Drug Evaluation
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Pozanicline for the treatment of attention-deficit/hyperactivity disorder 1.
Introduction
2.
Nicotinic acetylcholine receptors
3.
Pozanicline
4.
Conclusion
5.
Expert opinion
Ann Childress† & Floyd R Sallee †
Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA
Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder occurring in childhood and often continues into adolescence and adulthood. The pathophysiology of ADHD is complex and likely involves multiple neurotransmitter systems. Medications currently used for the treatment of ADHD enhance dopaminergic and/or noradrenergic transmission. However, none of these drugs target the cholinergic system, which is also thought to play a significant role in cognitive disturbances such as those found in ADHD. Areas covered: In this review, the authors briefly discuss the cholinergic system, including multiple neuronal nicotinic receptor (NNR) subtypes that mediate the positive and negative effects of nicotine, in the context of animal models of ADHD. They also discuss the pharmacology of the NNR pozanicline, a partial agonist with high in vitro binding affinity and selectivity for the a4b2 NNR subtype. Finally, the authors examine pozanicline’s clinical developments. Expert opinion: Pozanicline was shown to be effective in a pilot study in humans with ADHD, but larger trials were negative. Developing an efficacious therapy is difficult. ADHD is a complex disorder with an unknown cause, and it is unclear, at this time, which qualities from NNR agonists are needed to treat it. It is therefore necessary to develop a more enhanced understanding of the nicotinic cholinergic system and its role in ADHD. Furthermore, new research paradigms may need to be employed to find drugs that are effective in patients with ADHD. Keywords: attention-deficit/hyperactivity disorder, neuronal nicotinic receptor, pozanicline Expert Opin. Investig. Drugs (2014) 23(11):1585-1593
1.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children and adolescents. Parent reported diagnosis of ADHD in children and adolescents in the United States aged 4 -- 17 years was estimated at 9.5% using data from the National Survey of Children’s Health in 2007 [1]. Worldwide prevalence of ADHD in adults is estimated at 3.4% [2]. Core symptoms of ADHD include inattention and/or hyperactivity and impulsivity [3]. According to the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), children and adolescents must have at least six of nine inattentive and/or six of nine hyperactive/impulsive symptoms, and those symptoms must be inappropriate for developmental level and cause impairment [3]. In a majority of patients, at least some ADHD symptoms persist into adulthood [4]. DSM-5 requires only five of nine inattentive and/or hyperactive/impulsive symptoms for adults. Inattentive symptoms are often found to be more persistent as subjects age. However, ADHD is quite heterogeneous with evidence implicating that the disorder is influenced by both genetic and environmental factors [5].
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Pozanicline No developments reported ADHD Neuronal nicotinic receptor agonist Oral N H3C
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O
HN
Pivotal trial(s)
[33,35,36,38]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
Although a number of effective medications for the treatment of ADHD are available, there is no one medication that is optimal for every patient. The majority of efficacy data are available for psychostimulants, and they are firstline medications [6,7]. A review of crossover trials comparing amphetamine with methylphenidate found that 68 -- 97% of subjects responded to at least one class of stimulants [8]. However, psychostimulants have the disadvantage of being controlled substances, requiring monthly prescriptions without the option to call in refills in the United States. Although they are generally tolerable, common side effects reported with administration of psychostimulants include anorexia, anxiety, decreased appetite, nausea, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, vomiting, headache, dry mouth and hyperhidrosis [9,10]. Psychostimulants are available in many countries. Non-stimulant drugs approved for the treatment of ADHD include the selective norepinephrine reuptake inhibitor atomoxetine (ATX) and the central alpha2A-adrenergic receptor agonists guanfacine extended-release (GXR) and clonidine extended-release (CLON-XR). ATX is available in multiple countries, but GXR and CLON-XR are currently available only in the United States. Non-stimulants are not controlled substances and are more convenient to prescribe; however, they are not as effective as psychostimulants. ATX has been shown to have a lower effect size than lisdexamfetamine and OROS methylphenidate [11,12]. Tolerability can also be a problem with ATX. Common adverse events (AEs) reported during treatment with ATX include nausea, vomiting, fatigue, decreased appetite, abdominal pain, somnolence, constipation, dry mouth, dizziness, erectile dysfunction and urinary hesitation [13]. Rare AEs reported with ATX use include hepatotoxicity. In its label, suicidal ideation is listed in a black box warning, although no suicides occurred in clinical trials with 1586
ATX. The drug is metabolized though the CYP2D6 pathway and dosing may need to be adjusted if used with CYP2D6 inhibitors. Effect sizes for psychostimulants are also generally higher than those for GXR and CLON-XR [14-16]. Somnolence, fatigue, nausea, lethargy and hypotension are commonly occurring AEs with GXR [17]. With CLON-XR administration, somnolence, fatigue, upper respiratory tract infection (cough, rhinitis, sneezing), irritability, throat pain (sore throat), insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth and ear pain occurred in at least 5% of treated subjects and at twice the rate of placebo in clinical trials [18]. Although there are a number of drugs effective for the treatment of ADHD, there continues to be a need to develop novel compounds that reduce ADHD symptoms. The nicotinic-cholinergic system has been an area of focus because nicotine has been shown to be efficacious in the reduction of ADHD symptoms [19,20]. Currently available treatments for ADHD target neurons in the prefrontal cortex (PFC) and multiple other areas of the brain. 2.
