcetide-first (vs cinacalcet-first) facilities were more likely to be from small or independent dialysis organizations (86% vs 22%) and had higher total calcimimetic use (43% vs 29%) and lower active vitamin D use (66% vs 82%). In the cross-sectional analysis comparing etelcalcetide-first and cinacalcet-first HD facilities, the adjusted mean difference in PTH levels was -115 pg/mL (95% CI, -196 to -34) and the prevalence of a PTH level of >600 pg/mL was lower (prevalence difference, -11.4%; 95% CI, -19.3% to -3.5%). Among facilities that switched to etelcalcetide-first, the mean PTH level decreased from 671 to 484 pg/mL and the prevalence of a PTH level of >600 pg/mL decreased from 39% to 21%. Among facilities that remained cinacalcet-first, the mean PTH level increased from 632 to 698 pg/mL and the prevalence of a PTH level of >600 pg/mL increased from 37% to 43%. The adjusted difference-in-difference between the switch to etelcalcetide-first and the continuation of cinacalcet-first was -169 pg/mL (-249 to -90 pg/mL) for the mean PTH and -14.4% (-22.0% to -6.8%) for a PTH level of >600 pg/mL. We also observed slightly lower serum calcium levels and minimal differences in serum phosphorus levels between the etelcalcetide-first and the cinacalcet-first facilities. Limitations: Residual confounding. Conclusions: We observed better PTH control in HD facilities that switched from using cinacalcet to etelcalcetide as the primary calcimimetic therapy. Further research is needed to investigate how the greater real-world effectiveness of intravenous etelcalcetide (vs oral cinacalcet) may affect clinical outcomes.

Long-term efficacy and safety of erenumab in patients with chronic migraine in whom prior preventive treatments had failed: A subgroup analysis.

OBJECTIVE: To assess the long-term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52-week, open-label treatment period (OLTP) of the parent study. BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene-related peptide receptor. There are limited long-term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed. METHODS: Patients who had completed the 12-week double-blind treatment period (DBTP) in the parent study were eligible to participate in the 52-week OLTP, during which they received erenumab every 4 weeks. The TF subgroups (≥1, ≥2, and ≥3 TF medication categories) were not mutually exclusive; patients in whom prior preventive treatments from ≥3 medication categories had failed were also counted in the ≥2 and ≥1 medication categories. Endpoints included monthly migraine days (MMD), monthly acute migraine-specific medication days (MSMD), achievement of ≥50%, ≥75%, and 100% reduction from baseline in MMD, and exposure-adjusted patient incidence rates of adverse events (AEs; per 100 patient-years). RESULTS: Erenumab treatment provided sustained mean reductions in MMD and MSMD relative to the parent study baseline throughout the 52 weeks of the OLTP across all TF subgroups. At Week 52, the mean MMD change was -8.6 (SD 6.6) (baseline: 18.4 [SD 4.5] days) in the ≥1 TF subgroup. A post hoc completer analysis (52 weeks [OLTP] erenumab) showed that compared with erenumab 70 mg, the 140 mg dose was associated with numerically greater reductions in the mean MMD (Week 40: -8.6 and -7.2 days; Week 52: -9.7 and -7.9 days [≥1 TF subgroup]) and a higher proportion of patients achieved ≥50%, ≥75%, and 100% response thresholds across all subgroups at Weeks 40 and 52. Overall the exposure-adjusted patient incidence rates of AEs did not increase during the OLTP versus the DBTP (≥1 TF subgroup: 141.9/100 versus 317.9/100 patient-years), and no new safety signals occurred. CONCLUSION: The long-term treatment with erenumab was well tolerated and showed sustained efficacy in patients with CM in whom prior preventive treatments had failed, with numerically greater treatment effects for 140 mg versus 70 mg.

Early onset of efficacy with erenumab for migraine prevention in Japanese patients: Analysis of two randomized, double-blind, placebo-controlled studies.

