EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH https://doi.org/10.1080/14737167.2020.1768850

ORIGINAL RESEARCH Cost of , , and onabotulinumtoxinA associated adverse events, for prophylaxis in Spain Pablo Irimiaa, Sonia Santos-Lasaosab,c, Laura García Bujalanced, Luis Ramos Pinazod, Darío Rubio-Rodrígueze and Carlos Rubio-Terrése aDepartment of Neurology and Neurosurgery, Navarra University Clinic, Pamplona, Spain; bNeurology Department, Lozano Blesa University Clinical Hospital, Zaragoza, Spain; cInstituto de Investigación Sanitaria Aragón (IISA), Zaragoza, Spain; dTeva Pharma Spain, Madrid, Spain; eHealth Value, Madrid, Spain

ABSTRACT ARTICLE HISTORY Objective: To compare the cost of adverse events (AEs) associated with preventive treatment of Received 13 March 2020 migraine with fremanezumab, versus erenumab, galcanezumab, and onabotulinumtoxinA. Accepted 11 May 2020 Methods: A probabilistic modeling analysis was performed, using second-order Monte Carlo simula- KEYWORDS tions, with 1,000 simulations, in patients with at least 4 days of migraine per month, from the Fremanezumab; erenumab; perspective of the National Health System and a time horizon of 12 weeks. The frequency of AEs galcanezumab; described in the clinical trials was analyzed with 12 weeks of treatment. Unit costs (€) of management onabotulinumtoxinA; of AEs were obtained from public health prices, expert panels, and published Spanish studies. adverse effects; cost; Results: Fremanezumab would generate average savings of -€469 (95% CI -€303; -€674) versus erenumab, migraine disorders -€268 (95% CI -€171; -€391) versus galcanezumab, -€1,100 (95% CI -€704; -€1,608) or -€1,295 (95% CI -€835; -€1,893) versus onabotulinumtoxinA using real-life or data, respectively. Conclusions: The different safety profile of treatment with fremanezumab, compared to erenumab, galca- nezumab, and onabotulinumtoxinA, would generate savings in health-care resources in all the scenarios considered.

1. Introduction generally well-tolerated in the prevention of EM and CM [12,13]. Currently, the European Medicines Agency has Migraine is a frequent, disabling neurological disease with high approved the use of monoclonal antibodies against CGRP economic costs for the health system [1]. Migraine, according to (fremanezumab, galcanezumab) or their receptor (erenu- the frequency of pain episodes, can be divided into two large mab) for the treatment of migraine, and it has been pro- groups: episodic migraine (EM) and chronic migraine (CM). posed that these drugs, due to their higher cost, be used Patients with EM suffer from headache less than 15 days in those patients who have not responded to other pre- amonth,whileinCMthepainappears15ormoredayseach ventive treatments [14]. The approved indications and the month, at least 8 of which meet migraine diagnostic criteria [2]. It is cost of MAs acting through the CGRP route are identical, estimated that more than four million people in Spain suffer from but each drug has specific characteristics and different migraine, with a prevalence of 12–13% [3,4] and approximately 3% adverse events (AEs). of EM patients progress to a chronic form each year [5]. CM is more AEs from drugs represent a cause of high morbidity in all disabling than EM and represents a greater cost to the health developed health systems and also have an important eco- system [6]. nomic impact [15,16]. Therefore, a relevant aspect when estab- Treatment of migraine includes drugs for pain attacks lishing whether a therapy is efficient in migraine is to evaluate and preventive treatment [7]withtheaimtoreducethe the cost of the AEs associated with the use of drugs indicated frequency, duration, and intensity of the episodes. Several in the preventive treatment of migraine [17,18]. oral drugs are currently available for migraine prophylaxis, The aim of this study was to estimate the cost of manage- and for patients with CM, onabotulinumtoxinA could be ment of the AEs observed in Phase III clinical trials with used [7]. However, there is a need for new preventive fremanezumab, in comparison with other treatments for pre- treatments for migraine as a considerable percentage of vention of migraine (erenumab, galcanezumab, and patients do not respond to or adequately tolerate the onabotulinumtoxinA) in Spain. These comparators were available drugs [8–10], which determines low adherence selected because they are the only drugs currently indicated to preventive treatments [11]. Recently, monoclonal anti- for migraine prophylaxis after the failure of other preventive bodies (MA) to the calcitonin gene-related (CGRP) therapies as established by European guidelines [14]. or its receptor have been shown to be effective and

CONTACT Darío Rubio-Rodríguez [email protected] Health Value, C/Virgen De Aránzazu, 21, Madrid 28034 This article has been republished with minor changes. These changes do not impact the academic content of the article. © 2020 Informa UK Limited, trading as Taylor & Francis Group 2 P. IRIMIA ET AL.