Nicotinic acetylcholine receptors
The PFC has been shown to have a role in executive functioning, working memory, attention, long-term memory, social behavior and personality [21]. In rats, lesions in the PFC cause severe attentional deficits [22]. Human neuroimaging studies have shown that the PFC is involved in behavioral tasks that require sustained attention [23]. The PFC contains many acetylcholine receptors, and research suggests that cholinergic innervation here specifically impacts attention. Cholinergic lesions in the PFC caused by specific immunotoxins cause severe impairment in sustained attention tasks [24]. Furthermore, elevated acetylcholine concentration has been detected during tasks requiring attention [25]. Nicotinic acetylcholine receptors (NNRs) are assembled from pentameric transmembrane subunits and are found in the central nervous system, peripheral nervous system and at neuromuscular junctions [26]. These receptors can be formed from a range of a and b subunits, and two of the most common subunit types found in multiple areas of the brain are the a7 and a4b2 receptors [27]. The a4b2 and a7 subunits are thought to play a role in neuroprotection and cognitive functioning [21,28,29]. Multiple NNR agonists have been studied in animal models of attention. One specific animal model of attention is the 5-choice serial reaction time task (5-CSRTT) in which rodents have to respond to five different cue lights by poking their noses into the corresponding hole to obtain food [30]. This task is thought to be analogous to the continuous performance task (CPT) used to measure attention in humans. Research has shown that mice without the b2 nicotinic receptor subunits have impaired attention [31]. Several drugs that target NNRs have advanced to clinical trials in Alzheimer’s disease, Parkinson’s disease, schizophrenia and ADHD. Only one NNR agonist, varenicline, is
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Pozanicline
approved by the United States Food and Drug Administration, with an indication for smoking cessation [32]. 3.
Pozanicline
Pharmacology Although multiple NNR agonist compounds have been developed, one of the most extensively studied in the treatment of ADHD has been pozanicline. A PubMed search on December 8, 2013 using the keywords ABT-089, pozanicline and ADHD returned seven results. A PsychINFO search performed on July 27, 2014 using the keywords pozanicline or ABT-089 and ADHD was added and returned five results. Results from PsychINFO included one review with no new information on pozanicline, which was not included in the PubMed search. Pozanicline and relevant manuscripts are reviewed below. Pozanicline [2-methyl-3-(2-(S)-pyrrolidinylmethoxy) pyridine dihydrochloride salt] is a selective NNR modulator that enhances cognition in animal models [33]. Pozanicline’s structure is shown in Box 1. It is a white crystalline powder with melting point of 253 C and is soluble in water. When administered orally to monkeys, it has a half-life of 119 min, reaches maximum concentration at 1.4 h and has an oral bioavailability of 26.3%. In vitro studies indicate that pozanicline undergoes minimal liver metabolism (< 10%). Pozanicline has at least four metabolites including a lactam, pyrrolidine N’oxide, pyridine N-oxide and hydroxylamine compound. Pozanicline has activity at multiple NNR receptor subtypes. Pozanicline is a partial NNR agonist selective for the cysteine binding site on the a4b2 receptor subtype, and is also a partial agonist for the a7 subtype and an antagonist at the a3b4 receptor subtype [33]. Pozanicline also has demonstrable agonist activity at the a6b2 receptors [34].
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3.1
Animal studies In animal studies, pozanicline was about as potent as nicotine in causing [3H]acetylcholine release from rat hippocampal synaptosomes [33]. Pozanicline also stimulated [3H]dopamine release from rat striatal slices. It improved cognitive performance in aged and lesioned rats and mature monkeys. In mice, pozanicline was found to enhance inhibitory avoidance in the inhibitory avoidance paradigm. For aged monkeys, performance in a standard delayed-match-to-sample test was improved with pozanicline after a long delay. Pozanicline was much less likely than nicotine to cause unwanted effects such as seizures, ataxia, hypothermia and decreased locomotor activity. It also did not have significant gastrointestinal or cardiac effects. Pozanicline was also found to protect cells against multiple cytotoxic insults in vitro. Success in preclinical and Phase I studies led to later phase studies in humans. 3.2
Human studies The safety and effectiveness of pozanicline for the treatment of ADHD was studied in adults. In one trial, a total of 61 subjects 3.3
aged 18 -- 60 years with ADHD diagnosed by (DSM-IV--TR) criteria were enrolled [35]. Further criteria for eligibility included a score of ‡ 2 on six of nine items on at least one of the Conners’ adult ADHD rating scales (CAARS) subscales at screening and day 1. The CAARS measures the presence and severity of ADHD symptoms and includes an 18-item subscale that relates to DSM-IV ADHD criteria. There are versions that can be completed by the subject and an observer. Both contain identical items. Subjects were also required to demonstrate at least moderate severity of symptoms on the clinical global impressions-ADHD severity scale (CGIADHD-S) at screening. The CGI-ADHD-S is a measurement of overall severity of ADHD symptoms as judged by the investigator. Subjects who had smoked or used nicotine product in the 3 months before study enrollment were excluded. Other exclusion criteria included schizoaffective disorder, bipolar disorder, obsessive-compulsive disorder, schizophrenia, psychotic disorders, alcohol abuse or dependence and other DSM-IV disorders requiring treatment. Subjects with chronic medical problems and abnormal laboratory values and those using stimulants or other psychotropic medications were also excluded. Subjects completed a 2-week screening period and were randomized to an 8-week double-blind treatment period including each of the four following treatments. Subjects were randomized to receive pozanicline 2, 4, 20 mg and placebo each twice daily each for 2 weeks during the 8-week trial. There was no washout between treatment sequences. The primary efficacy variable was the CAARS total ADHD symptom score at the end of each treatment period. Secondary efficacy measures included CAARS subscale scores, the CGI-ADHD-S and a computerized cognitive assessment battery at baseline at the end of each treatment period. The Hamilton depression scale (HAM-D) and Hamilton anxiety scale (HAM-A) were also completed at baseline and at the completion of each treatment period to assess current levels of anxiety and depression. Only 11 subjects had completed the study when it was terminated prematurely to obtain additional preclinical data. Of those who completed the study, six had inattentive subtype ADHD and five met criteria for combined subtype. Mean (Standard Deviation or SD) baseline CAARS total scores were 39.1 (8.08). Six subjects were male and five were female. The mean age was 32.0 (10.15). HAM-D and Ham-A scores did not indicate significant depression or anxiety. At baseline, subjects had impairment in reaction times on attentional computerized cognitive measures when compared with healthy controls. On the last treatment day, CAARS total symptom score was statistically significant for the pozanicline 2 mg two times a day (b.i.d.) (p = 0.021) and 4 mg b.i.d. (p = 0.047) doses compared with placebo. For the 20 mg b.i.d. dose (p = 0.056), the total symptom score approached significance. Effect sizes were 0.92 for the 2 mg b.i.d. dose, 0.76 for the 4 mg b.i.d. dose and 0.71 for the 20 mg b.i.d. dose. Response
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Table 1. Pozanicline adverse events of special interest percent of subjects reporting events.