PURPOSE: In two 24-week migraine prevention studies in Japan, erenumab was associated with significantly greater reductions in migraine frequency versus placebo over Weeks 13-24 (primary endpoint). This post hoc analysis evaluated the onset of efficacy within the first 4 weeks after the initiation of erenumab from the 24-week double-blind periods of these studies. METHODS: Placebo-adjusted differences in least squares mean (LSM) change from baseline in weekly migraine days (WMD) were assessed weekly in each study and by migraine type (episodic (EM]/chronic [CM]) (Study 20170609). RESULTS: A total of 407 patients from Study 20120309 (70 mg: N = 135; 140 mg: N = 136; placebo: N = 136) and 261 patients from Study 20170609 ([EM] 70 mg: N = 78; placebo: N = 81; [CM] 70 mg: N = 52; placebo: N = 50) were included. For Study 20120309, onset of efficacy was observed as early as Week 1 in favor of erenumab versus placebo. Placebo-adjusted differences in LSM (95% confidence interval [CI]) change from baseline in WMD at Week 1 were -0.38 (-0.71 to -0.05; p = .022) and -0.49 (-0.82 to -0.16; p = .004) in favor of erenumab 70 and 140 mg, respectively. For Study 20170609, significant placebo-adjusted differences were observed with erenumab 70 mg at Week 1 in patients with EM (LSM [95% CI]: -0.55 [-0.97 to -0.12; p = .012]), and at Week 2 in patients with CM (LSM [95% CI]: -0.81 [-1.53 to -0.09; p = .028]) and for the overall population (LSM [95% CI]: -0.71 [-1.09 to -0.33; p < .001]). CONCLUSIONS: Erenumab treatment significantly reduced WMD compared with placebo. Onset of erenumab efficacy occurred as early as Week 1 in patients with migraine.

Calcimimetic use in US hemodialysis facilities in first 2 years after the launch of etelcalcetide: A descriptive analysis of real-world clinical practice and outcomes.

INTRODUCTION: This study described control of parathyroid hormone (PTH), phosphorus, and corrected calcium in adults initiating calcimimetics in small dialysis organizations after the introduction of etelcalcetide. METHODS: This retrospective study using Visonex Clarity electronic health records between October 1, 2017, and December 31, 2019, identified adults ≥ 18 years of age receiving in-center hemodialysis as either a cinacalcet or etelcalcetide initiator based on their first calcimimetic use in 2018 (index date) with no prior calcimimetic use in the 3 months preindex date. Patients were stratified by PTH at index date and were followed for 15 months. Subcohorts of patients who were persistent on a single calcimimetic for 15 months and of patients who had their calcimimetic changed from cinacalcet to etelcalcetide were also analyzed. FINDINGS: A total of 677 patients initiated cinacalcet and 711 initiated etelcalcetide. Mean PTH (pg/ml), phosphorus, and corrected calcium (mg/dl) at baseline were 864, 5.9, and 9.3 for cinacalcet and 804, 5.9, and 9.4 for etelcalcetide, respectively. During follow-up, the proportion of initiators considered in-target (monthly average PTH < 600) increased from 48% to 62% with cinacalcet and from 56% to 86% with etelcalcetide in the baseline PTH 600 to < 800 subgroup; increased from 30% to 64% with cinacalcet and 31% to 59% with etelcalcetide among those with baseline PTH 800 to < 1000; and increased from 14% to 41% with cinacalcet and 12% to 58% with etelcalcetide among those with baseline PTH ≥1000. A similar pattern was observed for persistent users (n = 646). For patients changed from cinacalcet to etelcalcetide (n = 183), the proportion of patients considered in-target increased from 22% in the month prior to the treatment change to 51% in Month 6 postchange. DISCUSSION: Patients initiating calcimimetics at lower baseline PTH had better biochemical control than patients starting at higher PTH. Patients changed from cinacalcet to etelcalcetide had improvements in PTH control postchange.

A Phase I, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Pharmacokinetics, Safety, and Tolerability of Etelcalcetide Administered Intravenously to Chinese Patients With Chronic Kidney Disease Undergoing Hemodialysis.