different treatments are comparable and are those used in nor- Article highlights mal clinical practice. Sensitivity analyses were performed by modifying the criteria of the base case of the analysis (see 2.6). ● A probabilistic modeling analysis was performed, using second-order Monte Carlo simulations, with 1,000 simulations, in patients with at least Regarding the comparison of fremanezumab with erenu- 4 days of migraine per month, from the perspective of the National Health mab and galcanezumab, an additional analysis was performed, System and a time horizon of 12 weeks. including all available studies that met the criteria, except for ● The different safety profile of treatment with fremanezumab, com- pared to erenumab, galcanezumab, and onabotulinumtoxinA, would criterion (iii), i.e. admitting all studies, regardless of the dura- result in savings per patient of -€469, -€268 and -€1,100 or -€1,296, tion of treatment. respectively. ● Savings from this concept were found in 100% of the simulations. 2.4. Candidate clinical trials The clinical studies that were candidates for inclusion in the analysis are summarized in Table 1. Three studies with fremane- 2. Design and methods zumab, HALO [25–28]andFOCUS[29,30]; two with erenumab, 2.1. Type of analysis STRIVE [31,32]andARISE[33,34]; three with galcanezumab, the so-called EVOLVE-1 [35,36], EVOLVE-2 [37,38]andREGAIN[39,40]; A modeled, probabilistic analysis was performed using second- and finally, for onabotulinumtoxinA, the results of the PREEMPT 1 order Monte Carlo simulations, with 1,000 simulations in adult and 2 studies, reviewed by Diener et al. [22] and those of the patients with at least 4 days of migraine per month, from the COMPEL study in clinical practice [23]wereidentifiedby Spanish National Health System (NHS) perspective. This methodol- a systematic literature review. Based on the criteria set out ogy makes it possible to analyze theindividualevolutionofeach above, the base case excluded phase II clinical studies (such as patient, as well as the uncertainty ofthevariables(frequencyofAEs the phase IIb study of erenumab of Tepper et al. or the phase IIb and costs of their management) [19,20]. The probabilistic analysis study of Bigal et al. by fremanezumab) [41,42] and those without was performed considering that the frequencies of the AEs are an outcome report on clinicaltrials.gov (such as the LIBERTY adjusted to beta distributions and the unit costs of the AEs to studyoferenumabbyReuteretal.)[43]. gamma distributions [21]. Only the costs derived from the man- agement of AEs observed with the treatments compared (frema- nezumab, erenumab, galcanezumab, and onabotulinumtoxinA) 2.5. AEs management costs were considered. The costs associated with the management of AEs were obtained from the public health prices of the Spanish NHS 2.2. AEs analyzed [44,45] and from several published Spanish studies [19,44–54]. The use of AEs resources was validated by several panels of ≤ The frequency of mild-moderate AEs [grades 2] and severe AEs Spanish clinical experts [19]. [grades 3–4] was analyzed separately and together for each treatment. The AEs were defined according to ClinicalTrials.gov (www.clinicaltrials.gov) criteria. A grade 3–4AEisconsideredto 2.6. Analyses carried out be one that is life-threatening, requires hospitalization or pro- A base case was analyzed, including only studies with longed hospitalization, results in continued or significant disabil- 12 weeks of treatment. Three sensitivity analyses were also ity, substantially interferes with normal life functions, or causes performed: (i) including all studies, regardless of treatment a congenital anomaly or birth defect. All other AEs were consid- duration; (ii) including the phase IIb study of erenumab in ered grade 1–2. patients with CM [42,55] because in the base case, according to the inclusion criteria, no clinical study of erenumab in 2.3. Criteria for inclusion of studies patients with CM was included; and (iii) performing separate analyses, according to the type of migraine (EM or CM). The In the base case analysis, clinical studies with the following FOCUS study [29,30] of fremanezumab was not included in characteristics were included: (i) patients with EM and/or CM; this analysis, since it included both types of migraine, and it (ii) randomized, double-blind, placebo-controlled, phase III trials; was not possible to separate AEs by type. (iii) with a treatment duration of12weeks(thatoffremanezu- mab clinical studies; time horizon of analysis); and (iv) with AEs outcome report published in the U.S. National Library of Medicine 3. Results (www.clinicaltrials.gov). For the comparison of fremanezumab 3.1. Selected clinical trials with onabotulinumtoxinA, point (iii) was omitted because no studies of this duration were available and point (iv) because In the base case study, for monoclonal antibodies that antag- a systematic review published in 2014 was used [22]. A second onize the CGRP pathway, the 12-week studies were included. analysis was performed against onabotulinumtoxinA, using the The studies of fremanezumab HALO-CM [19,27], HALO-EM rates of AEs observed with this treatment in a clinical practice [26,27] and FOCUS [29,30], the study of erenumab ARISE study (COMPEL study) which included 716 patients with CM [33,34] and the study of galcanezumab REGAIN [39,40]. The treated with 155 units of onabotulinumtoxinA every 12 weeks PREEMPT 1 and 2 studies of onabotulinumtoxinA [22] and the and follow-up for 108 weeks [23,24]. The doses used of the COMPEL study (Table 1)[23] were also included. The phase IIb EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 3

a) Fremanezumab vs erenumab: AEs grades ≤ 2 b) Fremanezumab vs erenumab: AEs grades 3-4 100% saving probability 100% saving probability 0,00 € 0,00 € -50,00 € -50,00 € -100,00 € -100,00 € -150,00 € -150,00 € -200,00 € -200,00 € -250,00 € -300,00 € -250,00 € -350,00 € -300,00 € -400,00 € -350,00 € -450,00 €

-400,00 € -500,00 €

c) Frenamezumab vs galcanezumab: AEs grades 1-2 d) Fremanezumab vs galcanezumab: AEs grades 3-4 0% saving probability 100% saving probability 80,00 € 0,00 € 70,00 € -100,00 € 60,00 €

50,00 € -200,00 €

40,00 € -300,00 € 30,00 € -400,00 € 20,00 €

10,00 € -500,00 €

0,00 € -600,00 €

e) Fremanezumab vs onabotulinumtoxinA: AEs grades 1-2 f) Fremanezumab vs onabotulinumtoxinA: AEs grades 3-4 100% saving probability 100% saving probability (PREEMPT 1 & 2 studies) (PREEMPT 1 & 2 studies) 0,00 € 0,00 €

-50,00 € -500,00 €

-100,00 € -1.000,00 € -150,00 € -1.500,00 € -200,00 €

-2.000,00 € -250,00 €

-2.500,00 € -300,00 €

g) Fremanezumab vs onabotulinumtoxinA: AEs grades 1-2 h) Fremanezumab vs onabotulinumtoxinA: AEs grades 3-4 100% saving probability 100% saving probability (COMPEL study) (COMPEL study) 0,00 € 0,00 € -50,00 € -100,00 € -200,00 € -150,00 € -400,00 € -200,00 € -250,00 € -600,00 € -300,00 € -350,00 € -800,00 € -400,00 € -1.000,00 € -450,00 €

-500,00 € -1.200,00 €

Figure 1. Difference in costs due to the management of adverse events (AEs) associated with fremanezumab migraine prophylaxis, compared to erenumab, galcanezumab, and onabotulinumtoxinA. One thousand simulations were performed in each analysis. Negative values indicate savings with fremanezumab compared to the comparator; positive values indicate the opposite.

study of erenumab in patients with CM [17,55] was not 3.3. AEs management costs included in the base case analysis according to the inclusion The costs of the management of the different AEs associated criteria, but because of the absence of patients with CM in the with the treatments are described in Table 7. analysis, it was included in an ad hoc sensitivity analysis.

3.4. Cost per patient of the AEs, depending on treatment

3.2. AEs frequency 3.4.1. Base case: studies with 12 weeks of treatment The cost per patient of each of the AEs associated with treatment AEs frequency observed in clinical trials is described with with fremanezumab, compared toerenumab,galcanezumab, fremanezumab (Table 2), erenumab (Table 3), galcanezumab and onabotulinumtoxinA, is described in Table 8 and difference (Table 4), and onabotulinumtoxinA (Tables 5 and 6). in costs is shown in Figure 1. 4 .III TAL. ET IRIMIA P.