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Cholinergic
Placebo (%)
Nausea 2.9 Vomiting 3.4 Dry mouth 2.4 Diarrhea 3.4 Dizziness 1.9 Visual changes 0.5 Psychiatric and nervous system Anxiety 0.5 Agitation 0 Altered mood 0 Irritability 2.4
Pozanicline (%) 3.5 0.5 2.5 4.0 2.0 1.0 1.0 1.0 1.0 5.5
Data derived from [36].
to placebo was similar across all treatment periods for the primary end point, showing an absence of learning effects. For the CGI-ADHD-S, treatment differences for drug compared with placebo were significant only for the pozanicline 2 mg b.i.d. dose (p = 0.031). Computerized cognitive assessment results suggested that the dose-response curve for attention and memory effects was dose linear. For spatial working memory, statistically significant improvement was seen only at the highest dose, 20 mg b.i.d. (p = 0.21). A CPT was part of the assessment. This test is used to measure attention and impulse control. For the CPT, statistically significant improvement was seen with all pozanicline doses in the number of commission errors. Pharmacokinetic samples were collected, and values were within the range of 5-15 ng/ml for the 2 and 4 mg b.i.d. doses. There were no serious AEs in this trial. Most AEs were mild to moderate. The most commonly reported treatment-related events reported by more than one subject in any treatment period included headache (three subjects on 2 mg b.i.d., two subjects on 20 mg b.i.d.), somnolence (one subject on placebo, two subjects on 20 mg b.i.d.), pain (two subjects on 20 mg b.i.d.), increased appetite (one subject on placebo and one subject on 20 mg b.i.d.) and nervousness (one subject on 2 mg b.i.d. and one subject on 20 mg b.i.d). One subject reported nausea at the 4 mg dose, and the same subject reported diarrhea on the 4 mg and 20 mg doses. There were no significant changes in laboratory results, vital signs or ECGs during the study. In a much larger randomized, double-blind, placebocontrolled, 2 2 crossover study, 221 adult subjects who had ADHD received one of the following doses of pozanicline 2, 5, 15, 40 mg once a day (q.d.), or 40 mg b.i.d and placebo in randomized sequences [36]. The authors noted that data on file supported pharmacological effects over a broad range of 4 -- 80 mg daily. Subjects received each treatment for 4 weeks. Treatment sequences were separated by a 2-week washout. The investigator-rated CAARS total score at the end of each treatment period was the primary efficacy measure. Secondary 1588
efficacy measures included the CAARS investigator-rated subscale scores, the adult ADHD investigator symptom report scale (AISRS), the CAARS self-rated and CGI-ADHD-S. The AISRS is a modified version of the ADHD Rating Scale that includes prompts for adult ADHD symptoms. A total of 171 subjects completed the study. For the primary efficacy measure, 40 mg q.d. and 40 mg b.i.d. were significantly better than placebo (model-based least square mean difference from placebo for 40 mg q.d. -- 4.33 p = 0.02 and for 40 mg b.i.d. -- 3.02, p = 0.03). Effect sizes were small (0.29 for 40 mg q.d. of pozanicline and 0.30 for 40 mg b.i.d.). There were no statistically significant differences in the CAARS: Inv total score for the 2, 5 or 15 mg q.d. doses compared with placebo and no statistically significant differences on the secondary efficacy measures. For secondary efficacy measures, the pozanicline 40 mg b.i.d. dosing showed significant improvement on the CAARS:INV Inattentive and ADHD Index subscales. The pozanicline 40 mg q.d. dose showed significant improvement on all CAARS:INV subscales (Inattentive, Hyperactive/Impulsive and ADHD Index) compared with placebo. Both the 40 mg q.d. and 40 mg b.i.d. dose significantly decreased ADHD symptoms on the AISRS and the CAARS: self-total score, inattention/memory, hyperactivity/restlessness and ADHD index subscale scores. For pozanicline 40 mg b.i.d., the CAARS:selfimpulsive/emotional liability and problems with self-concept subscale scores as well as the CGI ADHD-S were improved. The overall incidence of AEs with pozanicline and placebo was comparable (70.4% pozanicline and 65.5% for placebo). There was no apparent relationship to dose of pozanicline. Three serious AEs included vasovagal syncope on pozanicline 5 mg q.d., cholelithiasis during washout from pozanicline 40 mg q.d. and a myocardial infarction that occurred 3 weeks after pozanicline 5 mg q.d. was discontinued. None were thought to be related to pozanicline by investigators. Insomnia occurred in 5.5% of pozanicline-treated subjects compared with 4.9% of placebo-treated subjects, and decreased appetite occurred in 0.5% of pozanicline-treated subjects compared with 1.9% of placebo-treated subjects. Irritability was the only common AE that occurred with pozanicline at twice the rate of placebo (5.5 vs 2.4%). Other AEs that did not occur at twice the rate of placebo included nausea, vomiting, dry mouth, diarrhea, dizziness, visual changes, anxiety, agitation and altered mood. Cholinergic and central nervous system adverse events are listed in (Table 1). Changes in heart rate and weight were similar in the drug and placebo groups. There were no clinically significant laboratory findings or significant changes in ECGs, vital signs or on physical examinations. Another randomized, double-blind, parallel-group study was conducted with pozanicline in 160 adults aged 18 -- 59 years [37]. The study consisted of a screening/washout period of up to 4 weeks and an 8-week double-blind treatment period. Subjects were randomized to pozanicline 40 mg once daily, pozanicline 80 mg once daily or placebo in a 1:1:1 ratio. The primary
