Drug Profile
Suvorexant for the treatment of insomnia Expert Rev. Clin. Pharmacol. 7(6), 711–730 (2014)
Laura H Jacobson1, Gabrielle E Callander1,2 and Daniel Hoyer*1,2 1 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia 2 Department of Pharmacology and Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia *Author for correspondence: Tel.: +61 390 357 119 [email protected]
Suvorexant (Belsorma) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5–15 mg were efficient and probably safe, whereas the sponsors had proposed 15–40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant’s market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds. KEYWORDS: almorexant • Belsorma • drug development • FDA • hypocretin • insomnia • NDA • orexin • orexin receptor antagonists • pharmacodynamics, pharmacokinetics • SB649868 • sleep disorders • suvorexant
Merck submitted New Drug Application # 204569 for suvorexant (Belsorma) a.k.a. MK4305, an orexin receptor antagonist, to the US FDA for approval in the treatment of primary insomnia in adults and elderly patients in November 2012, which was discussed by the committee on 22 May 2013. On 1 July 2013, Merck received the FDA’s complete response letter: in essence a strong recommendation to resubmit and concentrate on doses lower than the ones proposed by the sponsor. The suvorexant submission discussed at the FDA followed several extensive and long duration Phase II and III trials [1–7], but approval was withheld due to differences in opinions of Merck and the FDA with respect to side effects and effective doses [8,9]. In April 2014, Merck submitted a revised suvorexant New Drug Application, and the FDA acknowledged re-submission. Details thereof have not been made public, but on 13 August 2014, the FDA approved suvorexant at the doses of 5, 10, 15 and 20 mg, pending approval by the Drug Enforcement Administration (DEA). The DEA issued a final rule on 28 August 2014 placing suvorexant into schedule IV of the Controlled Substances Act [10]. This final approval opened the path to market for suvorexant, and Merck has estimated that it will become available in late 2014 or early 2015. informahealthcare.com
10.1586/17512433.2014.966813
Suvorexant is the first orexin receptor antagonist approved for sleep disorders, more specifically primary insomnia, but is actually one in four development candidates that have reached Phase II or Phase III. The other three are filorexant or MK6096 [11,12], a potential backup to suvorexant, SB649868 or GW649868 from Glaxo, and almorexant from Actelion, a Swiss biotech known for developing endothelin antagonists such as bosentan for pulmonary hypertension. Almorexant nearly completed Phase III [13–17], and at that time was codeveloped with Glaxo, when it was stopped for unspecified safety reasons [18]. The first clinical data on almorexant, and for that matter of any orexin receptor antagonist, were presented at a sleep meeting in Australia and published in 2007 in Nature Medicine [13], taking the sleep research field by surprise, since no previous communications had been made on almorexant; although it was known that Actelion was working on orexin receptor antagonists. This was remarkable on several accounts: when presented, almorexant had already completed successfully Phase II trials, and Actelion researchers had been ‘sitting’ on the data without revealing the structure of the compound. What is even more remarkable is the speed at which these developments happened: the
2014 Informa UK Ltd
ISSN 1751-2433
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Jacobson, Callander & Hoyer
neuropeptide orexin also known as hypocretin, and its cognate two G-protein coupled receptors (GPCRs) were discovered and reported almost simultaneously in 1998, by two independent teams. Yanagisawa and collaborators in Dallas at the Howard Hughes Medical Research Institute [19] were investigating orphan receptors, in collaboration with SmithKline Beecham’s orphan receptor project. One of these receptors, HFGAN72, identified as an Expression Sequence Tag, turned out to be an orexin receptor. The endogenous peptide ligand orexin was found in brain extracts, soon followed by a second receptor, sequenced by homology screening [19]. On the other hand, de Lecea et al. at Scripps in San Diego [20] discovered hypocretin as a neuropeptide candidate in the hypothalamus, by using subtractive hybridization. de Lecea et al. were searching for potential neuropeptides and their true receptor targets. The names, orexin and hypocretin, which are still in use, relate to either the location (hypothalamus, hypocretin) or presumed effects (eating behavior, orexin). Orexin was proposed, since the peptide knockout (KO) mice had shown altered feeding behavior, thus ‘orexin’ (that stimulates feeding). Hypocretin was proposed, since the peptide is produced very specifically in the hypothalamus; in rodents there are only about 3000–7000 orexin-producing cells, all in the lateral hypothalamus (LH). In humans, these cells (up to 70,000) are also restricted to the LH. The cells project throughout the brain, matching a rather wide receptor distribution. After some debate, the following nomenclatures were agreed upon [21]: the peptides are called orexin A and B, receptors are orexin receptors 1 and 2 (OX1R and OX2R), according to IUPHAR, the International Union of Pharmacology. The respective genes are called hypocretins (HCRT 1/2) and hypocretin receptors 1 and 2, according to HUGO, the Human Genome Organisation. The present paper addresses the preclinical and clinical fate of suvorexant a.k.a. MK4305, a dual orexin receptor antagonist (DORA) with high affinity and potency for OX1R and OX2R (Ki 0.55 and 0.35 nM). A further aim of this paper is to critically evaluate the therapeutic strategy of dual OX1/OX2 receptor targeting for improving sleep, in which studies with suvorexant have been so informative. Suvorexant has a remarkable 6000- to 10,000-fold intrinsic selectivity for OX1R/OX2R over 165 receptors and enzymes (in vitro screening). Suvorexant has been extensively characterized in preclinical models with respect to sleep [22–25] and it appears to be safe and devoid of the classic side effects produced by benzodiazepines or Z drugs in rodent models [7,25]. It is the hypnotic drug candidate that has been most extensively studied and for the longest time in volunteers and insomnia patients so far [4,6,7]. According to the sponsor, studies in rats, dogs and rhesus monkeys demonstrated that suvorexant induces rapid sleep and increases both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep under conditions where target engagement, that is, orexin receptor occupancy in the brain, is demonstrated. However, as will be discussed in detail, slow wave sleep (SWS) is less affected, especially in humans, whereby much of the increased total sleep is contributed by REM sleep. 712
Orexin & orexin receptors in the brain