Table 1. Characteristics of clinical studies that were candidates for inclusion in the analysis. Fremanezumab Erenumab Galcanezumab OnabotulinumtoxinA type A Characteristics HALO EM1 HALO CM2 FOCUS3 STRIVE4 ARISE5 FASE 2b6# EVOLVE 17 EVOLVE 28 REGAIN9 PREEMPT 1 & 210 COMPEL11 Type of migraine EM CM EM and CM EM EM CM EM EM CM CM CM Design R,DB,PBO Idem Idem Idem Idem Idem Idem Idem Idem Idem UC Dose (mg) MON/QUA Idem Idem 70/140 MON 70 MON 70/140 MON 120/240 MON 120/240 MON 120/140 MON 75–260 U every 12 weeks 155 U every 12 weeks N 290/291 379/376 283/276 317/319 286 191/190 213/212 231/223 278/277 1,384 716 Treatment duration (weeks) 12 12 12 28 12 12 24 24 12 24 108 Safety follow-up (weeks) 12 12 12* 28** 12¶ -161612¥ 32 108 Age 40.6/42.0 42.9/41.1 45.9/45.8 41.1/40.4 42 41.4/42.9 40.9/39.1 40.9/41.9 39.7/41.1 42.1 43.0 Women (%) 87/88 84.1/86.3 84/83 84.5/85.3 85.7 87/84 85.0/82.6 85.3/85.7 85/82 86.4 84.8 Time from diagnosis (years) 20.1/19.7 20.7/20.0 24.0/24.3 N/A 22 21.1/21.5 21.1/19.3 19.9/20.0 N/A 20.1 N/A Preventive medication (%) 22/20 21.4/19.9 N/A 55.2/58.6 43 67/66 62.4/59.0 68.0/64.6 76/79 96.2 N/A Prior OnabotulinumtoxinA (%) 13/18 N/A 25/27 N/A N/A 26/23 N/A N/A N/A N/A N/A (1) Dodick, 2018a [28]; (2) Silberstein, 2017 [27]; (3) Ferrari, 2019 [30]; (4) Goadsby, 2017 [32]; (5) Dodick, 2018b [34]; (6) Tepper, 2017 [42]; (7) Stauffer, 2018 [36]; (8) Skljarevski, 2018 [38]; (9) Detke, 2018 [40]; (10) Diener, 2014 [22]; (11) Winner, 2019 [23]. *Only 12-week results are available, although the study performs a follow-up of up to 6 months; **Only 28-week results are available, although a follow-up of 12 more weeks was performed; ¶ Only 12-week results are available, although a safety follow-up was performed for 12 more weeks; ¥ Only 12-week results are available, although a safety follow-up of 16 more weeks was performed. # Only included in a sensitivity analysis, despite being a phase 2b study, due to the absence in the base case of CM patients treated with erenumab. Abbreviations: R: randomized; DB: double-blind; CM: chronic migraine; EM: episodic migraine; MON: monthly; UC: uncontrolled; N/A: not available; PBO: placebo-controlled; QUA: quarterly. EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 5

Table 2. Grade ≤2 and grade 3–4 adverse events observed with fremanezumab [25–30]. Fremanezumab Grade ≤ 2 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Erythema at the injection site 17.1% 13.7% 20.6% 0.01749 Beta 79.4 383.8 Peripheral edema 10.7% 8.5% 12.8% 0.01087 Beta 85.7 718.7 Periodontitis 4.7% 3.8% 5.6% 0.00479 Beta 91.5 1857.5 Upper respiratory traction infection 2.7% 2.2% 3.2% 0.00274 Beta 93.4 3380.0 Fremanezumab Grade 3–4 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Minor fracture 0.32% 0.25% 0.38% 0.00032 Beta 95.7 30,155.9 Kidney stones 0.21% 0.17% 0.25% 0.00022 Beta 95.9 60,504.4 Reproductive system disorders 0.21% 0.17% 0.25% 0.00022 Beta 95.9 60,504.4 Dysmenorrhea/endometriosis 0.16% 0.13% 0.19% 0.00016 Beta 95.9 60,504.4 Cholelithiasis 0.16% 0.13% 0.19% 0.00016 Beta 95.9 60,504.4 Low back pain 0.11% 0.08% 0.13% 0.00011 Beta 95.9 90,852.9 Hypertension 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Depression/suicidal thoughts 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Chronic obstructive pulmonary disease 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Optic neuritis 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Multiple sclerosis 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Seizures 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Intracranial aneurysm 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Atrial fibrillation 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Retinal tear 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Gastroesophageal reflux 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Anal polyp 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Gastrointestinal bleeding 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Anaphylactic response 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Anal abscess 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Appendicitis 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Diverticulitis 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Pneumonia 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Ligament rupture 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Fall 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Major bone fracture 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8 Angiomyxoma 0.05% 0.04% 0.06% 0.00005 Beta 96.0 181,898.8

Table 3. Grade ≤2 and grade 3–4 adverse events observed with erenumab [33]. Erenumab Grade ≤ 2 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Peripheral edema 15.7% 12.6% 18.9% 0.01603 Beta 80.8 433.4 Pain at the injection site 5.7% 4.6% 6.9% 0.00584 Beta 90.5 1490.1 Erenumab Grade 3–4 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Asthenia 5.72% 4.58% 6.87% 0.00548 Beta 90.5 1490.1 Malignant melanoma 0.24% 0.19% 0.29% 0.00025 Beta 95.8 39,231.6 Unstable angina 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Atrial fibrillation 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Abdominal pain 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Anal abscess 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Periodontitis 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Staphylococcus bacteremia 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Tracheobronchitis 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Post-surgical infection 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Ligament rupture 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Major fractures 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Basal cell carcinoma 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Seizures 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Oropharyngeal pain 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Cough 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9 Insomnia 0.12% 0.10% 0.15% 0.00012 Beta 95.9 78,655.9

3.4.1.1. Fremanezumab versus erenumab. Compared to 3.4.1.2. Fremanezumab versus galcanezumab. Compared erenumab, an average saving of -€469 (95% CI -€303; -€674) to galcanezumab, this would generate an average saving of would be generated. Savings were found in both grade 1–2AEs -€268 (95% CI -€171; -€391). Savings occurred in grade 3–4 AEs (-€208 [95% CI -€136; -€296]) and grade 3–4AEs(-€261 [95% CI (-€312 [95% CI -€199, -€455]) but not in grade 1–2, with an -€167; -€378]). additional cost per patient of €44 [95% CI 28; €63]). However, 6 P. IRIMIA ET AL.