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efficacy measure was the change from baseline to final visit in the CAARS Investigator-rated (CAARS-INV) total score in each active treatment group compared with placebo. Secondary measures included the CAARS inattentive and hyperactive/ impulsive subscales, the CAARS ADHD Index, CGI-ADHDS, AISRS, Conners’ Adult ADHD Rating ScaleSelf report, Time-Sensitive ADHD Symptom Scale, Behavior Rating Inventory of Executive Function-Adult Version, Adult ADHD Quality of Life Questionnaire and the Work Productivity and Activity Impairment scale. Nicotine use was also queried to determine the potential pozanicline effects on nicotine use. Drug safety was evaluated with AE queries, vital sign, laboratory and ECG measurements and physical examinations. Pharmacokinetic samples were also obtained at multiple study visits. Of the 160 subjects randomized, 159 took at least one dose of study medication and 137 (86%) completed the study. Mean age of study subjects was 35.9 years, and most subjects were white (84%) and male (62%). For nicotine use, 30% reported current use and 15% reported previous use. Type of ADHD included combined subtype 119/159 (75%) or inattentive subtype for 39/159 (25%) of subjects. One subject met criteria for hyperactive-impulsive subtype, and 40% of subjects were newly diagnosed with ADHD at screening. The mean (SD) CAARS-INV total scores were 36.9 (8.88) in the placebo group, 40.0 (7.40) in the pozanicline 40 mg daily group and 37.3 (7.79) in the pozanicline 80 mg daily group. No statistically significant improvement occurred in either drug treatment group compared with placebo on the primary efficacy measure or on any secondary efficacy measure. Pozanicline plasma levels were measured and were consistent with those found in previous trials. The most commonly reported treatment-emergent AEs, which occurred in at least 5% of subjects and were greater than in the placebo group, included nasopharyngitis (6.6%), upper respiratory tract infection (6.6%) and somnolence (5.7%). Two subjects had serious AEs. One subject was hospitalized with colitis not thought to be related to study drug, and a second subject had suicidal ideation requiring hospitalization. Because of stressors and previous psychiatric history, the suicidal ideation was thought to be probably not related to study drug. Three other subjects discontinued study drug secondary to AEs. The events were depression, irritability and erectile dysfunction. All of these were deemed possibly related to study drug. The reasons for the lack of positive results were examined for this trial and were not thought to be secondary to site selection. However, the study design using parallel groups was different from that of previous positive studies using a crossover design. The authors concluded that the withinsubject comparisons may be more sensitive in detecting pozanicline treatment effects. The safety and efficacy of pozanicline in children was also studied in two multicenter, randomized, placebo-controlled, double-blind, parallel-group trials [38]. Subjects were children aged 6 -- 12 years diagnosed with ADHD of at least moderate
severity. Other significant diagnoses, including bipolar disorder, psychotic disorder, autism spectrum disorders, tics and Tourette syndrome, were excluded. Other current psychiatric disorders that required treatment were also excluded as were subjects who had failed to respond to two or more prior trials of ADHD medication. The demographic characteristics did not differ between studies or between treatment groups within studies. In both trials, 66% of subjects were male. The mean age was 8.6 years in Study 1 and 8.5 years in Study 2. In Study 1, 80% of subjects were diagnosed with ADHD combined subtype and in Study 2, 76% were diagnosed with ADHD combined subtype. The first study lasted 8 weeks and contained six treatment groups (n = 274) dosed once daily. Four groups were dosed with pozanicline: 0.085, 0.260, 0.520, 0.700 mg/kg [38]. A fifth group was given ATX at 1.2 mg/kg, and the last group received placebo. A total of 278 subjects were randomized, 274 received at least one dose of study drug and 236 subjects (86%) completed the study. Study 2 included a 2-week screening period and 6 weeks of double-blind treatment [38]. Subjects were randomized to pozanicline 0.7 mg/kg, pozanicline 1.4 mg/kg or placebo in 1:1:1 ratio. For this trial, 121 subjects were randomized, 119 received at one dose of study drug and 96 (81%) completed the trial. For both trials, the primary efficacy measure was mean change in the ADHD rating scale (ADHD-RS-IV) Total Score administered by trained raters from baseline to final evaluation. Secondary efficacy measures included the CGIADHD-S, ADHD-RS-IV total score assessed at every visit, the ADHD-RS-IV attention and hyperactivity/impulsivity subscale scores, the Conners’ Global Index-Parent Version, Behavior Rating Inventory of Executive Function-Parent Questionnaire, Child’s Sleep Habits Questionnaire the Child Health Questionnaire and ADHD Impact Module-Child. Steady-state plasma concentrations of pozanicline were also assessed. There were no statistically significant differences between any pozanicline dose and placebo on the primary efficacy measures for either study. However, there was a statistically significant treatment effect between ATX and placebo at each evaluation during Study 1. There were no statistically significant differences between any pozanicline dose and placebo for the mean changes from baseline to final evaluation for the CGI-ADHD-S. There were no statistically significant differences between subjects who had received prior treatment for ADHD and treatment naı¨ve subjects. 4.
Conclusion
Pozanicline is an a4b2 NNR agonist developed after finding that nicotine improved cognition in animals and in humans with ADHD. Pozanicline has been shown to be effective in animal models by improved cognitive performance in rats and monkeys.
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In mice, pozanicline was found to enhance inhibitory avoidance. For older monkeys, memory was improved with pozanicline after a long delay. Pozanicline was much less potent than nicotine in causing unwanted effects such as seizures, ataxia, hypothermia and decreased locomotor activity. It also had minimal gastrointestinal and cardiovascular effects. Pozanicline has also been found to protect cells against multiple cytotoxic insults in vitro. Pozanicline showed promise in initial crossover pilot study in adults with ADHD. The drug was found to be effective compared with placebo with tolerable side effects. The initial findings in the small crossover trial in adults were encouraging; however, larger randomized trials in children and adults yielded disappointing results. In the first trial, effect sizes of 0.92, 0.76 and 0.71 were seen with doses of 2, 4 and 20 mg b.i.d. pozanicline doses. This trial had some serious limitations. The sample size was small because the trial was ended while further preclinical data were collected, time on treatment was only 2 weeks and there was no washout between treatments. In another larger adult trial, there was no significant difference between pozanicline and placebo. In a third larger trial in adults, the effect sizes were small. In two trials in children and adolescents, pozanicline was not significantly better than placebo. 5.