Orexin A and B are the products of prepro-orexin, a 133 amino acid (aa) precursor that is cleaved to produce orexin A and orexin B. Orexin A has 33 aa with a double cysteine bond, is C terminally amidated and is well conserved among various species (human, mouse, rat, bovine, porcine, canine, sheep). Orexin B is 28 aa long in most species, is also C terminally amidated and has about 46% sequence identity with orexin A. Orexin B shows some variation across species, although the bovine, porcine, canine and sheep sequence is identical. The precursor protein prepro-orexin is unique in that it shows very little sequence homology with any of the known neuropeptides [19,20,26–28]. Orexin receptors are GPCRs that may couple to a variety G proteins: OX1R couples to Gq, whereas OX2R is coupled to Gq and Gi/Go. Orexin A has high affinity for OX1R and somewhat lower affinity for OX2R, whereas orexin B binds primarily to the OX2R. Thus, activation of OX1R or OX2R will trigger phospholipase C activity and the phosphatidyl inositol and calcium cascade. OX2R activation can, in addition, also lead to inhibition of adenylate cyclase. Orexin receptor ligands have been found in screening campaigns using calcium accumulation as readout [11,13,23]. However, there is little doubt that depending on cell and/or tissue type, other transduction mechanisms and signaling pathways are activated by orexins, for example, ERK, p38, MAPK, PKC, to name a few. Orexin is rather unique since it is produced by a very limited number of neurons in the perifornical area/latero-posterior hypothalamus [29,30]. From the LH, projections reach much of the brain, including nuclei involved in sleep–wake regulation, feeding and arousal: for example, tuberomammillary nucleus, laterodorsal tegmental nucleus (LDT), paraventricular thalamic nucleus, arcuate nucleus (Arc) of the hypothalamus, with very strong innervation of aminergic nuclei in the brainstem, such as the locus coeruleus (LC), and the serotonergic raphe nuclei, and less dense projections to the amygdala, hippocampus, cerebral cortex and colliculi [29,31–33]. Orexin receptors in projection areas show a varied expression pattern. Some nuclei express primarily OX1R, for example, LC, dorsal raphe (DR), ventral tegmental area (VTA), prefrontal and infralimbic cortex, hippocampus (CA2), amygdala and bed nucleus of the stria terminalis (BNST), anterior hypothalamus, LDT/pedunculopontine nucleus [34–36]. OX2R is expressed in the amygdala, tuberomammillary nucleus, Arc and dorsomedial hypothalamic nuclei, paraventricular nucleus, LH, BNST, paraventricular thalamic nucleus, DR, VTA, LDT/ nucleus, CA3 in the hippocampus and medial septal nucleus [34,35]. The LH orexin neurons receive innervation from the ventrolateral preoptic area (GABA, adenosine), suprachiasmatic nucleus via the dorso-medial hypothalamic nuclei, LC (NA), DR (5-HT), VTA (DA), amygdala and BNST (CRF), suggesting a strong control by/or relationship with centers involved in sleep–wake regulation, but also energy homeostasis, arousal/emotion/fear and motivation/reward [37]. In spite of their name, orexins have rather limited direct effects on feeding Expert Rev. Clin. Pharmacol. 7(6), (2014)
Suvorexant for the treatment of insomnia
behavior or body weight, whereas their effects on sleep–wake regulation are predominant. When directly administered into the brain, orexin A produces an increase in wakefulness, motor activity and vigilance, and indeed, when animals are awake, addition of orexin can increase food intake. Orexin neurons are fully active during waking periods and become increasingly silent as sleep develops, especially during deep sleep and REM sleep [38], a clear testimony to their role in the regulation of sleep and wakefulness. Furthermore, based on the distribution of orexin receptors, motivation and reward have also been amply studied and it is clear that orexin receptor antagonists, especially OX1R selective but also DORAs, have shown pronounced effects in a variety of addiction paradigms [21,39–43]. Orexin & sleep disorders
It did not take long to associate orexin with sleep disorders [44–47]. In 1999, evidence was presented that narcolepsy with cataplexy is associated with the absence of orexinproducing neurons in the brain of patients suffering from this disease, with a nearly complete lack of orexin in the CSF. Interestingly, in dogs, narcolepsy is due to a functional defect in the OX2R receptors, but this appears to be species specific, since no receptor defect has ever been documented in human patients [30,48–54]. The absence of orexin in the CSF of narcolepsy patients has since become an established diagnostic tool for the disease [55]. Work performed in mice rapidly offered further insights on the role of orexin and its receptors. Preproorexin KO mice display very fractionated sleep patterns [48,54,56], with rapid transitions from wake to apparent sleep, characterized by absence of muscle tone and dominated by theta EEG activity, similar to the human situation. Although this pattern bears resemblance to narcolepsy in human patients, it should be noted that human narcoleptic patients can remain awake and conscious during an attack, with occasional transition into REM sleep [57]. However, it is challenging to infer consciousness in rodents under such conditions, and thus leaders the field cautiously interpret this state as ‘murine cataplexy’, while acknowledging that the murine state is not yet fully understood [57]. The International Working Group on Rodent Models of Narcolepsy therefore recommended that in mice these behaviors should be referred to as ‘behavioural arrest’ when interpreted from video alone, and as ‘cataplexy-like’ when assessed by EEG/EMG without video, and as ‘murine cataplexy’ when both methods are used and specific criteria are applied [57]; for the sake of space we use these definitions interchangeably. These observations in KO mice were remarkable as cataplectic attacks occur primarily during the night, when the mouse is active. Such attacks are not very frequent and rather short lasting; and fortunately Yanagisawa and collaborators employed infrared cameras to better characterize the behavioral profile of their KO mice. Similar findings were made with double orexin receptor KO mice, although the cataplectic-like attacks may be less frequent than in the peptide KO. On the other hand, single receptor KO mice show much less of a sleep or cataplecticinformahealthcare.com
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like phenotype: in OX2R KO mice, cataplectic attacks are rare events (contrary to dogs that have an OX2R defect), whereas OX1R KO mice have almost no sleep phenotype, with the exception of a modest increase in sleep fractionation [58]. Similar effects can be obtained in mice or rats where the orexinproducing cells are destroyed using the ataxin system [59]. Further studies using electrophysiology, cFos expression and microdialysis show that activity of orexin-producing cells or orexin production are cyclic events: the cells in the LH are highly active during wake, especially at the end of the day (or active period) and become inactive during sleep. Using optogenetics, Adamantidis et al. [60] showed that stimulation of these neurons induced transition from sleep to wake. On the other hand, optogenetic silencing [61] of these cells resulted in sleep, but only during the dark/active phase, not during the light/ inactive phase. Similar findings were made by application of DREADDS [62], a pharmacogenetic method used to inactivate very specific targets. These features are compatible with the switch or flip-flop hypothesis of Saper et al. [63,64], which proposes that orexin neurons are a master regulator of sleep–wake transitions: when the cells are active (switch on), the subject is awake; when sleep pressure increases, other centers such as the ventrolateral preoptic area become predominant, flipping the switch, such that the LH cells become inactive so that sleep can proceed (switch off). Thus, stable sleep and wake states depend on mutually inhibitory connections. The circuit is stable as long as the switch is present and the ‘on’ or ‘off’ state is