Development of onabotulinumtoxina for chronic migraine

Transcription

1 Ann. N.Y. Acad. Sci. ISSN ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2013 Development of onabotulinumtoxina for chronic migraine Scott M. Whitcup, 1 Catherine C. Turkel, 1 Ronald E. DeGryse, 1 and Mitchell F. Brin 1,2 1 Allergan, Inc., Irvine, California. 2 Department of Neurology, University of California, Irvine, California Address for correspondence: Scott M. Whitcup, M.D., Allergan, Inc., 2525 Dupont Drive, Irvine, CA Whitcup_Scott@allergan.com Discovery of the neuromuscular effects of botulinum toxin began in the early 19th century and has continued to evolve. Currently, onabotulinumtoxina is approved by the U.S. Food and Drug Administration for two cosmetic and eight medical indications, including chronic migraine (CM). CM is a disabling form of migraine characterized by 15 headache days monthly and is believed to result from neuronal hypersensitivity to proinflammatory mediators, upregulation of sensory receptors, and consequent maladaptive pain responses with peripheral and central sensitization. OnabotulinumtoxinA achieves migraine prophylaxis in CM through regulation of vesicular trafficking and exocytosis, inhibition of peripheral release of neuropeptides and inflammatory peptides, and reduced cell surface expression of certain ion channels and receptors. Clinically, efficacy of onabotulinumtoxina for CM has been shown in two phase III, placebo-controlled trials (PREEMPT 1 and PREEMPT 2). OnabotulinumtoxinA significantly reduced the number of headache days per 28-day cycle relative to placebo at week 24 (change from baseline: 8.4 days for onabotulinumtoxina versus 6.6 days for placebo; P < 0.001, pooled data). OnabotulinumtoxinA improved healthrelated quality of life and had an acceptable safety profile. OnabotulinumtoxinA is the only approved treatment specifically for CM prevention and represents a safe and effective therapeutic for chronic migraineurs. Keywords: onabotulinumtoxina; chronic migraine; PREEMPT; migraine; drug development Introduction OnabotulinumtoxinA (Botox R, Allergan, Inc., Irvine, CA) is derived from the anaerobic bacteria Clostridium botulinum. Of the seven known toxin serotypes (A G), only serotypes A and B are used medicinally. An additional serotype H was recently described, 1 but has not been independently confirmed. OnabotulinumtoxinA was first approved by the U.S. Food and Drug Administration (FDA) in 1989 for two therapeutic indications: blepharospasm (abnormal eyelid spasm) and strabismus (crossed eyes). 2 It is popularly known for cosmetic use to temporarily improve the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity and moderate to severe lateral canthal ( crow s feet ) lines associated with orbicularis oculi activity. 3 However, treatment with onabotulinumtoxina for medical conditions exceeds cosmetic use. The therapeutic use of onabotulinumtoxina includes several indications such as cervical dystonia, severe primary axillary hyperhidrosis, upper limb spasticity, blepharospasm, strabismus, overactive bladder, urinary incontinence from neurogenic detrusor overactivity, and chronic migraine (CM). 2 In total, onabotulinumtoxina is approved by the FDA for eight therapeutic and two cosmetic indications across multiple therapeutic categories (see Ref. 4 for history). Globally, onabotulinumtoxina is approved in more than 85 countries for at least 27 indications. The safety and efficacy of onabotulinumtoxina across these indications has been established in over 60 randomized placebo-controlled trials spanning the past 25 years. We describe the unique efficacy and safety of onabotulinumtoxina in CM, a disabling condition in which individuals experience 15 or more days of headache per month for more than 3 months (at least 8 of these days have migraine features). CM affects approximately 1.3% of the U.S. adult doi: /nyas Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 67 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 OnabotulinumtoxinA for chronic migraine Whitcup et al. population ( 3 million people) and % of the European adult population. CM occurs times more often in women than in men, 5 8 and is associated with significant disability, lost productivity, lack of vitality, psychological stress, and overall poor quality of life for the migraineur As such, CM places a substantial burden to the healthcare system in resource utilization Defining the diagnosis of CM It is now understood that CM is distinguished from episodic migraine (<15 headache days per month), 12,13 with distinct pathophysiologic features, 14 epidemiology, 15 and clinical response to treatments. 