Expert opinion
Acetylcholine receptors are established therapeutic targets for Alzheimer’s disease, schizophrenia, Parkinson’s disease, smoking cessation, pain, attention-deficit hyperactivity disorder, epilepsy, autism and depression [39-41]. Based on the effectiveness of nicotine in the improvement of attention in animals and healthy human volunteers and the reduction of ADHD symptoms in early studies, multiple nicotinic receptor agonists have been developed. Pharmacological and genetic studies have demonstrated that the a4b2 subunits of NNRs play an important role in attention. Agonists selective for the a4b2 subunits have improved sustained attention and vigilance, decreased distractibility and improved accuracy in animals. ABT-418 was the first NNR agonist studied in humans with ADHD [42]. It was found to be effective in a small placebo-controlled, randomized trial of adults with ADHD. However, because of its short half-life the drug had to be delivered transdermally. It also caused nausea and dizziness, similar to nicotine. Side effects and a short half-life made the drug unsuitable for larger trials. Further research identified pozanicline, which had a longer half-life and fewer potential side effects. Based on the effectiveness of pozanicline in improving cognitive functioning in animal models, this NNR was thought to be a good candidate for extensive study in patients with ADHD. NNR compounds were among the first to utilize animal models for early target validation and proof of concept. Models including the 5-CSRTT and the operant signal detection 1590
task (SDT) are used to assess sustained attention while selective attention is often measured using a novel object recognition (NOR) task and sand-digging test. A limitation of these models is that attention is not measured directly but surmised based on behavior. Some of the tests, such as the 5-CSRTT and SDT, require extensive animal training, while the NOR and sand-digging do not. However, the NOR and SDT are not as specific in assessing attention as the other models. Humans are given little practice for cognitive testing in trials. Based on the failure of pozanicline to dramatically improve attention in humans, one may conclude that animal models employed to assess cognitive effects of the cholinergic system do not appear to translate to efficacy for ADHD symptoms in humans. The models for attention have not always correlated even between strains of the same species. For example, nicotine has been shown to improve attention in some strains of rats but not others [43]. There may be subtle critical differences in the neural systems associated with the expression of nicotinic receptors even within species that make extrapolation to humans difficult. Other factors that make it difficult to extrapolate efficacy from animals to humans include the complexity of the nervous system. The exact mechanism by which nicotinic agonists exert cognitive effects is not clear. Initially, only stimulatory effects were thought to be important in enhancing cognition; however, compounds such as pozanicline also desensitize receptors [44]. Nicotinic systems interact with multiple neurotransmitter systems promoting the release of many neurotransmitters including acetylcholine, dopamine, serotonin, g-aminobutyric acid and glutamate, all of which are involved in cognitive functioning [43]. Due to the complicated interactions of nicotinic agonists with other transmitter systems, development of specific targets based on animal models is difficult. Despite the lack of positive evidence associated with pozanicline, the continued development of non-stimulant therapies to treat ADHD is warranted. However, to be useful clinically, these drugs need to have effect sizes at least comparable to those of medications currently used to treat ADHD. Stimulants have an effect size close to 1.0, and all of the non-stimulants have an effect size of ~ 0.7. Effect sizes for pozanicline in an initial small crossover trial in adults were good with effect sizes of 0.71 -- 0.92. In a second trial in adults, the effect sizes of 0.29 and 0.30 for pozanicline were quite small compared to the effect sizes of currently available medications to treat ADHD. In a third adult trial, there were no significant differences between pozanicline and placebo. Although the exact reasons for the failure of pozanicline are not clear, it does not appear to be secondary to design flaws in the trials. The first double-blind clinical trial in children used ATX as an active comparator and ATX separated from placebo as expected. The results of other NNRs in large human clinical trials found to improve cognition based on animal models have also been disappointing. Another a4b2 NNR agonist, AZD
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Pozanicline
3480 or ispronicline, also showed promise in a small trial of 24 adults with ADHD [45]. The study included a Stop Signal Task to measure response inhibition, and the CAARS:Inv was the primary efficacy measure. Subjects showed greater improvement on inattention than hyperactivity/impulsivity. Subjects with higher baseline cognitive impairment and not greater clinical ADHD symptoms had a greater treatment response. Ispronicline also had a beneficial effect on cognition in subjects with age-associated memory impairment [46]. However, it failed to demonstrate improvement in cognition in a large study of stable patients with schizophrenia treated with an atypical antipsychotic [47]. A third a4b2 NNR agonist, AZD1446, improved attention and memory in rodents [48]. Although it was well tolerated in humans, it failed to show improvement in cognitive functioning in subjects with ADHD [49]. It was unclear why the drug failed to separate from placebo. The authors postulated that the selectivity and affinity for b2 subunits, different agonism profiles, and potential for dopamine release may impact clinical effect. Because the nicotinic acetylcholine system is so complex, it is unclear which attributes for NNR agonists are needed for efficacy in ADHD. Furthermore, ADHD is a complex disorder that has been shown to be highly heritable but the cause is unknown. The diversity of symptoms in ADHD comprising both cognitive and behavioral components makes the development of specific receptor targets even more difficult. Additionally, there may be differences in the maturation of the attentional control system between juveniles and adults Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 2007;190:402-9
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American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th edition. American psychiatric association; Arlington, VA, USA: 2013
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Biederman J, Petty CR, Evans M, et al. How persistent is ADHD? a controlled 10-year follow-up study of boys with ADHD. Psychiatry Res 2010;177(3):299-304 Thapar A, Cooper M, Eyre O, Langley K. What have we learnt about
that may explain divergent findings between early adult studies and child studies with pozanicline. An enhanced understanding of the nicotinic cholinergic system and its role in ADHD in humans is needed. Further research in the development of novel NNR agonists may need to employ new research paradigms to find drugs that are effective in patients with ADHD.