PURPOSE: This study reports data from the first evaluation of etelcalcetide treatment in Chinese adults with chronic kidney disease and secondary hyperparathyroidism. METHODS: This phase I, randomized study compared thrice-weekly etelcalcetide (5 mg per dose intravenously) and placebo in 33 Chinese adults (aged 18-70 years) receiving hemodialysis. Patients in both treatment groups received standard-of-care treatment with a total of 12 doses of the investigational product during a 4-week treatment period, followed by 4 weeks of washout and follow-up. Pharmacokinetic (PK) parameters (primary endpoint), tolerability (secondary endpoint), and changes in intact parathyroid hormone (iPTH) and corrected calcium (cCa) concentrations (exploratory endpoints) were assessed. PK parameters, ie, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-last), assessed over the interdialytic interval following the first and last doses were evaluated. The incidence of treatment-emergent adverse events (AEs) and anti-etelcalcetide antibodies was assessed. FINDINGS: Etelcalcetide administered to 25 patients was compared with placebo administered to 8 patients. Etelcalcetide exposure, assessed by Cmax and AUC0-last, increased after multiple-dose administration of etelcalcetide through day 27, with a mean (SD) accumulation ratio of 3.02 (0.61) based on AUC. At least one AE was reported for all patients in the etelcalcetide group and for 87.5% of patients in the placebo group. Serious AEs were reported in 12% of patients in the etelcalcetide group only. No deaths occurred, and a single discontinuation because of patient withdrawal of consent was reported in the etelcalcetide group. Preexisting anti-etelcalcetide antibodies were detected in one patient. The mean serum cCa level for all patients was maintained at >1.75 mmol/L. The iPTH and cCa concentrations decreased as expected, and a maximum mean decrease from baseline of 35.13% in iPTH levels was detected on day 27. IMPLICATIONS: Multiple doses of 5 mg etelcalcetide were well tolerated, and observed etelcalcetide PK and safety profiles were similar to those in reports in adults of ethnicities other than Chinese. Changes in serum iPTH and serum calcium levels were consistent with expected responses to etelcalcetide. ClinicalTrials.gov identifier: NCT03283098.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials.

BACKGROUND: In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline. RESULTS: In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM. CONCLUSIONS: In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM. TRIAL REGISTRATIONS: NCT02456740; NCT02066415; NCT02174861.

Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study.

OBJECTIVES: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. Global studies have demonstrated its efficacy in chronic and episodic migraine (EM). Here we report the outcomes from a Phase 3 study of erenumab in Japanese patients with chronic migraine (CM) or EM. METHODS: Japanese patients with EM (<15 headache days/month, including ≥4 migraine days/month) or CM (≥15 headache days/month, including ≥8 migraine days/month) were randomized 1:1 to placebo or erenumab 70 mg once monthly for a 24-week double-blind treatment phase (DBTP). The primary endpoint of change from baseline in mean monthly migraine days (MMD) over months 4, 5, and 6 of the DBTP was compared between erenumab and placebo groups. Secondary efficacy and safety endpoints were also assessed. RESULTS: A total of 261 patients were randomized to placebo (n = 131) or erenumab 70 mg (n = 130); all patients were included in the efficacy and safety analyses. The mean (standard deviation) MMD at baseline was 11.84 (5.70) for the placebo group and 12.40 (5.99) for erenumab 70 mg. The mean (standard error) change in MMD was -1.98 (0.38) for the placebo group (n = 131) and -3.60 (0.38) for erenumab 70 mg (n = 130). The difference in MMD reduction between groups was -1.67 (95% CI: -2.56, -0.78, p < 0.001) for EM and -1.57 (95% CI: -3.39, 0.24, p = 0.089) for CM. Adverse events (AEs) were consistent with earlier studies. The most frequent AEs (placebo, erenumab) were nasopharyngitis (28.2% and 26.9%, respectively), back pain (4.6% and 5.4%), and constipation (0.8% and 4.6%). CONCLUSION: Treatment with erenumab 70 mg once monthly demonstrated favorable efficacy and safety findings in Japanese patients with EM or CM.

Efficacy of erenumab in chronic migraine patients with and without ictal allodynia.

BACKGROUND: Ictal cutaneous allodynia, common in chronic migraine, is associated with reduced responses to acute treatment with triptans. Allodynia's impact on the efficacy of newer preventive treatments such as erenumab is unknown. METHODS: Post-hoc subgroup analysis of a double-blind, randomized, placebo-controlled 12-week study of erenumab in chronic migraine, contrasting those with no allodynia with those with moderate-severe allodynia assessed with the Allodynia Symptom Checklist-12, was undertaken. RESULTS: Of 648 randomized individuals with baseline Allodynia Symptom Checklist-12 scores, 386 (59.6%) had no allodynia and 153 (23.6%) had moderate-to-severe allodynia. Mean (standard deviation) baseline monthly migraine days were 17.6 (4.8) and 18.9 (4.3), respectively. Compared to placebo, the erenumab group had greater reductions in monthly migraine days and monthly acute migraine-specific medication days in both no allodynia and allodynia subgroups. Mean (95% confidence interval) treatment differences in change from baseline for monthly migraine days at week 12 were -2.5 (-3.7, -1.4) in the no allodynia subgroup and -3.3 (-5.3, -1.3) in the moderate-severe allodynia subgroup. Change in acute migraine-specific medication days were -3.3 (-4.3, -2.3) and -2.5 (-4.3, -0.8), respectively. CONCLUSIONS: Erenumab's efficacy in reducing monthly migraine days and acute migraine-specific medication days in chronic migraine was not impacted by the presence of moderate-severe ictal allodynia.Trial registration: ClinicalTrials.gov NCT02066415.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