16 However, at the time of clinical development of onabotulinumtoxina in CM, headache classification guidelines were simultaneously evolving as greater awareness developed about the distinct medical condition CM represents and, to some extent, the knowledge gleaned from the phase II trials of onabotulinumtoxina helped clinicians further understand CM. In 2013, well after the development program for onabotulinumtoxina in CM was completed, the International Classification of Headache Disorders, third edition beta (ICHD-3b)formallydefined CM. 17 The 2013 formalization of the definition is important for diagnostic and treatment considerations, and allows physicians to better differentiate between episodic migraine and CM. Early developmental history of onabotulinumtoxina In the early 19th century, Justinus Kerner published the first case study of botulism and described the clinical effects of botulinum toxin derived from sour sausages (Fig. 1). 18 Kerner postulated that botulinum toxin could act on the motor and autonomic peripheral nervous system. 18 Around 1895, Emile Pierre-Marie van Ermengem, a bacteriologist at the University of Ghent, isolated C. botulinum. 4,19 Early classification of botulinum serotypes A and B was published in 1919 by Stanford University professor Georgina Burke. 20 The bacterial exotoxin was first purified and crystalized in the 1920s, 21 with continued refinement of the isolation and purification process throughout midcentury. 22 As mechanism-of-action studies evolved, it was discovered that botulinum toxin may be useful in weakening hyperactive muscles. 4 Nearly 60 years later, Alan Scott, an ophthalmologist, described the beneficial effects of botulinum toxin type A for strabismus, 23,24 and paved the path to regulatory approval and the subsequent expanding therapeutic use of botulinum toxin in medicine. The name of Scott s original product, Oculinum, was later changed to Botox and, in 2011, this therapeutic was assigned the nonproprietary name onabotulinumtoxina. Developmental history of onabotulinumtoxina for CM The developmental path for onabotulinumtoxina for the treatment of patients with CM was not a direct one. In the 1990s, a facial-plastic surgeon observed that, when treating patients with onabotulinumtoxina for cosmetic enhancement, some of his patients with an incidental history of migraine reported a reduction or elimination of the number or intensity of their headaches concurrently with the cosmetic effect. 25 In 1998, the first openlabel study of onabotulinumtoxina reported efficacy in patients with frequent migraines, 26 and the first peer-reviewed publication appeared in Clinical development was initiated in 1997, incorporating exploratory studies of onabotulinumtoxina for migraine and other headache subtypes, including chronic daily headache, chronic tension-type headache, 31 and episodic migraine. 32,33 In addition, laboratory research explored the nonmotor aspects of onabotulinumtoxina effects, which as a novel mechanism, supported clinical development decisions and, ultimately, regulatory filings. 34,35 The results from the phase II program demonstrated decreased headache in some patients, and the drug was well tolerated. Nevertheless, the most consistent efficacy in phase II studies was in patients with more severe disease, characterized by frequent headache days per month, and with headaches that had migraine characteristics and symptoms On the basis of these observations, a refined patient population was pursued for the phase III clinical trial program, from which it was proposed that onabotulinumtoxina might be a therapeutic option for patients with transformed migraine (which would later be further defined as CM). Until this point, these severely affected, complex patients were explicitly excluded from other headache treatment registration programs. 68 Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences

3 Whitcup et al. OnabotulinumtoxinA for chronic migraine Figure 1. Timeline of important developmental milestones for use of onabotulinumtoxina for chronic migraine. CM, chronic migraine; CLARITY, a phase IV study evaluating durability of benefit with 7 9 onabotulinumtoxina cycles; COMPEL, Chronic migraine OnabotulinumtoxinA Prolonged Efficacy open-label; FDA, Food and Drug Administration; MOA, mechanism of action; PREEMPT, Phase III REsearch Evaluating Migraine Prophylaxis Therapy. OnabotulinumtoxinA mechanism of action in CM Pathophysiology of CM Elucidation of the complex pathophysiology of migraine pain continues to evolve, but current evidence supports the involvement of brain excitability, structural and functional brain alterations, and activation and sensitization of the trigeminovascular pathway When perturbed, pain-processing systems can change their state and lead to the perception of pain in the absence of a noxious stimulus. 39 While factors that predispose an individual to migraine and those leading to attack initiation are not fully understood, the current notion is that some aspects of migraine and some associated symptoms reflect abnormal excitability in both central and peripheral neurons, and in particular those of the trigeminal neural and vascular structures. 40 This neural pathway consists of first-order sensory trigeminal neurons whose axons convey nociceptive information from the face, skull, meninges, Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 69