Declaration of interest A Childress has consulted for Shire Pharmaceuticals, Inc., Novartis, NextWave Pharmaceuticals and Ironshore Pharmaceuticals. She has also received research support from Shire Pharmaceuticals, Inc., Novartis, Pfizer, Inc., Somerset Pharmaceuticals, NextWave Pharmaceuticals, Abbott Pharmaceuticals, Eli Lilly & Co., Ortho-McNeill Janssen Scientific Affairs, Johnson & Johnson, Otsuka, Shionogi, Sunovion, Noven Pharmaceuticals, Ironshore Pharmaceuticals and Rhodes Pharmaceuticals, Purdue Pharma, Forest Laboratories, Arbor Pharmaceuticals and Tris Pharma. She has received speaker fees from Shire Pharmaceuticals, Novartis and Shionogi and is also on the advisory board of Shionogi. FR Sallee is a consultant of Ironshore Pharma, AstraZeneca, Impax Laboratories, Inc., Purdue Pharma, Otsuka Research and Development, as well as Reckitt Benckiser. They also have received research support from Shire PLC. FR Sallee only is a stockholder and on the board of P2D Bioscience.
the causes of ADHD? J Child Psychol Psychiatry 2013;54(1):3-16 6.
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Marks MJ, Wageman CR, Grady SR, et al. Selectivity of ABT-089 for alpha4beta2* and alpha6beta2* nicotinic acetylcholine receptors in brain. Biochem Pharmacol 2009;78(7):795-802 Wilens TE, Verlinden MH, Adler LA, et al. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol Psychiatry 2006;59(11):1065-70 This manuscript describes a pilot study of pozanicline in adults with attentiondeficit/hyperactivity disorde. Apostol G, Abi-Saab W, Kratochvil CJ, et al. Efficacy and safety of the novel alpha(4)beta(2) neuronal nicotinic receptor partial agonist ABT-089 in
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Expert Opin. Investig. Drugs (2014) 23(11)
Affiliation
Ann Childress†1,2 MD & Floyd R Sallee3 MD PhD † Author for correspondence 1 President, Center for Psychiatry and Behavioral Medicine, Inc., 7351 Prairie Falcon Road, Suite 160, Las Vegas, NV 89128, USA 2 Clinical Assistant Professor, University of Nevada School of Medicine, Department of Family Medicine, Reno, NV, USA; Tel: +1 702 838 0742; Fax: +1 702 838 6749; E-mail: [email protected] 3 Professor of Psychiatry, University of Cincinnati, 260 Stetson Street, Suite 3200, Cincinnati, OH 45219, USA
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Pozanicline for the treatment of attention-deficit/hyperactivity disorder 1.
Introduction
2.
Nicotinic acetylcholine receptors
3.
Pozanicline
4.
Conclusion
5.
Expert opinion
Ann Childress† & Floyd R Sallee †
Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA
Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder occurring in childhood and often continues into adolescence and adulthood. The pathophysiology of ADHD is complex and likely involves multiple neurotransmitter systems. Medications currently used for the treatment of ADHD enhance dopaminergic and/or noradrenergic transmission. However, none of these drugs target the cholinergic system, which is also thought to play a significant role in cognitive disturbances such as those found in ADHD. Areas covered: In this review, the authors briefly discuss the cholinergic system, including multiple neuronal nicotinic receptor (NNR) subtypes that mediate the positive and negative effects of nicotine, in the context of animal models of ADHD. They also discuss the pharmacology of the NNR pozanicline, a partial agonist with high in vitro binding affinity and selectivity for the a4b2 NNR subtype. Finally, the authors examine pozanicline’s clinical developments. Expert opinion: Pozanicline was shown to be effective in a pilot study in humans with ADHD, but larger trials were negative. Developing an efficacious therapy is difficult. ADHD is a complex disorder with an unknown cause, and it is unclear, at this time, which qualities from NNR agonists are needed to treat it. It is therefore necessary to develop a more enhanced understanding of the nicotinic cholinergic system and its role in ADHD. Furthermore, new research paradigms may need to be employed to find drugs that are effective in patients with ADHD. Keywords: attention-deficit/hyperactivity disorder, neuronal nicotinic receptor, pozanicline Expert Opin. Investig. Drugs (2014) 23(11):1585-1593
1.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children and adolescents. Parent reported diagnosis of ADHD in children and adolescents in the United States aged 4 -- 17 years was estimated at 9.5% using data from the National Survey of Children’s Health in 2007 [1]. Worldwide prevalence of ADHD in adults is estimated at 3.4% [2]. Core symptoms of ADHD include inattention and/or hyperactivity and impulsivity [3]. According to the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), children and adolescents must have at least six of nine inattentive and/or six of nine hyperactive/impulsive symptoms, and those symptoms must be inappropriate for developmental level and cause impairment [3]. In a majority of patients, at least some ADHD symptoms persist into adulthood [4]. DSM-5 requires only five of nine inattentive and/or hyperactive/impulsive symptoms for adults. Inattentive symptoms are often found to be more persistent as subjects age. However, ADHD is quite heterogeneous with evidence implicating that the disorder is influenced by both genetic and environmental factors [5].
10.1517/13543784.2014.956078 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Pozanicline No developments reported ADHD Neuronal nicotinic receptor agonist Oral N H3C
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O
HN
Pivotal trial(s)
[33,35,36,38]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
Although a number of effective medications for the treatment of ADHD are available, there is no one medication that is optimal for every patient. The majority of efficacy data are available for psychostimulants, and they are firstline medications [6,7]. A review of crossover trials comparing amphetamine with methylphenidate found that 68 -- 97% of subjects responded to at least one class of stimulants [8]. However, psychostimulants have the disadvantage of being controlled substances, requiring monthly prescriptions without the option to call in refills in the United States. Although they are generally tolerable, common side effects reported with administration of psychostimulants include anorexia, anxiety, decreased appetite, nausea, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, vomiting, headache, dry mouth and hyperhidrosis [9,10]. Psychostimulants are available in many countries. Non-stimulant drugs approved for the treatment of ADHD include the selective norepinephrine reuptake inhibitor atomoxetine (ATX) and the central alpha2A-adrenergic receptor agonists guanfacine extended-release (GXR) and clonidine extended-release (CLON-XR). ATX is available in multiple countries, but GXR and CLON-XR are currently available only in the United States. Non-stimulants are not controlled substances and are more convenient to prescribe; however, they are not as effective as psychostimulants. ATX has been shown to have a lower effect size than lisdexamfetamine and OROS methylphenidate [11,12]. Tolerability can also be a problem with ATX. Common adverse events (AEs) reported during treatment with ATX include nausea, vomiting, fatigue, decreased appetite, abdominal pain, somnolence, constipation, dry mouth, dizziness, erectile dysfunction and urinary hesitation [13]. Rare AEs reported with ATX use include hepatotoxicity. In its label, suicidal ideation is listed in a black box warning, although no suicides occurred in clinical trials with 1586
ATX. The drug is metabolized though the CYP2D6 pathway and dosing may need to be adjusted if used with CYP2D6 inhibitors. Effect sizes for psychostimulants are also generally higher than those for GXR and CLON-XR [14-16]. Somnolence, fatigue, nausea, lethargy and hypotension are commonly occurring AEs with GXR [17]. With CLON-XR administration, somnolence, fatigue, upper respiratory tract infection (cough, rhinitis, sneezing), irritability, throat pain (sore throat), insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth and ear pain occurred in at least 5% of treated subjects and at twice the rate of placebo in clinical trials [18]. Although there are a number of drugs effective for the treatment of ADHD, there continues to be a need to develop novel compounds that reduce ADHD symptoms. The nicotinic-cholinergic system has been an area of focus because nicotine has been shown to be efficacious in the reduction of ADHD symptoms [19,20]. Currently available treatments for ADHD target neurons in the prefrontal cortex (PFC) and multiple other areas of the brain. 2.