Table 4. Grade ≤ 2 and grade 3–4 adverse events observed with galcanezumab [39]. Galcanezumab Grade ≤ 2 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Pain at the injection site 6.67% 5.33% 8.00% 0.00680 Beta 89.6 1254.0 Nasopharyngitis 4.68% 3.75% 5.62% 0.00478 Beta 91.5 1861.6 Erythema at the injection site 4.1% 3.3% 5.0% 0.00423 Beta 92.0 2128.4 Galcanezumab Grade 3–4 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Myocardial infarction 0.36% 0.29% 0.43% 0.00037 Beta 95.7 26,458.4 Kidney stones 0.36% 0.29% 0.43% 0.00037 Beta 95.7 26,458.4 Unstable angina 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Heart failure 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Acute pancreatitis 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Cholelithiasis 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Kidney infection 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Hypokalemia 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Colon cancer 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Squamous cell carcinoma 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Pulmonary embolism 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3 Erythema at the injection site 0.18% 0.14% 0.22% 0.00018 Beta 95.9 53,109.3

Table 5. Grade ≤2 and grade 3–4 adverse events observed with onabotulinumtoxinA in the PREEMPT 1 and 2 studies [22]. OnabotulinumtoxinA Grade ≤ 2 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Headache/migraine 25.07% 20.06% 30.09% 0.02558 Beta 71.7 214.3 Muscle weakness 19.44% 15.55% 23.32% 0.01983 Beta 77.2 319.9 Facial paresis 10.62% 8.50% 12.75% 0.01084 Beta 85.7 721.4 Musculoskeletal pain 7.51% 6.01% 9.02% 0.00767 Beta 88.7 1092.3 Upper respiratory traction infection 6.07% 4.86% 7.28% 0.00619 Beta 90.2 1395.2 Sinusitis 5.49% 4.39% 6.59% 0.00560 Beta 90.7 1561.2 Pain at the injection site 4.91% 3.93% 5.90% 0.00501 Beta 91.3 1766.4 Nasopharyngitis 4.70% 3.76% 5.64% 0.00479 Beta 91.5 1856.4 Eyelid drooping 4.55% 3.64% 5.46% 0.00464 Beta 91.6 1921.2 Nausea 3.68% 2.95% 4.42% 0.00376 Beta 92.5 2416.8 Influenza 2.53% 2.02% 3.03% 0.00258 Beta 93.6 3607.1 Dizziness 2.38% 1.91% 2.86% 0.00243 Beta 93.7 3837.1 Depression 1.73% 1.39% 2.08% 0.00177 Beta 94.4 5346.9 OnabotulinumtoxinA Grade 3–4 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Headache 0.58% 0.46% 0.69% 0.00059 Beta 95.5 16,422.4 Depression 0.22% 0.17% 0.26% 0.00022 Beta 95.8 44,113.6 Uterine leiomyoma 0.22% 0.17% 0.26% 0.00022 Beta 95.8 44,113.6 Pneumonia 0.22% 0.17% 0.26% 0.00022 Beta 95.8 44,113.6 Breast cancer 0.14% 0.12% 0.17% 0.00015 Beta 95.9 66,266.7 Appendicitis 0.14% 0.12% 0.17% 0.00015 Beta 95.9 66,266.7 Cholelithiasis 0.14% 0.12% 0.17% 0.00015 Beta 95.9 66,266.7 Abdominal pain 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Cholecystitis 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Endometriosis 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Basal cell carcinoma 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Intervertebral disc protrusion 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Ureterolithiasis 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 Kidney stones 0.07% 0.06% 0.09% 0.00007 Beta 96.0 132,726.4 overall, fremanezumab generated savings compared to -€704; -€1,608). Savings in managing grade 1–2 AEs would be galcanezumab. -€195 (95% CI -€131; -€284) and for grade 3–4 AEs it would be -€905 (95% CI -€573; -€1,324).

3.4.1.3. Fremanezumab versus onabotulinumtoxinA. Using data from the PREEMPT 1 and 2 studies, an average 3.4.2. Sensitivity analysis saving of -€1,296 (95% CI -€835; -€1,893) would be gener- The results of the sensitivity analyses are presented in Table 9. ated, in all AEs, regardless of their severity. Average savings a)All studies, regardless of treatment duration in grade 1–2 AEs would be -€1,133 (95% CI -€728; -€1,660) In this scenario, fremanezumab would generate an average and in grade 3–4 AEs it would be -€162 (95% CI -€107; -€233). saving of -€413 (95% CI -€267; -€605) compared to erenumab. In the second analysis, including onabotulinumtoxinA AEs Savings in grade 1–2 AEs would be -€220 (95% CI -€142; -€323) observed in the COMPEL study, the average savings per patient and for in grade 3–4AEs-€192 (95% CI -125; -€282). Compared to treated with fremanezumab would amount to -€1,100 (95% CI galcanezumab, savings with fremanezumab would amount to EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 7

Table 6. Grade ≤2 and grade 3–4 adverse events observed with onabotulinumtoxinA in the COMPEL study [23,24]. OnabotulinumtoxinA Grade ≤ 2 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Headache, migraine 5.31% 4.25% 6.37% 0.00542 Beta 90.9 1621.7 Sinusitis 5.17% 4.13% 6.20% 0.00527 Beta 91.0 1670.4 Fatigue 3.99% 3.19% 4.78% 0.00407 Beta 92.2 2219.5 Cataract 0.00% 0.00% 0.00% 0.00000 Beta 0.0 0.0 Pain at the injection site 1.59% 1.28% 1.91% 0.00163 Beta 94.5 5830.2 Hemiparesis 1.12% 0.89% 1.34% 0.00114 Beta 95.0 8410.4 Low back pain, muscular 1.01% 0.81% 1.21% 0.00103 Beta 95.1 9347.8 Nasopharyngitis 0.80% 0.64% 0.96% 0.00081 Beta 95.3 11,851.1 Influenza 0.64% 0.51% 0.77% 0.07% Beta 95.4 14,861.8 OnabotulinumtoxinA Grade 3–4 adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Depression, suicidal thoughts 1.40% 1.12% 1.68% 0.00143 Beta 94.7 6684.7 Headache, migraine 1.40% 1.12% 1.68% 0.00143 Beta 94.7 6684.7 Limb pain 0.45% 0.67% 0.06% 0.00057 Beta 95.5 16,998.6 Malignant melanoma 0.42% 0.34% 0.50% 0.00043 Beta 95.6 22,728.9 Fall 0.42% 0.34% 0.50% 0.00043 Beta 95.6 22,728.9 Minor bone fracture 0.42% 0.34% 0.50% 0.00043 Beta 95.6 22,728.9 Syncope, dizziness 0.42% 0.34% 0.50% 0.00043 Beta 95.6 22,728.9 Atrial fibrillation 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Congestive cardiomyopathy 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Gastrointestinal infection 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Arthritis 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Intervertebral disc protrusion 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Basal cell carcinoma 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Paresthesia 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Dysmenorrhea, endometriosis 0.28% 0.22% 0.34% 0.00029 Beta 95.8 34,189.5 Aortic valve incompetence 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 Myocardial infarction 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 Cushing 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 Eyelid drooping 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 Cataract 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 OTHER AEs (listed at the bottom of the table)a 0.14% 0.11% 0.17% 0.00014 Beta 95.9 68,571.7 aThe following AEs had the same frequency (0.14%) in the study (presented in alphabetical order): acute pancreatitis, acute pyelonephritis, anal polyp, angiomyolipoma, anaphylactic reaction, appendicitis, arthritis, breast cancer, chest pain, constipation, deep vein thrombosis, dysmenorrhea/endometriosis, dyspnea, erythema at injection site, fatigue, gastritis, hiatus hernia, hypercalcemia/hypocalcemia, hyperglycemia, hypoglycemia, influenza, intestinal obstruction, kidney stones, ligament rupture, major bone fracture, malignant pulmonary neoplasm, pneumonia, pyrexia, respiratory infection, seizures, sinusitis, stroke, ureterolithiasis, viral meningitis.