4 OnabotulinumtoxinA for chronic migraine Whitcup et al. and intracranial blood vessels; second-order neurons of the spinal trigeminal nucleus which extends from the brain stem down to the third cervical segment; third-order thalamic neurons; and, ultimately, higher-order neurons in cortical regions that process this information. 40 As with other chronic pain states, some clinical symptoms associated with CM involve peripheral and central sensitization. Peripheral sensitization describes a state where primary sensory neurons exhibit maladaptive responses to peripheral stimuli with increased responsiveness to external mechanical or thermal stimuli. 41 This may manifest as a decreased threshold to experience pain. Neuronal hyperactivity seen in peripheral sensitization may be due to sensitivity of existing receptors to increased release of proinflammatory mediators (e.g., substance P, glutamate, calcitonin gene related peptide (CGRP)) and/or upregulation of sensory receptors or ion channels (e.g., transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1), transient receptor potential cation channel ankyrin subfamily, member 1 (TRPA1)) on nociceptive nerve endings. 35,40 Central sensitization describes a state where sensory neurons in the central nervous system (CNS, e.g., spinal cord, brain stem) exhibit increased excitability (lower threshold for activation), increased synaptic strength (gain), and enlargement of their receptive fields Central sensitization is triggered by sensory inputs arriving from peripherally sensitized nociceptors (i.e., those manifesting the phenotype of peripheral sensitization). Once initiated, central sensitization may persist after the peripheral stimulus is removed. In pain conditions, allodynia is a clinical manifestation of intrinsic neuronal hyperexcitability whereby pain thresholds are lowered so that normally innocuous stimuli become painful. Hyperalgesia is a state whereby noxious stimuli produce exaggerated and prolonged pain. Clinically, migraine is generally a continuum from episodic to chronic forms, 12,45 and the pathophysiology between the two migraine types appears to be different (i.e., more than frequency change), suggesting the phenomenon of enhanced central sensitization (i.e., allodynia) in the latter population Unlike episodic migraine, patients with CM may have persistent cortical hyperexcitability, 14,48 often resulting in cutaneous allodynia, a marker of central sensitization, even between migraine attacks. 46,49 Table 1. Trigeminovascular activation in CM 40 Potential sources of trigeminovascular pathway activation in CM Cortical spreading depression Mast cell degranulation Neurogenic inflammation Hydrogen ions ATP release Mild head trauma Dura receptors that may undergo change (e.g., upregulation) as a consequence of trigeminovascular activation TRPV1 TRPA1 TRPM8 ATP-gated P2X 3 Dopaminergic D1 and D2 receptors Serotonergic 5HT1b/1d CGRP receptors (CRLR/RAMP1) TNF- ASIC3 ASIC3, acid-sensing ion channel 3; ATP, adenosine triphosphate; CGRP, calcitonin gene related peptide; CM, chronic migraine; 5-HT1b/1d, 5-hydroxytryptamine 1b/1d; P2X 3, purinergic receptor P2X; TNF-, tumor necrosis factor ; TRPA1, transient receptor potential cation channel ankyrin subfamily, member 1; TRPM8, transient receptor potential cation channel subfamily melastatin, member 8; TRPV1, transient receptor potential vanilloid subfamily, member 1. In CM, there are several reasons for activation of the peripheral trigeminovascular pathway, each of which involve receptor activation/upregulation on meningeal nociceptors found in the dura (Table 1). Ultimately, this peripheral sensitization of the meningeal nociceptors, followed by second-order trigeminovascular neuron activation, is thought to initiate large release of glutamate and, in turn, the development of central sensitization. 40 Mechanism of action of onabotulinumtoxina in CM OnabotulinumtoxinA is a 900-kDa complex composed of hemagglutinin and nonhemagglutinin proteins. 50 The active part of the protein complex is a single-chain 150-kDa protein containing 1296 amino acids 50 that must be cleaved for activation, resulting in a light chain (endopeptidase) and heavy chain linked by a disulfide bond. 51 The heavy chain includes a translocation domain (N-terminal side of the heavy chain) and the binding domain (Cterminal of the heavy chain; Fig. 2). 51 The intracellular machinery responsible for regulated synaptic vesicle trafficking is the key target for onabotulinumtoxina (Fig. 3A; see Refs. 53 and Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences

5 Whitcup et al. OnabotulinumtoxinA for chronic migraine Figure 2. 3-D crystalline structure of botulinum toxin type A illustrating the 150-kDa binding domain, translocation domain, and light chain portion of the complex. 52 for details). Once onabotulinumtoxina is injected into tissue, the heavy chain C-terminus binds specifically to extracellular transporter acceptors on relevant nerve terminals, including a ganglioside receptor (GT1b), synaptic vesicle glycoprotein 2 (SV2), and fibroblast growth factor receptor 3 (FGFR3) (Fig. 3B). 57,58 Following binding, the neurotoxin is internalized into an acidified neuronal endosome, where a conformational change in the neurotoxin protein molecule allows the light chain to traverse the endosomal wall and enter the neuronal cytosol. 59,60 Once internalized, 61 the light chain is a zinc-dependent protease that cleaves SNAP-25 (synaptosomal-associated protein of molecular weight 25 kda), one of the soluble NSF (N-ethylmaleimide-sensitive fusion) attachment protein receptors (SNARE) that allows the neurotransmitter-containing vesicle docked at the membrane at the synaptic cleft to rapidly fuse with the neuronal plasma membrane and results in neurotransmitter exocytosis. 62 When synaptic vesicle fusion is interrupted by onabotulinumtoxina, vesicular neurotransmitter release is impaired. When injected intramuscularly at therapeutic doses, onabotulinumtoxina produces a temporary graded chemical denervation of the muscle resulting in a localized relaxation and/or reduction in the activity of the muscle. When injected intradermally for axillary hyperhidrosis, onabotulinumtoxina produces temporary chemical denervation of the overactive sweat gland, resulting in local reduction in sweating. The chemical denervation is temporary, and nerve function is restored over time via return of neurotransmitter function at the nerve terminals. The effect of onabotulinumtoxina on sensory neurons relies upon the same biochemical mechanism of impairing synaptic vesicle fusion by cleaving SNAP-25 (Fig. 3A and B). 63,64 OnabotulinumtoxinA plays a role in regulating pain pathways by impairing release of substance P, glutamate, and CGRP, as seen in nonclinical pain models. 34 Although the exact mechanism of action of onabotulinumtoxina in the prophylactic treatment of CM has not been fully elucidated, the current notion is that one component comprises inhibition of neuropeptide and neurotransmitter release from peripheral trigeminal sensory nerve terminals and consequently mitigates development of peripheral sensitization and, secondarily, central sensitization. 34,35 Suppression of central sensitization after the injection in the periorbital skin has been demonstrated in human models. 65,66 A recently proposed second component 40 is one whereby onabotulinumtoxina exerts neuromodulatory effects on receptors and ion channels that are delivered to the cell surface membrane via the same regulated pathway that is responsible for synaptic vesicle containing neurotransmitter release. 67 Peripheral administration of onabotulinumtoxina disrupts the transfer of receptors (e.g., TRPV1 and P2X 3 ) to the nerve ending membranes by preventing the SNARE-mediated vesicle-fusion process via SNAP-25 cleavage. 35,68,69 This effect has also been demonstrated in autonomically innervated human bladder biopsy specimens from patients with neurogenic detrusor overactive bladder both before and after onabotulinumtoxina treatment Relevant to pain associated with CM, new evidence suggests that onabotulinumtoxina interferes with highthreshold mechanosensitive ion channels (possibly TRPA1) linked to mechanical pain by blocking vesicle trafficking in C-type, but not A -type meningeal nociceptors. 40 An alternate theory suggests that onabotulinumtoxinaeffectsonpainpathwaysmayberelatedto neurotoxin retrograde transport and transcytosis to second-order neurons. 73 However, in their review, 73 Mazzocchio and Caleo note that the biological underpinning for the hypothesis of direct effects on central pain processing is lacking. More specifically, a transcytosis mechanism for botulinum toxin has not been established and is controversial Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 71

6 OnabotulinumtoxinA for chronic migraine Whitcup et al. Figure 3. (A) Synaptic vesicle (SV) content delivery of neurotransmitters and cargo delivery of ion channels and receptors. SVs form a reserve pool at the nerve terminal and may be filled with neurotransmitter(s). Most SVs are decorated with multiple proteins: 54 membrane-associated protein receptors, transient receptor potential cation channel vanilloid subfamily, member 1 (TRPV1), and transient receptor potential cation channel ankyrin subfamily, member 1 (TRPA1) are depicted. SVs dock adjacent to the nerve terminal inner membrane active zone and undergo an adenosine triphosphate (ATP) dependent priming step that enables response to the Ca 2+ signal that triggers fusion, exocytosis, and consequent delivery of not only SV contents into the extracellular space but also lipid membrane and associated protein cargo into the cell surface. Successful fusion requires an interaction between the vesicle-associated membrane protein (VAMP)/synaptobrevin with the internal membrane surface proteins synaptosomal-associated protein of molecular weight 25 kda (SNAP-25) and syntaxin, which together form the SNARE (soluble NSF (N-ethylmaleimide sensitive factor) attachment protein receptor) complex; other associated proteins (e.g., Munc18, Rab) are involved but not depicted. 