Nicotinic acetylcholine receptors
The PFC has been shown to have a role in executive functioning, working memory, attention, long-term memory, social behavior and personality [21]. In rats, lesions in the PFC cause severe attentional deficits [22]. Human neuroimaging studies have shown that the PFC is involved in behavioral tasks that require sustained attention [23]. The PFC contains many acetylcholine receptors, and research suggests that cholinergic innervation here specifically impacts attention. Cholinergic lesions in the PFC caused by specific immunotoxins cause severe impairment in sustained attention tasks [24]. Furthermore, elevated acetylcholine concentration has been detected during tasks requiring attention [25]. Nicotinic acetylcholine receptors (NNRs) are assembled from pentameric transmembrane subunits and are found in the central nervous system, peripheral nervous system and at neuromuscular junctions [26]. These receptors can be formed from a range of a and b subunits, and two of the most common subunit types found in multiple areas of the brain are the a7 and a4b2 receptors [27]. The a4b2 and a7 subunits are thought to play a role in neuroprotection and cognitive functioning [21,28,29]. Multiple NNR agonists have been studied in animal models of attention. One specific animal model of attention is the 5-choice serial reaction time task (5-CSRTT) in which rodents have to respond to five different cue lights by poking their noses into the corresponding hole to obtain food [30]. This task is thought to be analogous to the continuous performance task (CPT) used to measure attention in humans. Research has shown that mice without the b2 nicotinic receptor subunits have impaired attention [31]. Several drugs that target NNRs have advanced to clinical trials in Alzheimer’s disease, Parkinson’s disease, schizophrenia and ADHD. Only one NNR agonist, varenicline, is
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Pozanicline
approved by the United States Food and Drug Administration, with an indication for smoking cessation [32]. 3.
Pozanicline
Pharmacology Although multiple NNR agonist compounds have been developed, one of the most extensively studied in the treatment of ADHD has been pozanicline. A PubMed search on December 8, 2013 using the keywords ABT-089, pozanicline and ADHD returned seven results. A PsychINFO search performed on July 27, 2014 using the keywords pozanicline or ABT-089 and ADHD was added and returned five results. Results from PsychINFO included one review with no new information on pozanicline, which was not included in the PubMed search. Pozanicline and relevant manuscripts are reviewed below. Pozanicline [2-methyl-3-(2-(S)-pyrrolidinylmethoxy) pyridine dihydrochloride salt] is a selective NNR modulator that enhances cognition in animal models [33]. Pozanicline’s structure is shown in Box 1. It is a white crystalline powder with melting point of 253 C and is soluble in water. When administered orally to monkeys, it has a half-life of 119 min, reaches maximum concentration at 1.4 h and has an oral bioavailability of 26.3%. In vitro studies indicate that pozanicline undergoes minimal liver metabolism (< 10%). Pozanicline has at least four metabolites including a lactam, pyrrolidine N’oxide, pyridine N-oxide and hydroxylamine compound. Pozanicline has activity at multiple NNR receptor subtypes. Pozanicline is a partial NNR agonist selective for the cysteine binding site on the a4b2 receptor subtype, and is also a partial agonist for the a7 subtype and an antagonist at the a3b4 receptor subtype [33]. Pozanicline also has demonstrable agonist activity at the a6b2 receptors [34].