-€126 (95% CI -€81; -€180). Savings would occur in both grade 1–2 In patients with CM only, compared to onabotulinumtoxinA, AEs (-€61 [95% CI -€39; -€86]) and grade 3–4AEs(-€65 [95% CI there would be an average saving of -€1,378 (95% CI -€898; -€42; -€93]). -€1,998) in each patient. Savings in grade 1–2 AEs would be b)Inclusion of the erenumab phase IIb study in CM -€1,178 (95% CI -€769; −1,703) and in 3–4 AEs would be -€200 In this assumption, average savings in grade 1–2 AEs would (95% CI -€129; -€295). be -€209 (CI 95% -€136; -€302) and in grade 3–4 AEs -€344 (CI 95% -€230; -€480). In total, -€553 (95% CI -€336; -€800). c)Separate analyses according to the type of migraine (EM or CM) 4. Discussion In patients with EM, compared to erenumab, fremanezu- In the present economic analysis, the direct cost associated € mab would generate an average saving of - 507 (95% CI with the diagnosis and treatment of the different AEs is com- € € – € - 331; - 735). Savings in grade 1 2 AEs would be - 177 (95% paratively lower with fremanezumab than with galcanezumab, € € – € € CI - 113; - 258) and in grade 3 4 AEs - 329 (95% CI - 218; erenumab, and onabotulinumtoxinA. No comparative studies -€477). Compared to galcanezumab, savings with fremanezu- have been identified on the cost of AEs associated with the mab in EM would amount to -€137 (95% CI -€88; -€199). use of monoclonal antibodies against the CGRP or its receptor, Savings would occur in both grade 1–2 AEs (-€48 [95% CI similar to the presented here. -€31; -€70]) and grade 3–4 AEs (-€89 [95% CI -€58; -€128]). In the different clinical trials evaluating the efficacy and In patients with CM, compared to erenumab, fremanezumab safety of monoclonal antibodies against CGRP (fremanezu- would generate an average savings of -€346 (95% CI -€221; mab, galcanezumab) or against their receptor (erenumab) for -€492). Savings in grade 1–2 AEs would be -€0.63 (95% CI the preventive treatment of migraine, the proportion of -€0.58; -€0.66) and for grade 3–4 AEs -€345 (95% CI -€221; patients who developed serious side effects is very low. -€491). Compared to galcanezumab, savings with fremanezu- However, the use of fremanezumab is associated with signifi- mab in CM, would amount to -€396 (95% CI -€263; -€569). cant economic savings in the diagnosis and treatment of Savings would not occur for grade 1–2 AEs (with a small addi- serious AEs compared to erenumab or galcanezumab. In addi- tional cost of €0.15 [95% CI 0.09, €0.21]) but would occur for tion, fremanezumab treatment is also associated with signifi- grade 3–4 AEs (with a savings of -€397 [95% CI -€264, -€569]). cant savings compared to onabotulinumtoxinA, mainly due to 8 Table 7. Unit costs of adverse events (€ of 2019) [44–54]. Grade ≤ 2 adverse effects Cost of adverse events