defined. In the absence of the switch, that is, when the LH orexin cells are missing or no orexin is produced, the system becomes unstable and flips back and forth, as seen in narcoleptic patients or KO mice. A similar mechanism for transitions between non-REM and REM sleep has been proposed. In individuals with normal orexin signaling, it is extremely rare to go from the wake state into REM sleep. Conversely, in patients with narcolepsy who lack orexin neurons, there are frequent and unwanted transitions between wake and the cataplectic state, and even occasionally to REM sleep [65]. Similar to the absence of orexin in narcolepsy, or in double receptor KO mice, one may expect that by blocking both receptors simultaneously, for instance, with a dual antagonist, there is a possibility for fast switching from wake to sleep and vice versa, with rapid transitions into REM sleep and concomitant muscle atonia (as suggested early on by Tafti [66]). However, it is fair to stress that dual antagonists have not produced such fast switches spontaneously, whether in rodents, canines, non-human primates or in man [13]. However, cataplectic attacks are mostly triggered by strong positive or negative emotions, and can be easily induced in dogs or humans that suffer from narcolepsy; similarly in orexin KO mice, cataplectic-like attacks can be stimulated by, for example, food, stress and other positive or negative stimuli [67,68]. Orexin replacement in deficient rodent models or intranasal application in humans corrects narcoleptic syndromes (mice [69,70]; humans [71,72]), although the effects in humans appear to be limited to correction of REM sleep abnormalities 713
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common in these patients and to the reset of sleep toward a physiological pattern more so than eliminating cataplectic events, which by definition are rare. Replacement studies naturally lead to the idea of developing orexin receptor agonists to treat narcolepsy with cataplexy. However, this has not yet resulted in a suitable development compound. This is not altogether surprising, since peptide receptor agonists are notoriously difficult to create, especially with regard to brain penetration. The number of low molecular weight agonists for peptide GPCRs is very limited, as the chemical space around the orthosteric binding site is rather larger than that of, for example, monoamine receptors [73]. On the other side of the coin, the aforementioned studies testified to the importance of the orexin system in the control of sleep and wake, and thus formed the foundation and ongoing support for orexin receptor antagonism as a therapeutic strategy to manipulate sleep. Orexin receptor antagonists & sleep/wake
The effects of orexin receptor antagonists in sleep–wake regulation have been amply documented in rats, mice, dogs, nonhuman primates and human volunteers or insomnia patients [13,74–79]. The initial emphasis was on DORAs, which block both OX2 and OX1 receptors, presumably because orexin KO or dual orexin receptor KO mice have the most pronounced sleep phenotype. Another factor is probably related to the fact that early discovery programs had concentrated on OX1R antagonists to treat eating disorders. In addition, selectivity at OX2 receptors was more difficult to achieve. Whatever the reasons, suvorexant is one of four DORAs that entered clinical development, along with SB649868, filorexant and almorexant. There are a few reports that suggest that OX2R antagonists may be effective in sleep induction and maintenance in rodents, but no human data have been presented so far. There is no evidence that blocking OX1R alone will affect sleep. There is some controversy about whether an OX2R antagonist is equivalent or superior to a DORA. It has been repeatedly shown in various animal models that knocking out the orexin peptide or its two receptors leads to narcolepsy with cataplexy; the same can be reached by ‘killing’ the cells producing orexin in the LH, using selective expression of toxins such as ataxin. Although there is no evidence from animal studies that simultaneous blockade of both receptors with DORAs leads to narcolepsy-like attacks, the alarm was raised very early on by Tafti [66] following the first publication on almorexant [13] (and see [80]). Tafti pointed out that absence of proof (of cataplexy following almorexant treatment) was not proof of absence. Indeed, narcolepsy with cataplexy when it occurs, either in rodents or humans, is seldom spontaneous. It is very much facilitated by triggers [67,68], in general by strong positive or negative emotions. Even in the orexin KO mouse, narcolepsy with cataplexy is a rather rare event, but it can be induced by emotive stimuli. It is also known that knocking out OX2 or OX1 receptors individually has much less or almost no respective sleep phenotype in rodents. 714
Almorexant, a dual antagonist, may have narcoleptic/ cataplectic effects in mice made cataplexy sensitive, that is, by destroying a fraction of the LH orexin-producing cells [81]. Further, whereas an OX2R selective antagonist promotes sleep in rodents, an OX1R antagonist is inactive. Importantly, a combination of the two principles fares less favorably [82,83]. Thus, dual antagonism appears to stimulate REM at the expense of NREM sleep. Almorexant produces its sleep effects almost exclusively via OX2 receptors: it had no sleep effects in double receptor KO or in OX2R KO mice, but was fully effective in OX1R KO [84]. A careful look at the almorexant data in OX1R KO mice suggests that compared with wild-type mice, the effects of almorexant on REM sleep were even more pronounced [84]. Along the same lines, it was reported that suvorexant, almorexant and other DORAs induce and maintain sleep, but that this sleep is not balanced nor physiological; especially suvorexant and SB649868 appear to shift the balance toward REM sleep [83], and it is clear that in humans REM sleep is increased, whereas REM sleep onset is much decreased by DORAs (reminiscent of the sleep pattern seen in narcoleptic patients). On the other hand, OX2R antagonists seem to induce/maintain a more physiologically balanced sleep in rodents [83,85]. In contrast, zolpidem and the Z drugs increase stage 2 sleep, SWS (stages 3 and 4) and latency to REM sleep, and decrease the duration of REM sleep [13,86–88]. Finally, suvorexant given to mice during the inactive phase shifts the balance toward REM sleep, whereas the OX2R selective IPSU (first described as compound 26 in [83]) had no effects on sleep and did not affect the balance between REM and NREM [85,89]. Interestingly, the clinical studies performed with DORAs focus much more on total sleep time (TST), wake after sleep onset (WASO), sleep efficiency (SE) and latency to persistent sleep (LPS) than on the effects on the various sleep phases. Although polysomnography (PSG) has been used in various clinical phases, none of the suvorexant primary clinical end points addresses sleep architecture. Clinical studies with suvorexant TABLE 1 summarizes the key elements of Phase II/III trials performed with suvorexant in insomnia patients. Suvorexant was targeted for primary insomnia, however for diagnostic purposes, DSM-5 has since abandoned the distinction between primary and secondary insomnia [90]. Now, insomnia disorders represent an umbrella category, with nighttime symptoms (prolonged sleep onset latency, difficulties in sleep maintenance, early morning awakening) and notable daytime sequelae (fatigue, reduced attention or mood irritability).