55 The SV membrane may fully fuse into the terminal membrane (full collapse fusion), thus delivering the protein receptors (e.g., TRPV1 or TRPA1) into the cell surface. Excess terminal recycled through one of the endocytosis pathways 56 is not depicted. OnabotulinumtoxinA cleaves SNAP-25, impairing SV fusion and the regulated delivery of receptors TRPV1 or TRPA1 to the terminal membrane, thus downregulating receptor activity. An SV with both content and cargo is diagrammed for illustration purposes. Figure courtesy of Maria Rivero (Allergan, Inc., Irvine, CA), modified from Ref. 40. (B) OnabotulinumtoxinA mechanism of action. (a) OnabotulinumtoxinA heavy chain binds to an acceptor complex comprised of three components: ganglioside GT1b, synaptic vesicle glycoprotein 2 (SV2), fibroblast growth factor receptor 3 (FGFR3); (b) internalization into an endosome that (c) acidifies; (d) conformational change that enables the light chain to traverse the endosomal wall; (e) cytosolic light chain specifically cleaves SNAP-25 (synaptosomal-associated protein of molecular weight 25 kda), one of the SNARE attachment protein receptors required for SV membrane docking; (f) SNARE disruption prevents SV fusion with the terminal membrane. This prevents SV content delivery of neurotransmitters to the synaptic cleft in addition to SV cargo delivery and cell surface expression of relevant peripheral nerve receptors and ion channels. Figure courtesy of Maria Rivero (Allergan, Inc., Irvine, CA). 72 Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences

7 Whitcup et al. OnabotulinumtoxinA for chronic migraine In summary, our current notion is that onabotulinumtoxina exerts a prophylactic effect on CM through a dual mechanism centered on inhibition of SNARE-mediated regulated synaptic vesicle trafficking: (1) by inhibiting the peripheral release of neurotransmitter and inflammatory neuropeptide-containing vesicles (e.g., glutamate, CGRP 77, substance P 78 ), and (2) by interfering with cell surface expression of relevant peripheral nerve receptors and ion channels. In a patient with CM, onabotulinumtoxina is injected into the trigeminally innervated craniofacial cervical region. Accordingly, in the periphery, peripheral sensitization is disrupted, and central sensitization is indirectly blocked, resulting in an antinociceptive response in the sensitized trigeminal nerve and cervical afferents. 34,35,65,68,77 Pioneering development program for a treatment for CM Historically, treatment paradigms have not concentrated on CM and have been divided empirically into acute treatment of migraine (analgesics, triptans, opioids, ergot derivatives) and prophylactic treatments ( -blockers, calcium-channel blockers, antiepileptics, antidepressants). However, many of these treatments have considerable side effects, which often limit their utility. To date, the only treatment approved by the FDA for CM prophylaxis is onabotulinumtoxina, which was established in two phase III trials. Review of phase III data from clinical trials of onabotulinumtoxina in CM The phase III program that led to regulatory approval of onabotulinumtoxina for the treatment of CM included the PREEMPT 1 (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) and PREEMPT 2 clinical trials (NCT ; NCT ). 79,80 These studies consisted of a 24-week randomized, double-blind, placebo-controlled phase followed by a 32-week onabotulinumtoxina open-label phase, and were published both as individual studies 79,80 and as a pooled data set. 81,82 Patients were recruited from 56 North American sites in PREEMPT 1 80 and from 66 European and North American sites in PREEMPT After a 28-day baseline screening period, patients were randomized to onabotulinumtoxina or placebo, stratified by frequency of acute medication overuse (yes/no), using balanced randomization blocks of four within strata for each site. The double-blind phase had two injection cycles (onabotulinumtoxina U or placebo every 12 weeks) that were followed by a three-injection open-label onabotulinumtoxina phase (Fig. 4A). Study injections were given intramuscularly at 31 fixed sites (total of 155 U) across seven head and neck muscle areas (procerus, corrugator, frontalis, temporalis, occipitalis, cervical paraspinal, and trapezius) (Fig. 4B, for a thorough review on injection-site history and selection, see Ref. 83) Some patients were allowed, at the investigator s discretion, to receive an additional 40 U (maximum 195 U), using a follow-the-pain strategy, into one or both sides of three muscle areas (temporalis, occipitalis, and trapezius). 