Cost of adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Mean Lower limit Upper limit SD Distribution Alpha Beta AL. ET IRIMIA P. Anal abscess €2,002.00 € 1,601.60 €2,402.40 204.286 Gamma €96.04 €20.845 €9,780.00 €7,824.00 €11,736.00 997.959 Gamma €96.04 €101.833 Anaemia €373.33 €298.67 €448.00 38.095 Gamma €96.04 €3.887 €504.76 €403.81 €605.71 51.506 Gamma €96.04 €5.256 Intracranial aneurysm €6,257.61 €5,006.09 €7,509.13 638.531 Gamma €96.04 €65.156 €7,284.65 €5,827.72 €8,741.58 743.331 Gamma €96.04 €75.850 Angiomyxoma vulvar/adenocarcinoma of the cervix €21,009.26 €16,807.40 €25,211.11 2143.802 Gamma €96.04 €218.755 €36,998.59 €29,598.87 €44,398.31 3775.367 Gamma €96.04 €385.241 Anxiety/confusion €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Appendicitis €2,846.00 €2,276.80 €3,415.20 290.408 Gamma €96.04 €29.633 €6,883.00 €5,506.40 €8,259.60 702.347 Gamma €96.04 €71.668 Ventricular arrhythmia €3,855.00 €3,084.00 €4,626.00 393.367 Gamma €96.04 €40.140 €6,793.00 €5,434.40 €8,151.60 693.163 Gamma €96.04 €70.731 Arthralgia €17.30 €13.84 €20.76 1.766 Gamma €96.04 €0.180 €17.30 €13.84 €20.76 1.766 Gamma €96.04 €0.180 Arthritis €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Asthenia €176.48 €141.18 €211.78 18.008 Gamma €96.04 €1.838 €176.48 €141.18 €211.78 18.008 Gamma €96.04 €1.838 Bacteremia €5,056.00 €4,044.80 €6,067.20 515.918 Gamma €96.04 €52.645 €8,173.50 €6,538.80 €9,808.20 834.031 Gamma €96.04 €85.105 Bronchiolitis €2,601.00 €2,080.80 €3,121.20 265.408 Gamma €96.04 €27.082 €7,200.00 €5,760.00 €8,640.00 734.694 Gamma €96.04 €74.969 Fall €1,349.90 €1,079.92 €1,619.88 137.745 Gamma €96.04 €14.056 €1,349.90 €1,079.92 €1,619.88 137.745 Gamma €96.04 €14.056 Kidney stones €2,100.00 €1,680.00 €2,520.00 214.286 Gamma €96.04 €21.866 €9,359.00 €7,487.20 €11,230.80 955.000 Gamma €96.04 €97.449 Tonsil cancer €9,011.00 €3,678.00 €14,344.00 2720.918 Gamma €10.97 €821.595 €9,167.00 €7,333.60 €11,000.40 935.408 Gamma €96.04 €95.450 Colon cancer €6,646.00 €2,764.00 €10,528.00 1980.612 Gamma €11.26 €590.254 €52,209.26 €39,854.40 €59,781.60 5083.469 Gamma €105.48 €494.963 Breast cancer €19,177.35 €15,341.88 €23,012.82 1956.873 Gamma €96.04 €199.681 €52,209.26 €41,767.41 €62,651.12 5327.476 Gamma €96.04 €543.620 Bladder cancer €5,951.59 €4,761.27 €7,141.91 607.305 Gamma €96.04 €61.970 €7,141.91 €5,713.53 €8,570.29 728.766 Gamma €96.04 €74.364 Cachexia €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Basal cell carcinoma €55,488.67 €44,390.93 €66,586.40 5662.109 Gamma €96.04 €577.766 €69,360.83 €55,488.67 €83,233.00 7077.636 Gamma €96.04 €722.208 Headache/migraine €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Cystitis/vaginal infection/cholecystitis €2,109.00 €1,687.20 €2,530.80 215.204 Gamma €96.04 €21.960 €6,752.00 €5,401.60 €8,102.40 688.980 Gamma €96.04 €70.304 Cholelithiasis €2,879.00 €2,303.20 €3,454.80 293.776 Gamma €96.04 €29.977 €9,545.00 €7,636.00 €11,454.00 973.980 Gamma €96.04 €99.386 Convulsions €46.86 €37.48 €56.23 4,781 Gamma €96.04 €0.488 €5,348.00 €4,278.40 €6,417.60 545.714 Gamma €96.04 €55.685 Depression €1,006.71 €805.36 €1,208.05 102.725 Gamma €96.04 €10.482 €1,073.07 €858.46 €1,287.69 109.497 Gamma €96.04 €11.173 Retinal tear €764.00 €611.20 €916.80 77.959 Gamma €96.04 €7.955 €764.00 €611.20 €916.80 77.959 Gamma €96.04 €7.955 Dysarthria €885.88 €708.71 €1,063.06 90.396 Gamma €96.04 €9.224 €885.88 €708.71 €1,063.06 90.396 Gamma €96.04 €9.224 Bladder dysfunction/ureterolithiasis €2,100.00 €1,680.00 €2,520.00 214.286 Gamma €96.04 €21.866 €9,359.00 €7,487.20 €11,230.80 955.000 Gamma €96.04 €97.449 Diverticulitis €1,972.00 €1,577.60 €2,366.40 201.224 Gamma €96.04 €20.533 €2,672.00 €2,137.60 €3,206.40 272.653 Gamma €96.04 €27.822 Abdominal pain €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Back/muscle pain/tendinitis/carpal tunnel syndrome €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Limb pain/deformity €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Chest pain €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.351 Peripheral edema €45.00 €36.00 €54.00 €4.59 Gamma €96.04 €0.47 €45.00 €36.00 €54.00 €4.59 Gamma €96.04 €0.469 Malignant pleural effusion €5,317.55 €4,254.04 €6,381.06 542.607 Gamma €96.04 €55.368 €24,133.34 €19,306.68 €28,960.01 2462.586 Gamma €96.04 €251.284 Pulmonary embolism €2,327.09 €1,861.68 €2,792.51 237.459 Gamma €96.04 €24.230 €3,490.13 €2,792.10 €4,188.16 356.136 Gamma €96.04 €36.340 Chronic obstructive pulmonary disease €2,601.00 €2,080.80 €3,121.20 265.408 Gamma €96.04 €27.082 €7,200.00 €5,760.00 €8,640.00 734.694 Gamma €96.04 €74.969 Erysipelas €3,274.00 €2,619.20 €3,928.80 334.082 Gamma €96.04 €34.090 €9,466.00 €7,572.80 €11,359.20 965.918 Gamma €96.04 €98.563 Erythema/urticaria at the injection site €2.12 €1.70 €2.55 0.217 Gamma €96.04 €0.022 €2.12 €1.70 €2.55 0.217 Gamma €96.04 €0.022 Multiple sclerosis €3,986.00 €3,188.80 €4,783.20 406.735 Gamma €96.04 €41.504 €10,123.00 €8,098.40 €12,147.60 1032.959 Gamma €96.04 €105.404 Pharyngitis/nasopharyngitis/rhinitis €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Faecaloma €2,160.00 €1,728.00 €2,592.00 220.408 Gamma €96.04 €22.491 €7,129.00 €5,703.20 €8,554.80 727.449 Gamma €96.04 €74.229 Atrial fibrillation €3,855.00 €3,084.00 €4,626.00 393.367 Gamma €96.04 €40.140 €6,793.00 €5,434.40 €8,151.60 693.163 Gamma €96.04 €70.731 Hip fracture €8,026.00 €6,420.80 €9,631.20 818.980 Gamma €96.04 €83.569 €24,012.00 €19,209.60 €28,814.40 2450.204 Gamma €96.04 €250.021 Major bone fracture (e.g.: femur) €6,200.62 €4,960.49 €7,440.74 632.716 Gamma €96.04 €64.563 €7,797.89 €6,238.32 €9,357.47 795.704 Gamma €96.04 €81.194 Minor bone fracture (e.g.: wrist) €2,404.00 €1,923.20 €2,884.80 245.306 Gamma €96.04 €25.031 €11,851.00 €9,480.80 €14,221.20 1209.286 Gamma €96.04 €123.397 Vertebral fracture/intervertebral disc disorder €3,155.00 €2,524.00 €3,786.00 321.939 Gamma €96.04 €32.851 €12,813.00 €10,250.40 €15,375.60 1307.449 Gamma €96.04 €133.413 Gastritis €46.21 €36.97 €55.45 4.715 Gamma €96.04 €0.481 €46.21 €36.97 €55.45 4.715 Gamma €96.04 €0.481 Gastroenteritis/Enterocolitis €3,035.00 €2,428.00 €3,642.00 309.694 Gamma €96.04 €31.601 €3,035.00 €2,428.00 €3,642.00 309.694 Gamma €96.04 €31.601 Influenza/flu-like symptoms €1,847.00 €1,477.60 €2,216.40 188.469 Gamma €96.04 €19.232 €4,544.00 €3,635.20 €5,452.80 463.673 Gamma €96.04 €47.314 Hemiparesis/hypesthesia of the face €6,257.61 €5,006.09 €7,509.13 638.531 Gamma €96.04 €65.156 €7,284.65 €5,827.72 €8,741.58 743.331 Gamma €96.04 €75.850 (Continued) Table 7. (Continued). Grade ≤ 2 adverse effects Cost of adverse events Cost of adverse events Mean Lower limit Upper limit SD Distribution Alpha Beta Mean Lower limit Upper limit SD Distribution Alpha Beta Intestinal bleeding €2,298.00 €1,838.40 €2,757.60 234.490 Gamma €96.04 €23.928 €10,164.00 €8,131.20 €12.196.80 1037.143 Gamma €96.04 €105.831 Abdominal hernia €3,452.00 €2,761.60 €4,142.40 352.245 Gamma €96.04 €35.943 €10,479.50 €8,383.60 €12,575.40 1069.337 Gamma €96.04 €109.116 Hypertension €712.14 €569.71 €854.56 72.667 Gamma €96.04 €7.415 €2,596.28 €2,077.02 €3,115.53 264.926 Gamma €96.04 €27.033 Hypokalemia €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Hypotension €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Myocardial infarction €8,814.10 €7,051.28 €10,576.92 899.398 Gamma €96.04 €91.775 €11,017.62 €8,814.10 €13,221.15 1124.247 Gamma €96.04 €114.719 Post-operative infection/abscess €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Clostridium difficile infection €3,986.82 €3,189.46 €4,784.19 406.819 Gamma €96.04 €41.512 €4,982.25 €3,985.80 €5,978.70 508.393 Gamma €96.04 €51.877 Kidney infection/pyelonephritis €2,109.00 €1,687.20 €2,530.80 215.204 Gamma €96.04 €21.960 €6,752.00 €5,401.60 €8,102.40 688.980 Gamma €96.04 €70.304 Upper respiratory tract infection €1,593.00 €1,274.40 €1,911.60 162.551 Gamma €96.04 €16.587 €1,593.00 €1,274.40 €1,911.60 162.551 Gamma €96.04 €16.587 Urinary infection €630.82 €504.66 €756.99 64.370 Gamma €96.04 €6.568 €1,843.68 €1,474.94 €2,212.42 188.131 Gamma €96.04 €19.197 Insomnia €1,006.71 €805.36 €1,208.05 102.725 Gamma €96.04 €10.482 €1,073.07 €858.46 €1,287.69 109.497 Gamma €96.04 €11.173 Heart failure €11,636.00 €9,308.80 €13,963.20 1187.347 Gamma €96.04 €121.158 €19,708.50 €15,766.80 €23,650.20 2011.071 Gamma €96.04 €205.211 Uterine leiomyoma €21,009.26 €16,807.40 €25,211.11 2143.802 Gamma €96.04 €218.755 €36,998.59 €29,598.87 €44,398.31 3775.367 Gamma €96.04 €385.241 Dizziness €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Nausea €219.18 €175.35 €263.02 22.366 Gamma €96.04 €2.282 €499.87 €399.90 €599.84 51.007 Gamma €96.04 €5.205 Benign bone neoplasm €13,295.25 €10,636.20 €15,954.30 1356.658 Gamma €96.04 €138.435 €18,513.00 €14,810.40 €22,215.60 1889.082 Gamma €96.04 €192.763 Pneumonia €630.82 €504.66 €756.99 64.370 Gamma €96.04 €6.568 €1,843.68 €1,474.94 €2,212.42 188.131 Gamma €96.04 €19.197 RESEARCH OUTCOMES & PHARMACOECONOMICS OF REVIEW EXPERT Optic neuritis €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Intestinal obstruction €2,160.00 €1,728.00 €2,592.00 220.408 Gamma €96.04 €22.491 €7,129.00 €5,703.20 €8,554.80 727.449 Gamma €96.04 €74.229 Sty €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Pancreatitis €7,799.00 €6,239.20 €9,358.80 795.816 Gamma €96.04 €81.206 €9,807.00 €7,845.60 €11,768.40 1000.714 Gamma €96.04 €102.114 Acute pancreatitis €15,766.00 €12,612.80 €18,919.20 1608.776 Gamma €96.04 €164.161 €36,294.00 €29,035.20 €43,552.80 3703.469 Gamma €96.04 €377.905 Dermal papilloma €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Duodenal perforation €8,529.00 €6,823.20 €10,234.80 870.306 Gamma €96.04 €88.807 €26,422.00 €21,137.60 €31,706.40 2696.122 Gamma €96.04 €275.115 Pericarditis €3,191.50 €2,553.20 €3,829.80 325.663 Gamma €96.04 €33.231 €8,152.50 €6,522.00 €9,783.00 831.888 Gamma €96.04 €84.887 Periodontitis €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Pyrexia €1,895.00 €1,516.00 €2,274.00 193.367 Gamma €96.04 €19.731 €2,916.00 €2,332.80 €3,499.20 297.551 Gamma €96.04 €30.362 Polypectomy €529.00 €423.20 €634.80 53.980 Gamma €96.04 €5.508 €529.00 €423.20 €634.80 53.980 Gamma €96.04 €5.508 Extra-ocular procedures, except orbit €2,486.00 €1,988.80 €2,983.20 253.673 Gamma €96.04 €25.885 €2,486.00 €1,988.80 €2,983.20 253.673 Gamma €96.04 €25.885 Spinal disc protrusion €6,230.00 €4,984.00 €7,476.00 635.714 Gamma €96.04 €64.869 €22,668.00 €18,134.40 €27,201.60 2313.061 Gamma €96.04 €236.027 Anaphylactic response €1,189.00 €951.20 €1,426.80 121.327 Gamma €96.04 €12.380 €3,674.00 €2,939.20 €4,408.80 374.898 Gamma €96.04 €38.255 Ligament rupture €8,739.00 €6,991.20 €10,486.80 891.735 Gamma €96.04 €90.993 €18,353.00 €14,682.40 €22,023.60 1872.755 Gamma €96.04 €191.097 Sarcoidosis €2,475.00 €1,980.00 €2,970.00 252.551 Gamma €96.04 €25.771 €9,264.00 €7,411.20 €11,116.80 945.306 Gamma €96.04 €96.460 Cough €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 €33.75 €27.00 €40.50 3.444 Gamma €96.04 €0.351 Tracheobronchitis €2,601.00 €2,080.80 €3,121.20 265.408 Gamma €96.04 €27.082 €7,200.00 €5,760.00 €8,640.00 734.694 Gamma €96.04 €74.969 Reproductive system disorders €2,366.50 €1,893.20 €2,839.80 241.480 Gamma €96.04 €24.641 €2,366.50 €1,893.20 €2,839.80 241.480 Gamma €96.04 €24.641 Disorders of the inner ear €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 €45.00 €36.00 €54.00 4.592 Gamma €96.04 €0.469 Vomiting €219.18 €175.35 €263.02 22.366 Gamma €96.04 €2.282 €499.87 €399.90 €599.84 51.007 Gamma €96.04 €5.205 9 10 P. IRIMIA ET AL.