Phase I studies
No fewer than 32 studies were conducted to assess the initial safety and tolerability, pharmacokinetics (PK) and pharmacodynamics of suvorexant, including evaluation of residual effects, abuse potential, respiratory safety and car driving. These studies were conclusive both in terms of efficacy and safety to continue Expert Rev. Clin. Pharmacol. 7(6), (2014)
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Phase IIb, multicenter, randomized, double-blind placebo-controlled, 2period adaptive crossover PSG trial in non-elderly patients
Design control type
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in non-elderly and elderly patients
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, long-term safety trial in non-elderly and elderly patients
Pivotal efficacy 2 (P029)
Long-term safety (P009)
12-month doubleblind treatment phase, followed by a 2-month randomized discontinuation phase
3-month treatment phase
3-month treatment phase, followed by 3-month extension phase
4-week treatment phase in each period
Duration
Evaluate long-term safety of suvorexant in patients with chronic insomnia and potential discontinuation effects
at night 1, month 1, and month 3 by PSG end points of LPS and WASO
– Evaluate efficacy at week 1, month 1 and month 3 by patient-reported outcomes of sTSTm, sTSOm and sWASOm;
– Evaluate the safety and tolerability of suvorexant in patients with chronic insomnia
– Evaluate efficacy at night 1 and week 4 by end points of SE – Evaluate the safety and tolerability of suvorexant in patients with chronic insomnia
Trial objective
Suvorexant HD • 40 mg (non-elderly) • 30 mg (elderly) Placebo
Suvorexant LD • 20 mg (non-elderly) • 15 mg (elderly) Placebo
Suvorexant HD • 40 mg (non-elderly) • 30 mg (elderly)
Suvorexant • 10 mg • 20 mg • 40 mg • 80 mg Placebo
Drugs dose, route and regimen
mg: mg: mg: mg:
62 61 59 61
Treatment phase Total: 779 • Suvorexant 521 • PBO: 258 Completed: 484 Randomized discontinuation phase Total entered: 484 • Suvorexant/Suvorexant: 156 • Suvorexant/PBO: 166 • PBO/PBO: 162 Completed: 470
Completed: 881
Treatment phase (P029) Total: 1009 • Suvorexant LD: 239 • Suvorexant HD: 387 • PBO: 383
• Suvorexant LD: 100 • Suvorexant HD: 172 • PBO: 151 Completed: 377
Treatment phase (P028) Total: 1021 • Suvorexant LD: 254 • Suvorexant HD: 383 • PBO: 384 Completed: 916 Extension phase Total: 423
Total: 254 • Suvorexant 10 • Suvorexant 20 • Suvorexant 40 • Suvorexant 80 • PBO: 249 Completed: 228
Numbers of patients treated (total, by treatment arm), and completed
HD: High dose; LD: Low dose; LPS: Latency to onset of persistent sleep; PBO: Placebo; Suvorexant/Suvorexant, Suvorexant/PBO, PBO/PBO: Therapy received during treatment phase/therapy received during randomized discontinuation phase; PSG: Polysomnography; PRO: Patient-reported outcomes; SE: Sleep efficiency; sTSTm: Mean subjective total sleep time; sTSOm: Mean subjective time-to-sleep onset; sWASOm: Mean subjective wake-time-after-sleep-onset; WASO: Wakefulness after persistent sleep onset.
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, trial in non-elderly and elderly patients
Pivotal efficacy 1 (P028)
Phase III pivotal studies
Dose finding (P006)
Phase IIb
Trial ID
Table 1. Summary of key elements of Phase IIb/III clinical trials with suvorexant.
Suvorexant for the treatment of insomnia
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tendency for a dose-dependent increase in the latter two parameters. On the PK Parameters Placebo Suvorexant 10 Suvorexant 50 Suvorexant 100 side, area under the curve (AUC) and SWA 102.0 105.0 107.0 98.8 Cmax increased in a dose-dependent, but not linear, manner. Of note, Tmax was 6.1† LPS 18.9 16.7 7.4† 3 h for the 3 doses, but with wide variaWASO 22.8 19.8† 15.9† 15.7† tion (from 1 to 8). Further, the apparent SE 91.7 93.1 95.2† 95.9† terminal half-life (T½) ranges from 9 to † † 13, with large variation. From these data, TST 440.7 448.3 458.9 461.4 it is clear that the PK is less than ideal for Stage 1 26.3 28.4 32.2 34.9 a sleep drug. The Tmax reaches after 3 h and the half-life is long, keeping in mind Stage 2 194.1 197.6 192.2 189.7 that a ‘normal night’ lasts 8 h. A closer Stage 3 74.1 72.0 74.1 72.6 look shows that 100 mg suvorexant after Stage 4 49.8 51.7 58.4 56.8 12 h results in a plasma concentration equivalent to Cmax of the 50 mg dose, SWS 123.9 123.7 132.5 129.4 and after 24 h, the plasma concentration REM 96.4 98.6 102.1 107.7 is equivalent to the Cmax of the 10 mg NREM 344.2 349.7 356.7 354.0 dose. The authors concluded that: ‘In healthy young men without sleep disorders, NSS 216.3 210.0 212.0 211.1 Suvorexant promoted sleep with some eviThe data are listed as time spent in the different stages as minutes, except for NSS, which is the absolute dence of residual effects at the highest doses’. number of stage shifts and SE (%). † indicate significance levels of changes versus placebo. In addition to sleep parameters, the study LPS: Latency to onset of persistent sleep; NREM: Non-rapid eye movement sleep; NSS: Number of stage shifts; also addressed simple reaction time, REM: Rapid eye movement sleep; SE: Sleep efficiency, (total sleep time/time in bed 100); sleep stages (stage 1, 2, 3, 4); SWA: Slow wave activity (assessed by power spectral analysis); SWS: Slow wave sleep (stage 3 + 4); choice reaction time and the digit symbol TST: Total sleep time; WASO: Wake after sleep onset. substitution test performed 10 h postAdapted from [6]. dose, as well as a questionnaire about patterns of awakening, behavior on waking, development in primary insomnia patients, both non-elderly getting to sleep and quality of sleep. Increased tiredness was (18 to 65 years). Study P028, which has not been formally published, is a parallel-group, fixed-dose study in which patients with insomnia were randomized to one of two fixed (low [LD] or high [HD]) doses of suvorexant or placebo for 3 months.