83 Men and women years of age meeting the diagnostic criteria for migraine in the 2004 International Classification of Headache Disorders, 2nd Edition. (ICHD-2) andwith 15 headache days in a 28-day period were eligible. They had to have 15 headache days, on which the attacks lasted 4continuous hours and 50% were migraine/probable migraine days, and the patients had to have 4 distinct headache episodes for 4 h.headachedays were defined as a calendar day consisting of 4hof continuous headache episode. Very specific criteria were required during the 28-day screening period; for example, patients were required to complete an electronic diary for 20 of 28 days. Use of electronic-diary data in the PRE- EMPT trials was the first time this innovative method of data collection was used in migraine trials. For the pooled analysis, 82 there were 1384 patients randomized to onabotulinumtoxina (n = 688) or placebo (n = 696) at the start of the doubleblind period (679 were from PREEMPT 1 80 and 705 were from PREEMPT 2 79 ). Most of the randomized patients were women ( 86%), with a mean age of 41 years. 82 Patients reporting acute medication overuse (acute headache medication at least twice weekly during any week with 5 diary days and 10 or 15 days, depending on the medication category, during the baseline period) were prominent and included approximately 65% of the 1384 patients. However, opioid-only and opioid-combination use among patients who overused acute medications Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 73

8 OnabotulinumtoxinA for chronic migraine Whitcup et al. Figure 4. (A) PREEMPT 1 and 2 study designs. 79,80 (B) Recommended injection sites for chronic migraine using fixed-site, fixed-dose injection site locations. 83 during the 28-day baseline period was low (1.7% and 9.3%, respectively). It is important to note that these studies represented a patient population at baseline that was severely disabled by CM, as evidenced by approximately 20 headache days per month, of which 18 were considered moderate to severe, despite many overusing acute headache medications. 82 Efficacy of onabotulinumtoxina The results of the phase III program demonstrated both the efficacy and safety of onabotulinumtoxina for CM Based on the primary efficacy end point of the pooled data set, use of onabotulinumtoxina significantly reduced the number of headache days per 28-day cycle relative to placebo at week 24 (change from baseline: 8.4 days for onabotulinumtoxina versus 6.6 days for placebo; P < 0.001, 95% CI 2.52 to 1.13). 82 This effect started as early as week 4 and continued for every time point through week 24 (P < at each visit). In addition, use of onabotulinumtoxina significantly reduced the frequency of migraine days, moderateorsevereheadachedays,cumulativehoursof headache on headache days, headache episodes, migraine episodes, the number of patients with severe Headache Impact Test (HIT-6) scores, and the use of triptans at week 24 (each P < 0.001, except for headache episodes (P = 0.009) and migraine episodes (P = 0.004)). Further, the percentage of patients with 50% decrease from baseline in the frequency of headache days relative to placebo was significantly increased (P < 0.001). In the pooled analysis, relative to placebo and despite a high placebo response, use of onabotulinumtoxina significantly improved measures of health-related quality of life (HRQoL), an important variable for patient well-being and productivity. 84 In-depth analysis of HRQoL scores for the Migraine-Specific Quality-of-Life Questionnaire (MSQ) at weeks 12 and 24 and the HIT-6 at each time point (Fig. 5A) showed improvements in areas such as pain, social and cognitive functioning, and the impact of migraine on patients daily 74 Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences

9 Whitcup et al. OnabotulinumtoxinA for chronic migraine Figure 5. (A) Mean change from baseline in total Headache Impact Test-6 (HIT-6) score with significant reductions in headache impact from weeks 4 through 24 for onabotulinumtoxina relative to placebo (P < 0.001). 84 (B) Efficacy of onabotulinumtoxina for CM: primary efficacy parameter in the pooled data from PREEMPT 1 and PREEMPT 2 of the mean change from baseline to each 4-week period through week 56 among patients who completed all five treatment cycles in the frequency of headache days (mean ± standard error). 85 performance. Furthermore, clinically meaningful differences (i.e., between-group minimally important differences) were achieved for those receiving onabotulinumtoxina versus placebo. 84 In an analysis of the double-blind and openlabel portions of the pooled trial data through week 56, those who received all five onabotulinumtoxina treatment cycles showed statistically better responses than those treated with placebo (double blind) followed by onabotulinumtoxina (open label) for headache days (Fig. 5B), migraine days, and moderate/severe headache days at week Nonetheless, patients switched from placebo to onabotulinumtoxina in the open-label portion did show a cumulative improvement over time in each time point, including HRQoL. 