Table 8. Cost per patient of adverse events associated with treatment with fremanezumab compared to erenumab, galcanezumab, and onabotulinumtoxinA. Base case of the analysis. Probability of Cost per patient of the savings with adverse events Fremanezumab Comparator Savings with fremanezumab fremanezumab Mean LL 95% CI UL 95% CI Mean LL 95% CI UL 95% CI Mean LL 95% CI UL 95% CI (a) Comparison of fremanezumab and erenumab Grade 1–2 adverse events €45.54 €29.89 €64.80 €253.33 €165.79 €360.35 -€207.79 -€135.90 -€295.54 100% Grade ≥ 3 adverse events €119.48 €76.28 €172.93 €380.79 €243.12 €551.15 -€-261.31 -€166.83 -€378.22 100% ALL Adverse events €165.02 €106.17 €237.73 €634.12 €408.90 €911.49 -€469.11 -€302.74 -€673.76 100% (b) Comparison of fremanezumab and galcanezumab Grade 1–2 adverse events €45.38 €29.47 €65.96 €1.82 €1.18 €2.65 €43.55 €28.29 €63.30 0% Grade ≥ 3 adverse events €119.07 €75.86 €173.95 €431.12 €275.34 €628.71 -€312.05 -€199.48 -€454.76 100% ALL Adverse events €164.45 €105.33 €239.91 €432.94 €276.53 €631.37 -€268.50 -€171.20 -€391.46 100% (c) Comparison of fremanezumab and onabotulinumtoxinA (PREEMPT 1 and 2 studies) Grade 1–2 adverse events €45.15 €29.04 €66.18 €1,178.48 €757.30 €1,726.42 -€1,133.32 -€728.26 -€1,660.24 100% Grade ≥ 3 adverse events €113.30 €74.40 €162.45 €275.53 €180.93 €395.06 -€162.23 -€106.53 -€232.61 100% ALL Adverse events €158.45 €103.44 €228.63 €1,454.01 €938.23 €2,121.48 -€1,295.56 -€834.79 -€1,892.85 100% (d) Comparison of fremanezumab and onabotulinumtoxinA (COMPEL study): Grade 1–2 adverse events 45.35 € 30.49 € 66.15 € 240.37 € 161.58 € 350.60 € −195.01 € −131.09 € −284.45 € 100% Grade ≥ 3 adverse events 114.29 € 72.56 € 166.63 € 1,019.70 € 645.42 € 1,490.19 € −905.41 € −572.86 € −1,323.56 € 100% ALL Adverse events 159.65 € 103.05 € 232.78 € 1,260.07 € 806.99 € 1,840.79 € −1,100.42 € −703,94 € −1,608.01 € 100% 95% CI: 95% confidence interval; LL: lower limit; UL: upper limit. The costs of adverse effects with fremanezumab are slightly different in the three analyses, due to the probabilistic nature of the model.