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Age
LD
HD
18 to 65
15 mg
30 mg
Patients were assessed either using questionnaires only (Qcohort) or by PSG and questionnaires (PQ-cohort). Suvorexant was taken just before bedtime. Patients were assessed at baseline, night 1, end of week 1 and months 1, 2 and 3. In the PQ-cohort, PSG was performed on night 1, and at months 1 and 3. The primary hypothesis compared the high dose on change from baseline on mean subjective (s) TST and change from baseline on (objective) WASO (both measures of sleep maintenance) and change from baseline in mean subjective time to sleep onset (TSO) and change from baseline in (objective) LPS, all at months 1 and 3. High-dose secondary hypotheses were sTST and sTSO at week 1, and WASO and LPS at night 1. A total of 1022 patients were randomized (79 centers in Asia/Eastern Europe/Africa [4%], Europe [35%], Japan [24%], North America [34%] and Central and South America [3%]). Study P029 had a similar design to that of P028 and was initially published only in abstract form. A total of 1019 patients were randomized at 90 centers in Asia/Central and Eastern Europe (14%), Europe (30%) and North America (48%). Patients ranged from 18 to 86 years old, with 41% (N = 410) older than 65 years. Seven hundred and fifty-three patients were randomized to the PQ cohort, 268 to the Qcohort. The combined data of P028 and P029 are summarized in TABLE 5, they are impressive: most of the readouts for sleep maintenance and sleep latency are met whether at the end of week 1 or after 3 months of treatment, although to a lesser extent for LPS and sTSO; perhaps for the same reasons as mentioned above, that is, Tmax. Again, although PSG was used in these studies, there was no attempt to look at sleep architecture. Study P009 was a 12-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial to assess longterm safety of suvorexant HD in subjects with primary insomnia. Parts of the trial were recently published [7]. It is unique in the sleep field at this stage of development, both by the 717
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Table 4. Phase II dose finding, 2-period crossover (4-week treatment phase in each period), multicenter trial in non-elderly adults with primary insomnia (P006). Sleep efficiency Night 1
p-value
TST Night 1
SWS Night 1
10 mg
5.2
Suvorexant for the treatment of insomnia Expert Rev. Clin. Pharmacol. 7(6), 711–730 (2014)
Laura H Jacobson1, Gabrielle E Callander1,2 and Daniel Hoyer*1,2 1 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia 2 Department of Pharmacology and Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia *Author for correspondence: Tel.: +61 390 357 119 [email protected]
Suvorexant (Belsorma) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5–15 mg were efficient and probably safe, whereas the sponsors had proposed 15–40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant’s market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds. KEYWORDS: almorexant • Belsorma • drug development • FDA • hypocretin • insomnia • NDA • orexin • orexin receptor antagonists • pharmacodynamics, pharmacokinetics • SB649868 • sleep disorders • suvorexant
Merck submitted New Drug Application # 204569 for suvorexant (Belsorma) a.k.a. MK4305, an orexin receptor antagonist, to the US FDA for approval in the treatment of primary insomnia in adults and elderly patients in November 2012, which was discussed by the committee on 22 May 2013. On 1 July 2013, Merck received the FDA’s complete response letter: in essence a strong recommendation to resubmit and concentrate on doses lower than the ones proposed by the sponsor. The suvorexant submission discussed at the FDA followed several extensive and long duration Phase II and III trials [1–7], but approval was withheld due to differences in opinions of Merck and the FDA with respect to side effects and effective doses [8,9]. In April 2014, Merck submitted a revised suvorexant New Drug Application, and the FDA acknowledged re-submission. Details thereof have not been made public, but on 13 August 2014, the FDA approved suvorexant at the doses of 5, 10, 15 and 20 mg, pending approval by the Drug Enforcement Administration (DEA). The DEA issued a final rule on 28 August 2014 placing suvorexant into schedule IV of the Controlled Substances Act [10]. This final approval opened the path to market for suvorexant, and Merck has estimated that it will become available in late 2014 or early 2015. informahealthcare.com
10.1586/17512433.2014.966813
Suvorexant is the first orexin receptor antagonist approved for sleep disorders, more specifically primary insomnia, but is actually one in four development candidates that have reached Phase II or Phase III. The other three are filorexant or MK6096 [11,12], a potential backup to suvorexant, SB649868 or GW649868 from Glaxo, and almorexant from Actelion, a Swiss biotech known for developing endothelin antagonists such as bosentan for pulmonary hypertension. Almorexant nearly completed Phase III [13–17], and at that time was codeveloped with Glaxo, when it was stopped for unspecified safety reasons [18]. The first clinical data on almorexant, and for that matter of any orexin receptor antagonist, were presented at a sleep meeting in Australia and published in 2007 in Nature Medicine [13], taking the sleep research field by surprise, since no previous communications had been made on almorexant; although it was known that Actelion was working on orexin receptor antagonists. This was remarkable on several accounts: when presented, almorexant had already completed successfully Phase II trials, and Actelion researchers had been ‘sitting’ on the data without revealing the structure of the compound. What is even more remarkable is the speed at which these developments happened: the
2014 Informa UK Ltd
ISSN 1751-2433
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neuropeptide orexin also known as hypocretin, and its cognate two G-protein coupled receptors (GPCRs) were discovered and reported almost simultaneously in 1998, by two independent teams. Yanagisawa and collaborators in Dallas at the Howard Hughes Medical Research Institute [19] were investigating orphan receptors, in collaboration with SmithKline Beecham’s orphan receptor project. One of these receptors, HFGAN72, identified as an Expression Sequence Tag, turned out to be an orexin receptor. The endogenous peptide ligand orexin was found in brain extracts, soon followed by a second receptor, sequenced by homology screening [19]. On the other hand, de Lecea et al. at Scripps in San Diego [20] discovered hypocretin as a neuropeptide candidate in the hypothalamus, by using subtractive hybridization. de Lecea et al. were searching for potential neuropeptides and their true receptor targets. The names, orexin and hypocretin, which are still in use, relate to either the location (hypothalamus, hypocretin) or presumed effects (eating behavior, orexin). Orexin was proposed, since the peptide knockout (KO) mice had shown altered feeding behavior, thus ‘orexin’ (that stimulates feeding). Hypocretin was proposed, since the peptide is produced very specifically in the hypothalamus; in rodents there are only about 3000–7000 orexin-producing cells, all in the lateral hypothalamus (LH). In humans, these cells (up to 70,000) are also restricted to the LH. The cells project throughout the brain, matching a rather wide receptor distribution. After some debate, the following nomenclatures were agreed upon [21]: the peptides are called orexin A and B, receptors are orexin receptors 1 and 2 (OX1R and OX2R), according to IUPHAR, the International Union of Pharmacology. The respective genes are called hypocretins (HCRT 1/2) and hypocretin receptors 1 and 2, according to HUGO, the Human Genome Organisation. The present paper addresses the preclinical and clinical fate of suvorexant a.k.a. MK4305, a dual orexin receptor antagonist (DORA) with high affinity and potency for OX1R and OX2R (Ki 0.55 and 0.35 nM). A further aim of this paper is to critically evaluate the therapeutic strategy of dual OX1/OX2 receptor targeting for improving sleep, in which studies with suvorexant have been so informative. Suvorexant has a remarkable 6000- to 10,000-fold intrinsic selectivity for OX1R/OX2R over 165 receptors and enzymes (in vitro screening). Suvorexant has been extensively characterized in preclinical models with respect to sleep [22–25] and it appears to be safe and devoid of the classic side effects produced by benzodiazepines or Z drugs in rodent models [7,25]. It is the hypnotic drug candidate that has been most extensively studied and for the longest time in volunteers and insomnia patients so far [4,6,7]. According to the sponsor, studies in rats, dogs and rhesus monkeys demonstrated that suvorexant induces rapid sleep and increases both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep under conditions where target engagement, that is, orexin receptor occupancy in the brain, is demonstrated. However, as will be discussed in detail, slow wave sleep (SWS) is less affected, especially in humans, whereby much of the increased total sleep is contributed by REM sleep. 712