OBJECTIVE: To assess long-term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients. BACKGROUND: Previously published results from the double-blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM. METHODS: Patients completing the 24-week placebo-controlled DBTP could continue into the 76-week open-label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine-specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6-item Headache Impact Test (HIT-6™) score, and safety (exposure-adjusted patient-incidence of adverse events [AEs], calculated as number of patients per 100 patient-years). RESULTS: Of 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of -2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of -1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT-6™ score was 58.4 (5.4) at baseline with a change of -6.4 (8.2) at week 100. The exposure-adjusted patient-incidence of AEs during the OLTP was 207.1/100 patient-years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient-years) or placebo (257.3/100 patient-years) during the DBTP, and no new safety signals were detected during the OLTP. CONCLUSION: Long-term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.

Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial.

BACKGROUND AND PURPOSE: Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long-term therapy. METHODS: This study was an open-label, 5-year treatment phase following a 12-week, double-blind, placebo-controlled trial in adults with episodic migraine. Patients initially received open-label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine-specific medication (AMSM) days, and health-related quality of life. RESULTS: Of 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open-label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was -5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was -4.4 (0.3) days at the end of 5 years. Patient-reported outcomes indicated stable improvements in disability, headache impact, and migraine-specific quality of life. Exposure-adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient-years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient-years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure. CONCLUSIONS: Treatment with erenumab was associated with reductions in migraine frequency and improvements in health-related quality of life that were maintained for at least 5 years. No new safety signals were observed.

Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension.

OBJECTIVE: To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. METHODS: A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1-12, 21-24, 37-40, and 49-52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. RESULTS: In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8-58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6-61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3-99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1-99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5-54.7]) patients; of these, 77.8% (95% confidence interval: 60.9-89.9) persisted in reversion through week 64. CONCLUSIONS: Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine.Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02066415.

Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study.

BACKGROUND: This study reports the long-term safety and efficacy of erenumab in chronic migraine patients. METHODS: This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-label treatment phase, the initial monthly dose was erenumab 70 mg. Following protocol amendment, patients continued to receive erenumab 70 mg if they had already completed their Week 28 visit, otherwise, patients switched from 70 mg to 140 mg; if enrolled after the amendment, patients received 140 mg monthly throughout. RESULTS: In all, 451/609 (74.1%) enrolled patients completed the study. The exposure-adjusted patient incidence rate for any adverse event was 126.3/100 patient-years for the overall erenumab group. Overall, the adverse event profile was similar to that observed in the double-blind treatment phase. Adverse event incidence rates did not increase with long-term erenumab treatment compared with the double-blind treatment phase, and no new serious or treatment-emergent events were seen. Efficacy was sustained throughout the 52 weeks. Clinically significant reductions from double-blind treatment phase baseline (about half) were observed for monthly migraine days and migraine-specific medication days. Achievement of ≥50%, ≥75% and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at Week 52 were reported by 59.0%, 33.2% and 8.9% of patients, respectively, for the combined dose group. A numerically greater benefit was observed with 140 mg compared with 70 mg at Weeks 40 and 52. CONCLUSIONS: Sustained efficacy of long-term erenumab treatment in patients with chronic migraine is demonstrated, with safety results consistent with the known safety profile of erenumab and adverse event rates comparable to placebo adverse event rates in the double-blind treatment phase. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT02174861).

One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis. METHODS: This 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, 'switch' study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium-phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231. RESULTS: Overall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and ∼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from -25.4% to -26.1% for PTH, -8.3% to -9.1% for Ca, -3.6% to -4.1% for P and -12.0% to -12.6% for Ca × P. CONCLUSIONS: Etelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

OBJECTIVE: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415). METHODS: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability. RESULTS: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population. CONCLUSION: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.

Vascular safety of erenumab for migraine prevention.