Table 9. Cost per patient of adverse effects associated with treatment with have not been taken into account, so it is possible that the fremanezumab compared to erenumab, galcanezumab, and savings on the overall cost of migraine are even greater. onabotulinumtoxinA. Sensitivity analysis. Although the choice of a preventive treatment for migraine Fremanezumab Cost difference Analysis compared to … per patient* should be based fundamentally on efficacy and safety criteria, Base case Erenumab -€469 it is also essential to incorporate concepts of cost, such as that Galcanezumab -€268 derived from the handling of the different AEs associated with OnabotulinumtoxinA -€1,100 the different therapeutic options. (RWE) OnabotulinumtoxinA -€1,296 MA are generally safe and have very favorable side-effects (RCT) profile to prevent CM [12–14]. The clinical significance of the All studies, regardless of the Erenumab -€413 adverse effects of CGRP, particularly gastrointestinal disorders duration of anti-CGRP treatment Galcanezumab -€126 Inclusion of the erenumab phase IIb Erenumab -€553 [56], and the lack of vascular events even when combined with study in CM have been recently highlighted [57,58]. The relationship Only patients with EM Erenumab -€507 between the AEs and the investigational intervention in clinical Galcanezumab -€137 Only patients with CM Erenumab** -€346 trials is established according to subjective clinical criteria, Galcanezumab -€396 which may vary according to the protocol of the clinical trial OnabotulinumtoxinA -€1,378 and, mainly, according to the investigator’s criterion [59]. *Negative results indicate a lower cost (savings) with fremanezumab compared to the Therefore, even understanding that some of the AEs described comparator; ** Inclusion of the erenumab IIb study. RCT: Randomized Clinical Trials; CM:chronicmigraine;EM:episodicmigraine;RWE:Real-WorldEvidence. may not be drug-related, in our study we opted to compare all the AEs described in clinical trials as the most impartial way of comparing the safety profile of drugs evaluated. the lower cost associated with the appearance of mild- The strengths and limitations of the study are outlined moderate AEs. below. With regard to the strengths, it should be noted that The efficacy and safety of the different monoclonal antibo- the reliability of the results was confirmed by a second-order dies against CGRP or its receptor marketed are very similar [12] Monte Carlo simulation with 1,000 simulations in patients with and the marketing prices can be overlapped. However, the migraine in clinical practice and the uncertainty associated with findings of the present study show the relevance of quantify- the variables analyzed (AEs rates and their associated costs). ing the cost associated with AEs related to the use of anti- This mathematical method makes it possible to reproduce the CGRP antibodies, since it allows to establish differences within effect of simultaneous and random changes in these para- this therapeutic group with relevance in clinical practice. The meters, attempting to simulate the clinical evolution of real use of fremanezumab represents potential savings in the cost life [19,20]. The consistency of the result was confirmed by of hospital admissions, medical visits, tests, and treatments the 95% confidence intervals and the 100% saving probability related to the appearance of AEs, compared to other mono- in the patient treated with fremanezumab compared to the clonal anti-CGRP antibodies, which could translate into lower other migraine treatments. AEs management costs were health-care costs. Furthermore, in this paper, only the direct obtained from Spanish studies and public prices, validated by cost associated with appearance of AEs has been evaluated, Spanish clinical experts. Sensitivity analyses confirmed the sta- but the indirect costs (associated with the loss of productivity) bility of the results obtained in the base case of the analysis. EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 11

With regard to the limitations of the study, firstly, it References should be borne in mind that a theoretical model has been Papers of special note have been highlighted as either of interest (•)orof used which is, by definition, a simplified simulation of reality. considerable interest (••) to readers. Secondly, it should be noted that in the comparison with 1. GBD 2016 Headache Collaborators. Global, regional, and national onabotulinumtoxinA the AEs observed in patients treated for burden of migraine and tension-type headache, 1990–2016: 12 weeks with fremanezumab and 24 weeks with the toxin a systematic analysis for the Global Burden of Disease Study were compared and may not be comparable. In this regard, 2016. Lancet Neurol. 2018;17:954–976. 2. International Headache Society. The international classification of it should be noted that only two doses of the toxin were headache disorders, 3rd edition. Cephalalgia. 2018;38:1–211. – administered in 24 weeks [22 24]. 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