Orexin & orexin receptors in the brain
Orexin A and B are the products of prepro-orexin, a 133 amino acid (aa) precursor that is cleaved to produce orexin A and orexin B. Orexin A has 33 aa with a double cysteine bond, is C terminally amidated and is well conserved among various species (human, mouse, rat, bovine, porcine, canine, sheep). Orexin B is 28 aa long in most species, is also C terminally amidated and has about 46% sequence identity with orexin A. Orexin B shows some variation across species, although the bovine, porcine, canine and sheep sequence is identical. The precursor protein prepro-orexin is unique in that it shows very little sequence homology with any of the known neuropeptides [19,20,26–28]. Orexin receptors are GPCRs that may couple to a variety G proteins: OX1R couples to Gq, whereas OX2R is coupled to Gq and Gi/Go. Orexin A has high affinity for OX1R and somewhat lower affinity for OX2R, whereas orexin B binds primarily to the OX2R. Thus, activation of OX1R or OX2R will trigger phospholipase C activity and the phosphatidyl inositol and calcium cascade. OX2R activation can, in addition, also lead to inhibition of adenylate cyclase. Orexin receptor ligands have been found in screening campaigns using calcium accumulation as readout [11,13,23]. However, there is little doubt that depending on cell and/or tissue type, other transduction mechanisms and signaling pathways are activated by orexins, for example, ERK, p38, MAPK, PKC, to name a few. Orexin is rather unique since it is produced by a very limited number of neurons in the perifornical area/latero-posterior hypothalamus [29,30]. From the LH, projections reach much of the brain, including nuclei involved in sleep–wake regulation, feeding and arousal: for example, tuberomammillary nucleus, laterodorsal tegmental nucleus (LDT), paraventricular thalamic nucleus, arcuate nucleus (Arc) of the hypothalamus, with very strong innervation of aminergic nuclei in the brainstem, such as the locus coeruleus (LC), and the serotonergic raphe nuclei, and less dense projections to the amygdala, hippocampus, cerebral cortex and colliculi [29,31–33]. Orexin receptors in projection areas show a varied expression pattern. Some nuclei express primarily OX1R, for example, LC, dorsal raphe (DR), ventral tegmental area (VTA), prefrontal and infralimbic cortex, hippocampus (CA2), amygdala and bed nucleus of the stria terminalis (BNST), anterior hypothalamus, LDT/pedunculopontine nucleus [34–36]. OX2R is expressed in the amygdala, tuberomammillary nucleus, Arc and dorsomedial hypothalamic nuclei, paraventricular nucleus, LH, BNST, paraventricular thalamic nucleus, DR, VTA, LDT/ nucleus, CA3 in the hippocampus and medial septal nucleus [34,35]. The LH orexin neurons receive innervation from the ventrolateral preoptic area (GABA, adenosine), suprachiasmatic nucleus via the dorso-medial hypothalamic nuclei, LC (NA), DR (5-HT), VTA (DA), amygdala and BNST (CRF), suggesting a strong control by/or relationship with centers involved in sleep–wake regulation, but also energy homeostasis, arousal/emotion/fear and motivation/reward [37]. In spite of their name, orexins have rather limited direct effects on feeding Expert Rev. Clin. Pharmacol. 7(6), (2014)
Suvorexant for the treatment of insomnia
behavior or body weight, whereas their effects on sleep–wake regulation are predominant. When directly administered into the brain, orexin A produces an increase in wakefulness, motor activity and vigilance, and indeed, when animals are awake, addition of orexin can increase food intake. Orexin neurons are fully active during waking periods and become increasingly silent as sleep develops, especially during deep sleep and REM sleep [38], a clear testimony to their role in the regulation of sleep and wakefulness. Furthermore, based on the distribution of orexin receptors, motivation and reward have also been amply studied and it is clear that orexin receptor antagonists, especially OX1R selective but also DORAs, have shown pronounced effects in a variety of addiction paradigms [21,39–43]. Orexin & sleep disorders
It did not take long to associate orexin with sleep disorders [44–47]. In 1999, evidence was presented that narcolepsy with cataplexy is associated with the absence of orexinproducing neurons in the brain of patients suffering from this disease, with a nearly complete lack of orexin in the CSF. Interestingly, in dogs, narcolepsy is due to a functional defect in the OX2R receptors, but this appears to be species specific, since no receptor defect has ever been documented in human patients [30,48–54]. The absence of orexin in the CSF of narcolepsy patients has since become an established diagnostic tool for the disease [55]. Work performed in mice rapidly offered further insights on the role of orexin and its receptors. Preproorexin KO mice display very fractionated sleep patterns [48,54,56], with rapid transitions from wake to apparent sleep, characterized by absence of muscle tone and dominated by theta EEG activity, similar to the human situation. Although this pattern bears resemblance to narcolepsy in human patients, it should be noted that human narcoleptic patients can remain awake and conscious during an attack, with occasional transition into REM sleep [57]. However, it is challenging to infer consciousness in rodents under such conditions, and thus leaders the field cautiously interpret this state as ‘murine cataplexy’, while acknowledging that the murine state is not yet fully understood [57]. The International Working Group on Rodent Models of Narcolepsy therefore recommended that in mice these behaviors should be referred to as ‘behavioural arrest’ when interpreted from video alone, and as ‘cataplexy-like’ when assessed by EEG/EMG without video, and as ‘murine cataplexy’ when both methods are used and specific criteria are applied [57]; for the sake of space we use these definitions interchangeably. These observations in KO mice were remarkable as cataplectic attacks occur primarily during the night, when the mouse is active. Such attacks are not very frequent and rather short lasting; and fortunately Yanagisawa and collaborators employed infrared cameras to better characterize the behavioral profile of their KO mice. Similar findings were made with double orexin receptor KO mice, although the cataplectic-like attacks may be less frequent than in the peptide KO. On the other hand, single receptor KO mice show much less of a sleep or cataplecticinformahealthcare.com