85 A subanalysis of patients from PREEMPT 1 and 2 was recently reported, which only included patients with CM and medication overuse (i.e., use of simple analgesics for 15 days or use of other medications for 10 days, including medication use 2 days per week in each week during the 28- day baseline period). 86 Of the 1384 patients in the pooled data set, 65% (n = 904) were stratified as having medication overuse. Similar to the overall study results, patients receiving onabotulinumtoxina had statistically fewer headache days at week 24 and at each 4-week interval assessed. Other efficacy and Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 75

10 OnabotulinumtoxinA for chronic migraine Whitcup et al. HRQoL end points (e.g., headache severity, triptan use, HIT-6 score, and MSQ) were also significantly improved with onabotulinumtoxina versus placebo, suggesting that its use is of particular benefit in this patient population. 86 Safety Pooled data from the PREEMPT studies showed no new safety signals, with the percentage of adverse events (AEs) reported similar in both the treated and placebo groups through 24 weeks. 82 Most AEs were of mild to moderate severity. Only neck pain (8.7%) and muscular weakness (5.5%) were reported in 5% of patients treated with onabotulinumtoxina. The number of patients who discontinued due to an AE was low, with 3.8% and 1.2% in the onabotulinumtoxina- and placebo-treated groups, respectively. 82 The most frequently reported AEs that led to discontinuation in the onabotulinumtoxina group were neck pain, muscular weakness, headache, and migraine (all <1% each). Serious AEs were reported in 4.8% of onabotulinumtoxinatreated patients and 2.3% in placebo-treated patients. No deaths were reported in either study. 82 Similarly, in a pooled safety analysis of two phase II and two phase III CM double-blind, placebocontrolled studies (n = 2436), onabotulinumtoxina treatment administered every 12 weeks for up to five treatment cycles showed a well-tolerated safety profile. 87 The good safety and tolerability profile of onabotulinumtoxina as a treatment for CM is an important consideration, especially when considering the typical AE profile of other headache prophylactic regimens. For instance, topiramate, a commonly prescribed antiepileptic drug for headache prophylaxis, has a profile of frequent AEs that can manifest as more severe; frequently the drug is less well tolerated, resulting in treatment discontinuation at a higher rate than for onabotulinumtoxina. 88 When looking across all five treatment cycles on the PREEMPT studies, those patients who completed all five cycles had a similar incidence of AEs as those in the intent-to-treat population, and the rate of treatment-related AEs declined with each subsequent onabotulinumtoxina treatment. 85 Because onabotulinumtoxina is a neurotoxin with bacterially derived proteins, it is important to assess possible immunogenic responses. Use of biologic drugs have the potential to cause the development of hypersensitivity, allergic reactions, immune-mediated AEs, and neutralizing antibodies (nabs), which result in loss of therapeutic effect. 89 Of 496 analyzable samples from onabotulinumtoxina-treated patients in phase II headache studies after three repeated treatments every 90 days (max dose 260 U), none had positive nabs and one had inconclusive results (0.2%). 82 In a meta-analysis of 16 studies of onabotulinumtoxina in 3006 patients across five medical and cosmetic indications, the development of a positive nab at one or more posttreatment time points was uncommon and occurred in 11 of 2240 (0.5%) patients who had a negative baseline Ab sample. 89 This was reduced to four patients (4/2240, 0.2%) by the final posttreatment visit. Average onabotulinumtoxina exposure per treatment cycle was 115 U, with a range of 1 15 treatment cycles (mean 3.8). Of the 11 patients who were nab +, none had hypersensitivity reactions or immune-related AEs. 89 This suggests that use of onabotulinumtoxina for CM should not increase the risk of immunogenicity. 82,89 Discussion The path from botulinum-tainted sausages to the treatment of CM pain was a bit serendipitous, but once identified, it illustrates the persistence of the scientific method that led to onabotulinumtoxina being approved as a safe and effective therapy in a traditionally difficult-to-treat population of migraineurs. The pivotal phase III clinical trials were heretofore the only studies conducted specifically in CM. OnabotulinumtoxinA represents a fundamental shift in the management of CM, a severely disabling condition 11,15 that continues to be underdiagnosed 90 and undertreated 91 in the healthcare community. With the support of international guidelines published in 2013 (ICHD-3b 17 ), the diagnostic criteria for CM are now more clearly outlined and together may support effective treatment of CM. Based on the phase III program, use of onabotulinumtoxina in this population effectively reduced the number of headache days per month and demonstrated significant reductions in the frequency of headache days, headache episodes, and triptan use. The effect was early, within 4 weeks, and consistent throughout the 24-week doubleblind period as well as during the 32-week openlabel extension study. Finally, onabotulinumtoxina 76 Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences

11 Whitcup et al. OnabotulinumtoxinA for chronic migraine had significant impacts on patient HRQoL in the 56- week PREEMPT studies, which may help alleviate the potential medical, financial, and social burdens that are often associated with CM. 15,92,93 Despite the fact that onabotulinumtoxina is a neurotoxin, it has an acceptable AE profile and did not induce any detected immunogenicity. The positive effect on parameters of efficacy and safety, along with the unique mechanism of action of onabotulinumtoxina, positions it as a unique treatment option to help manage patients with CM. It is injected into head and neck muscle areas that are known to be important in CM headache. OnabotulinumtoxinA blocks neurotransmitter and neuropeptide release, including substance P, CGRP, and glutamate, from the peripheral termini of primary afferents. 35,94 In addition, onabotulinumtoxina modulates cell surface receptor expression and trafficking of the vanilloid receptor TRPV1, in addition to interfering with the suprathreshold mechanical nociception in trigeminal neurons, suggesting a role in modulating high-threshold mechanosensitive ion channels, such as TRPA1. 40 The current notion is that onabotulinumtoxina inhibits peripheral signals to the CNS, which indirectly inhibits central sensitization. 35,94 This is important for patients with CM because they may be more susceptible to central sensitization and cutaneous allodynia than individuals who experience episodic migraine attacks. 46,49 Continued development of onabotulinumtoxina for CM will focus on longer-term studies to establish the long-term efficacy and safety of onabotulinumtoxina, including whether there are potential changes over time in either efficacy or safety. To date, data up to 56 weeks have been published for the PREEMPT studies. Longer term studies, both using real-world medical records data (e.g., CLAR- ITY, a phase IV study evaluating durability of benefit with 7 9 onabotulinumtoxina cycles), and in clinical trial settings (e.g., 96-week COMPEL (Chronic migraine OnabotulinumtoxinA Prolonged Efficacy open-label) phase IV trial, NCT ) are being conducted currently. In addition, a phase IV study to evaluate the efficacy and safety of onabotulinumtoxina as a treatment for CM in adolescents is ongoing (NCT ). Other trials are evaluating specific treatment benefit assessment tools in patients with CM who are receiving onabotulinumtoxina (NCT ). Acknowledgments This invited review article was sponsored by Allergan, Inc., Irvine, CA. Writing and editorial assistance was provided to the authors by Kristine W. Schuler, MS, of Complete Healthcare Communications, Inc. (Chadds Ford, PA) and Dana Franznick, PharmD, and was funded by Allergan, Inc. (Irvine, CA). All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. All authors are employees of Allergan, Inc. Conflicts of interest All authors are employees of Allergan, Inc., Irvine, CA, and receive stock or stock options in Allergan, Inc. References 1. Dover, N. et al Molecular characterization of a novel botulinum neurotoxin type H gene. J. Infect. Dis. 209: BOTOX R (onabotulinumtoxina) for injection, for intramuscular, intradetrusor, or intradermal use Full Prescribing Information. Irvine, CA: Allergan, Inc. 3. BOTOX R COSMETIC (onabotulinumtoxina) for injection, for intramuscular use Full Prescribing Information. Irvine, CA: Allergan, Inc. 4. Brin, M.F. & A. Blitzer History of onabotulinumtoxina therapeutic. In Botulinum Toxin. A. Carruthers& J. Carruthers, Eds.: London: Saunders Elsevier. 5. Castillo, J. et al Kaplan Award Epidemiology of chronic daily headache in the general population. Headache 39: Scher, A.I. et al Prevalence of frequent headache in a population sample. Headache 38: Lanteri-Minet, M. et al Prevalence and description of chronic daily headache in the general population in France. Pain 102: Natoli, J.L. et al Global prevalence of chronic migraine: asystematicreview.cephalalgia 30: Wang, S.J. et al Comparisons of disability, quality of life, and resource use between chronic and episodic migraineurs: a clinic-based study in Taiwan. Cephalalgia 33: Stokes, M. et al Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS). Headache 51: Blumenfeld, A.M. et al Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 31: Ann. N.Y. Acad. Sci (2014) C 2014 The Authors. Annals of the New York Academy of Sciences 77

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