OBJECTIVE: To examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies. METHODS: Vascular adverse events (AEs) and blood pressure data were integrated across 4 double-blind, placebo-controlled studies of erenumab and their open-label extensions in patients with chronic or episodic migraine. Subgroup analyses were conducted by acute migraine-specific medication use and number of vascular risk factors at baseline. Standardized search terms were used to identify vascular AEs (cardiovascular, cerebrovascular, or peripheral). An independent committee adjudicated whether targeted events were vascular in origin. RESULTS: In placebo-controlled studies, 2,443 patients received placebo (n = 1,043), erenumab 70 mg (n = 893), or erenumab 140 mg (n = 507) subcutaneously once monthly. Regardless of acute migraine-specific medication use or vascular risk factors at baseline, AE incidence was similar across the placebo and erenumab treatment groups. Hypertension AEs were reported for 0.9% (placebo), 0.8% (erenumab 70 mg), and 0.2% (erenumab 140 mg) of patients. Vascular AEs, which were similar across double-blind and open-label treatment, generally were confounded, with plausible alternative etiologies. In 18 patients with events reviewed by the independent committee, 4 events were positively adjudicated as cardiovascular in origin: 2 deaths and 2 vascular events. All 4 positively adjudicated cardiovascular events occurred during open-label erenumab treatment. CONCLUSION: Selective blockade of the canonical calcitonin gene-related peptide receptor with erenumab for migraine prevention had a vascular safety profile comparable to that of placebo over 12 weeks, with no increased emergence of events over time. Further study of long-term safety of erenumab in patients with migraine is needed. CLINICALTRIALSGOV IDENTIFIERS: NCT02066415, NCT02456740, NCT01952574, NCT02483585, NCT02174861, and NCT01723514. CLASSIFICATION OF EVIDENCE: This analysis provides Class II evidence that for patients with migraine, erenumab does not increase the risk of vascular AEs.

A Randomized Phase 2 Study of Erenumab for the Prevention of Episodic Migraine in Japanese Adults.

OBJECTIVE: A phase 2, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab for the prevention of episodic migraine in Japanese patients was conducted. BACKGROUND: Previous global clinical studies have demonstrated the efficacy of erenumab in the prevention of migraine. METHODS: Patients were randomized to placebo or erenumab 28, 70, or 140 mg administered subcutaneously once per month for 6 months. The primary endpoint was change from baseline in mean monthly migraine days over months 4-6 of the double-blind treatment phase. Secondary endpoints included the proportion of patients achieving ≥50% reduction from baseline in mean monthly migraine days (≥50% response) and change from baseline in mean monthly acute migraine-specific medication treatment days (MSMD) and mean Headache Impact Test (HIT-6™) scores. Efficacy outcomes were also determined at months 1, 2, and 3. RESULTS: Four hundred and seventy five patients were randomized 2:1:2:2 to placebo and erenumab 28, 70, and 140 mg, respectively. Greater reductions in monthly migraine days were observed for erenumab vs placebo with differences of -1.25 (95% CI: -2.10 to -0.41; P = .004), -2.31 (95% CI: -3.00 to -1.62; P < .001), and -1.89 (95% CI: -2.58 to -1.20; P < .001) days for erenumab 28, 70, and 140 mg. The odds of having a ≥50% response were 3.2, 5.6, and 4.7 times greater for erenumab 28 mg (95% CI: 1.30-7.88; P = .009), 70 mg (95% CI: 2.60-12.06; P < .001), and 140 mg (95% CI: 2.24-9.99; P < .001) than for placebo. Greater reductions from baseline in mean acute monthly MSMD were observed for erenumab vs placebo with differences of -1.07 (95% CI: -1.80 to -0.35; P = .004), -2.07 (95% CI: -2.66 to -1.49; P < .001), and -2.04 (95% CI: -2.63 to -1.45; P < .001) days for erenumab 28, 70, and 140 mg. Erenumab 70 and 140 mg also resulted in greater improvements in HIT-6™ scores. The safety profile was similar across treatment groups. The most common adverse event was nasopharyngitis, which occurred in 29.4% of patients in the placebo group and 28.9%-33.3% of patients in the erenumab groups. CONCLUSION: Monthly subcutaneous injections of erenumab 70 mg demonstrated statistically significant and numerically maximal efficacy with a favorable safety profile, suggesting that erenumab is a potential new therapy for migraine prevention in Japan.

Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine.

BACKGROUND: Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. METHODS: Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. RESULTS: Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. CONCLUSIONS: In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01952574.