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like phenotype: in OX2R KO mice, cataplectic attacks are rare events (contrary to dogs that have an OX2R defect), whereas OX1R KO mice have almost no sleep phenotype, with the exception of a modest increase in sleep fractionation [58]. Similar effects can be obtained in mice or rats where the orexinproducing cells are destroyed using the ataxin system [59]. Further studies using electrophysiology, cFos expression and microdialysis show that activity of orexin-producing cells or orexin production are cyclic events: the cells in the LH are highly active during wake, especially at the end of the day (or active period) and become inactive during sleep. Using optogenetics, Adamantidis et al. [60] showed that stimulation of these neurons induced transition from sleep to wake. On the other hand, optogenetic silencing [61] of these cells resulted in sleep, but only during the dark/active phase, not during the light/ inactive phase. Similar findings were made by application of DREADDS [62], a pharmacogenetic method used to inactivate very specific targets. These features are compatible with the switch or flip-flop hypothesis of Saper et al. [63,64], which proposes that orexin neurons are a master regulator of sleep–wake transitions: when the cells are active (switch on), the subject is awake; when sleep pressure increases, other centers such as the ventrolateral preoptic area become predominant, flipping the switch, such that the LH cells become inactive so that sleep can proceed (switch off). Thus, stable sleep and wake states depend on mutually inhibitory connections. The circuit is stable as long as the switch is present and the ‘on’ or ‘off’ state is defined. In the absence of the switch, that is, when the LH orexin cells are missing or no orexin is produced, the system becomes unstable and flips back and forth, as seen in narcoleptic patients or KO mice. A similar mechanism for transitions between non-REM and REM sleep has been proposed. In individuals with normal orexin signaling, it is extremely rare to go from the wake state into REM sleep. Conversely, in patients with narcolepsy who lack orexin neurons, there are frequent and unwanted transitions between wake and the cataplectic state, and even occasionally to REM sleep [65]. Similar to the absence of orexin in narcolepsy, or in double receptor KO mice, one may expect that by blocking both receptors simultaneously, for instance, with a dual antagonist, there is a possibility for fast switching from wake to sleep and vice versa, with rapid transitions into REM sleep and concomitant muscle atonia (as suggested early on by Tafti [66]). However, it is fair to stress that dual antagonists have not produced such fast switches spontaneously, whether in rodents, canines, non-human primates or in man [13]. However, cataplectic attacks are mostly triggered by strong positive or negative emotions, and can be easily induced in dogs or humans that suffer from narcolepsy; similarly in orexin KO mice, cataplectic-like attacks can be stimulated by, for example, food, stress and other positive or negative stimuli [67,68]. Orexin replacement in deficient rodent models or intranasal application in humans corrects narcoleptic syndromes (mice [69,70]; humans [71,72]), although the effects in humans appear to be limited to correction of REM sleep abnormalities 713
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common in these patients and to the reset of sleep toward a physiological pattern more so than eliminating cataplectic events, which by definition are rare. Replacement studies naturally lead to the idea of developing orexin receptor agonists to treat narcolepsy with cataplexy. However, this has not yet resulted in a suitable development compound. This is not altogether surprising, since peptide receptor agonists are notoriously difficult to create, especially with regard to brain penetration. The number of low molecular weight agonists for peptide GPCRs is very limited, as the chemical space around the orthosteric binding site is rather larger than that of, for example, monoamine receptors [73]. On the other side of the coin, the aforementioned studies testified to the importance of the orexin system in the control of sleep and wake, and thus formed the foundation and ongoing support for orexin receptor antagonism as a therapeutic strategy to manipulate sleep. Orexin receptor antagonists & sleep/wake
The effects of orexin receptor antagonists in sleep–wake regulation have been amply documented in rats, mice, dogs, nonhuman primates and human volunteers or insomnia patients [13,74–79]. The initial emphasis was on DORAs, which block both OX2 and OX1 receptors, presumably because orexin KO or dual orexin receptor KO mice have the most pronounced sleep phenotype. Another factor is probably related to the fact that early discovery programs had concentrated on OX1R antagonists to treat eating disorders. In addition, selectivity at OX2 receptors was more difficult to achieve. Whatever the reasons, suvorexant is one of four DORAs that entered clinical development, along with SB649868, filorexant and almorexant. There are a few reports that suggest that OX2R antagonists may be effective in sleep induction and maintenance in rodents, but no human data have been presented so far. There is no evidence that blocking OX1R alone will affect sleep. There is some controversy about whether an OX2R antagonist is equivalent or superior to a DORA. It has been repeatedly shown in various animal models that knocking out the orexin peptide or its two receptors leads to narcolepsy with cataplexy; the same can be reached by ‘killing’ the cells producing orexin in the LH, using selective expression of toxins such as ataxin. Although there is no evidence from animal studies that simultaneous blockade of both receptors with DORAs leads to narcolepsy-like attacks, the alarm was raised very early on by Tafti [66] following the first publication on almorexant [13] (and see [80]). Tafti pointed out that absence of proof (of cataplexy following almorexant treatment) was not proof of absence. Indeed, narcolepsy with cataplexy when it occurs, either in rodents or humans, is seldom spontaneous. It is very much facilitated by triggers [67,68], in general by strong positive or negative emotions. Even in the orexin KO mouse, narcolepsy with cataplexy is a rather rare event, but it can be induced by emotive stimuli. It is also known that knocking out OX2 or OX1 receptors individually has much less or almost no respective sleep phenotype in rodents. 714
Almorexant, a dual antagonist, may have narcoleptic/ cataplectic effects in mice made cataplexy sensitive, that is, by destroying a fraction of the LH orexin-producing cells [81]. Further, whereas an OX2R selective antagonist promotes sleep in rodents, an OX1R antagonist is inactive. Importantly, a combination of the two principles fares less favorably [82,83]. Thus, dual antagonism appears to stimulate REM at the expense of NREM sleep. Almorexant produces its sleep effects almost exclusively via OX2 receptors: it had no sleep effects in double receptor KO or in OX2R KO mice, but was fully effective in OX1R KO [84]. A careful look at the almorexant data in OX1R KO mice suggests that compared with wild-type mice, the effects of almorexant on REM sleep were even more pronounced [84]. Along the same lines, it was reported that suvorexant, almorexant and other DORAs induce and maintain sleep, but that this sleep is not balanced nor physiological; especially suvorexant and SB649868 appear to shift the balance toward REM sleep [83], and it is clear that in humans REM sleep is increased, whereas REM sleep onset is much decreased by DORAs (reminiscent of the sleep pattern seen in narcoleptic patients). On the other hand, OX2R antagonists seem to induce/maintain a more physiologically balanced sleep in rodents [83,85]. In contrast, zolpidem and the Z drugs increase stage 2 sleep, SWS (stages 3 and 4) and latency to REM sleep, and decrease the duration of REM sleep [13,86–88]. Finally, suvorexant given to mice during the inactive phase shifts the balance toward REM sleep, whereas the OX2R selective IPSU (first described as compound 26 in [83]) had no effects on sleep and did not affect the balance between REM and NREM [85,89]. Interestingly, the clinical studies performed with DORAs focus much more on total sleep time (TST), wake after sleep onset (WASO), sleep efficiency (SE) and latency to persistent sleep (LPS) than on the effects on the various sleep phases. Although polysomnography (PSG) has been used in various clinical phases, none of the suvorexant primary clinical end points addresses sleep architecture. Clinical studies with suvorexant TABLE 1 summarizes the key elements of Phase II/III trials performed with suvorexant in insomnia patients. Suvorexant was targeted for primary insomnia, however for diagnostic purposes, DSM-5 has since abandoned the distinction between primary and secondary insomnia [90]. Now, insomnia disorders represent an umbrella category, with nighttime symptoms (prolonged sleep onset latency, difficulties in sleep maintenance, early morning awakening) and notable daytime sequelae (fatigue, reduced attention or mood irritability).
Phase I studies
No fewer than 32 studies were conducted to assess the initial safety and tolerability, pharmacokinetics (PK) and pharmacodynamics of suvorexant, including evaluation of residual effects, abuse potential, respiratory safety and car driving. These studies were conclusive both in terms of efficacy and safety to continue Expert Rev. Clin. Pharmacol. 7(6), (2014)
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Phase IIb, multicenter, randomized, double-blind placebo-controlled, 2period adaptive crossover PSG trial in non-elderly patients
Design control type
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in non-elderly and elderly patients
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, long-term safety trial in non-elderly and elderly patients
Pivotal efficacy 2 (P029)
Long-term safety (P009)
12-month doubleblind treatment phase, followed by a 2-month randomized discontinuation phase
3-month treatment phase
3-month treatment phase, followed by 3-month extension phase
4-week treatment phase in each period
Duration
Evaluate long-term safety of suvorexant in patients with chronic insomnia and potential discontinuation effects
at night 1, month 1, and month 3 by PSG end points of LPS and WASO
– Evaluate efficacy at week 1, month 1 and month 3 by patient-reported outcomes of sTSTm, sTSOm and sWASOm;
– Evaluate the safety and tolerability of suvorexant in patients with chronic insomnia
– Evaluate efficacy at night 1 and week 4 by end points of SE – Evaluate the safety and tolerability of suvorexant in patients with chronic insomnia
Trial objective
Suvorexant HD • 40 mg (non-elderly) • 30 mg (elderly) Placebo
Suvorexant LD • 20 mg (non-elderly) • 15 mg (elderly) Placebo
Suvorexant HD • 40 mg (non-elderly) • 30 mg (elderly)
Suvorexant • 10 mg • 20 mg • 40 mg • 80 mg Placebo
Drugs dose, route and regimen
mg: mg: mg: mg:
62 61 59 61
Treatment phase Total: 779 • Suvorexant 521 • PBO: 258 Completed: 484 Randomized discontinuation phase Total entered: 484 • Suvorexant/Suvorexant: 156 • Suvorexant/PBO: 166 • PBO/PBO: 162 Completed: 470
Completed: 881
Treatment phase (P029) Total: 1009 • Suvorexant LD: 239 • Suvorexant HD: 387 • PBO: 383
• Suvorexant LD: 100 • Suvorexant HD: 172 • PBO: 151 Completed: 377
Treatment phase (P028) Total: 1021 • Suvorexant LD: 254 • Suvorexant HD: 383 • PBO: 384 Completed: 916 Extension phase Total: 423
Total: 254 • Suvorexant 10 • Suvorexant 20 • Suvorexant 40 • Suvorexant 80 • PBO: 249 Completed: 228
Numbers of patients treated (total, by treatment arm), and completed
HD: High dose; LD: Low dose; LPS: Latency to onset of persistent sleep; PBO: Placebo; Suvorexant/Suvorexant, Suvorexant/PBO, PBO/PBO: Therapy received during treatment phase/therapy received during randomized discontinuation phase; PSG: Polysomnography; PRO: Patient-reported outcomes; SE: Sleep efficiency; sTSTm: Mean subjective total sleep time; sTSOm: Mean subjective time-to-sleep onset; sWASOm: Mean subjective wake-time-after-sleep-onset; WASO: Wakefulness after persistent sleep onset.
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, trial in non-elderly and elderly patients
Pivotal efficacy 1 (P028)
Phase III pivotal studies
Dose finding (P006)
Phase IIb
Trial ID
Table 1. Summary of key elements of Phase IIb/III clinical trials with suvorexant.
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tendency for a dose-dependent increase in the latter two parameters. On the PK Parameters Placebo Suvorexant 10 Suvorexant 50 Suvorexant 100 side, area under the curve (AUC) and SWA 102.0 105.0 107.0 98.8 Cmax increased in a dose-dependent, but not linear, manner. Of note, Tmax was 6.1† LPS 18.9 16.7 7.4† 3 h for the 3 doses, but with wide variaWASO 22.8 19.8† 15.9† 15.7† tion (from 1 to 8). Further, the apparent SE 91.7 93.1 95.2† 95.9† terminal half-life (T½) ranges from 9 to † † 13, with large variation. From these data, TST 440.7 448.3 458.9 461.4 it is clear that the PK is less than ideal for Stage 1 26.3 28.4 32.2 34.9 a sleep drug. The Tmax reaches after 3 h and the half-life is long, keeping in mind Stage 2 194.1 197.6 192.2 189.7 that a ‘normal night’ lasts 8 h. A closer Stage 3 74.1 72.0 74.1 72.6 look shows that 100 mg suvorexant after Stage 4 49.8 51.7 58.4 56.8 12 h results in a plasma concentration equivalent to Cmax of the 50 mg dose, SWS 123.9 123.7 132.5 129.4 and after 24 h, the plasma concentration REM 96.4 98.6 102.1 107.7 is equivalent to the Cmax of the 10 mg NREM 344.2 349.7 356.7 354.0 dose. The authors concluded that: ‘In healthy young men without sleep disorders, NSS 216.3 210.0 212.0 211.1 Suvorexant promoted sleep with some eviThe data are listed as time spent in the different stages as minutes, except for NSS, which is the absolute dence of residual effects at the highest doses’. number of stage shifts and SE (%). † indicate significance levels of changes versus placebo. In addition to sleep parameters, the study LPS: Latency to onset of persistent sleep; NREM: Non-rapid eye movement sleep; NSS: Number of stage shifts; also addressed simple reaction time, REM: Rapid eye movement sleep; SE: Sleep efficiency, (total sleep time/time in bed 100); sleep stages (stage 1, 2, 3, 4); SWA: Slow wave activity (assessed by power spectral analysis); SWS: Slow wave sleep (stage 3 + 4); choice reaction time and the digit symbol TST: Total sleep time; WASO: Wake after sleep onset. substitution test performed 10 h postAdapted from [6]. dose, as well as a questionnaire about patterns of awakening, behavior on waking, development in primary insomnia patients, both non-elderly getting to sleep and quality of sleep. Increased tiredness was (18 to 65 years). Study P028, which has not been formally published, is a parallel-group, fixed-dose study in which patients with insomnia were randomized to one of two fixed (low [LD] or high [HD]) doses of suvorexant or placebo for 3 months.
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Age
LD
HD
18 to 65
15 mg
30 mg
Patients were assessed either using questionnaires only (Qcohort) or by PSG and questionnaires (PQ-cohort). Suvorexant was taken just before bedtime. Patients were assessed at baseline, night 1, end of week 1 and months 1, 2 and 3. In the PQ-cohort, PSG was performed on night 1, and at months 1 and 3. The primary hypothesis compared the high dose on change from baseline on mean subjective (s) TST and change from baseline on (objective) WASO (both measures of sleep maintenance) and change from baseline in mean subjective time to sleep onset (TSO) and change from baseline in (objective) LPS, all at months 1 and 3. High-dose secondary hypotheses were sTST and sTSO at week 1, and WASO and LPS at night 1. A total of 1022 patients were randomized (79 centers in Asia/Eastern Europe/Africa [4%], Europe [35%], Japan [24%], North America [34%] and Central and South America [3%]). Study P029 had a similar design to that of P028 and was initially published only in abstract form. A total of 1019 patients were randomized at 90 centers in Asia/Central and Eastern Europe (14%), Europe (30%) and North America (48%). Patients ranged from 18 to 86 years old, with 41% (N = 410) older than 65 years. Seven hundred and fifty-three patients were randomized to the PQ cohort, 268 to the Qcohort. The combined data of P028 and P029 are summarized in TABLE 5, they are impressive: most of the readouts for sleep maintenance and sleep latency are met whether at the end of week 1 or after 3 months of treatment, although to a lesser extent for LPS and sTSO; perhaps for the same reasons as mentioned above, that is, Tmax. Again, although PSG was used in these studies, there was no attempt to look at sleep architecture. Study P009 was a 12-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial to assess longterm safety of suvorexant HD in subjects with primary insomnia. Parts of the trial were recently published [7]. It is unique in the sleep field at this stage of development, both by the 717
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Table 4. Phase II dose finding, 2-period crossover (4-week treatment phase in each period), multicenter trial in non-elderly adults with primary insomnia (P006). Sleep efficiency Night 1
p-value
TST Night 1
SWS Night 1
10 mg
5.2