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3.1
Animal studies In animal studies, pozanicline was about as potent as nicotine in causing [3H]acetylcholine release from rat hippocampal synaptosomes [33]. Pozanicline also stimulated [3H]dopamine release from rat striatal slices. It improved cognitive performance in aged and lesioned rats and mature monkeys. In mice, pozanicline was found to enhance inhibitory avoidance in the inhibitory avoidance paradigm. For aged monkeys, performance in a standard delayed-match-to-sample test was improved with pozanicline after a long delay. Pozanicline was much less likely than nicotine to cause unwanted effects such as seizures, ataxia, hypothermia and decreased locomotor activity. It also did not have significant gastrointestinal or cardiac effects. Pozanicline was also found to protect cells against multiple cytotoxic insults in vitro. Success in preclinical and Phase I studies led to later phase studies in humans. 3.2
Human studies The safety and effectiveness of pozanicline for the treatment of ADHD was studied in adults. In one trial, a total of 61 subjects 3.3
aged 18 -- 60 years with ADHD diagnosed by (DSM-IV--TR) criteria were enrolled [35]. Further criteria for eligibility included a score of ‡ 2 on six of nine items on at least one of the Conners’ adult ADHD rating scales (CAARS) subscales at screening and day 1. The CAARS measures the presence and severity of ADHD symptoms and includes an 18-item subscale that relates to DSM-IV ADHD criteria. There are versions that can be completed by the subject and an observer. Both contain identical items. Subjects were also required to demonstrate at least moderate severity of symptoms on the clinical global impressions-ADHD severity scale (CGIADHD-S) at screening. The CGI-ADHD-S is a measurement of overall severity of ADHD symptoms as judged by the investigator. Subjects who had smoked or used nicotine product in the 3 months before study enrollment were excluded. Other exclusion criteria included schizoaffective disorder, bipolar disorder, obsessive-compulsive disorder, schizophrenia, psychotic disorders, alcohol abuse or dependence and other DSM-IV disorders requiring treatment. Subjects with chronic medical problems and abnormal laboratory values and those using stimulants or other psychotropic medications were also excluded. Subjects completed a 2-week screening period and were randomized to an 8-week double-blind treatment period including each of the four following treatments. Subjects were randomized to receive pozanicline 2, 4, 20 mg and placebo each twice daily each for 2 weeks during the 8-week trial. There was no washout between treatment sequences. The primary efficacy variable was the CAARS total ADHD symptom score at the end of each treatment period. Secondary efficacy measures included CAARS subscale scores, the CGI-ADHD-S and a computerized cognitive assessment battery at baseline at the end of each treatment period. The Hamilton depression scale (HAM-D) and Hamilton anxiety scale (HAM-A) were also completed at baseline and at the completion of each treatment period to assess current levels of anxiety and depression. Only 11 subjects had completed the study when it was terminated prematurely to obtain additional preclinical data. Of those who completed the study, six had inattentive subtype ADHD and five met criteria for combined subtype. Mean (Standard Deviation or SD) baseline CAARS total scores were 39.1 (8.08). Six subjects were male and five were female. The mean age was 32.0 (10.15). HAM-D and Ham-A scores did not indicate significant depression or anxiety. At baseline, subjects had impairment in reaction times on attentional computerized cognitive measures when compared with healthy controls. On the last treatment day, CAARS total symptom score was statistically significant for the pozanicline 2 mg two times a day (b.i.d.) (p = 0.021) and 4 mg b.i.d. (p = 0.047) doses compared with placebo. For the 20 mg b.i.d. dose (p = 0.056), the total symptom score approached significance. Effect sizes were 0.92 for the 2 mg b.i.d. dose, 0.76 for the 4 mg b.i.d. dose and 0.71 for the 20 mg b.i.d. dose. Response
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Table 1. Pozanicline adverse events of special interest percent of subjects reporting events.
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Cholinergic
Placebo (%)
Nausea 2.9 Vomiting 3.4 Dry mouth 2.4 Diarrhea 3.4 Dizziness 1.9 Visual changes 0.5 Psychiatric and nervous system Anxiety 0.5 Agitation 0 Altered mood 0 Irritability 2.4
Pozanicline (%) 3.5 0.5 2.5 4.0 2.0 1.0 1.0 1.0 1.0 5.5
Data derived from [36].
to placebo was similar across all treatment periods for the primary end point, showing an absence of learning effects. For the CGI-ADHD-S, treatment differences for drug compared with placebo were significant only for the pozanicline 2 mg b.i.d. dose (p = 0.031). Computerized cognitive assessment results suggested that the dose-response curve for attention and memory effects was dose linear. For spatial working memory, statistically significant improvement was seen only at the highest dose, 20 mg b.i.d. (p = 0.21). A CPT was part of the assessment. This test is used to measure attention and impulse control. For the CPT, statistically significant improvement was seen with all pozanicline doses in the number of commission errors. Pharmacokinetic samples were collected, and values were within the range of 5-15 ng/ml for the 2 and 4 mg b.i.d. doses. There were no serious AEs in this trial. Most AEs were mild to moderate. The most commonly reported treatment-related events reported by more than one subject in any treatment period included headache (three subjects on 2 mg b.i.d., two subjects on 20 mg b.i.d.), somnolence (one subject on placebo, two subjects on 20 mg b.i.d.), pain (two subjects on 20 mg b.i.d.), increased appetite (one subject on placebo and one subject on 20 mg b.i.d.) and nervousness (one subject on 2 mg b.i.d. and one subject on 20 mg b.i.d). One subject reported nausea at the 4 mg dose, and the same subject reported diarrhea on the 4 mg and 20 mg doses. There were no significant changes in laboratory results, vital signs or ECGs during the study. In a much larger randomized, double-blind, placebocontrolled, 2 2 crossover study, 221 adult subjects who had ADHD received one of the following doses of pozanicline 2, 5, 15, 40 mg once a day (q.d.), or 40 mg b.i.d and placebo in randomized sequences [36]. The authors noted that data on file supported pharmacological effects over a broad range of 4 -- 80 mg daily. Subjects received each treatment for 4 weeks. Treatment sequences were separated by a 2-week washout. The investigator-rated CAARS total score at the end of each treatment period was the primary efficacy measure. Secondary 1588
efficacy measures included the CAARS investigator-rated subscale scores, the adult ADHD investigator symptom report scale (AISRS), the CAARS self-rated and CGI-ADHD-S. The AISRS is a modified version of the ADHD Rating Scale that includes prompts for adult ADHD symptoms. A total of 171 subjects completed the study. For the primary efficacy measure, 40 mg q.d. and 40 mg b.i.d. were significantly better than placebo (model-based least square mean difference from placebo for 40 mg q.d. -- 4.33 p = 0.02 and for 40 mg b.i.d. -- 3.02, p = 0.03). Effect sizes were small (0.29 for 40 mg q.d. of pozanicline and 0.30 for 40 mg b.i.d.). There were no statistically significant differences in the CAARS: Inv total score for the 2, 5 or 15 mg q.d. doses compared with placebo and no statistically significant differences on the secondary efficacy measures. For secondary efficacy measures, the pozanicline 40 mg b.i.d. dosing showed significant improvement on the CAARS:INV Inattentive and ADHD Index subscales. The pozanicline 40 mg q.d. dose showed significant improvement on all CAARS:INV subscales (Inattentive, Hyperactive/Impulsive and ADHD Index) compared with placebo. Both the 40 mg q.d. and 40 mg b.i.d. dose significantly decreased ADHD symptoms on the AISRS and the CAARS: self-total score, inattention/memory, hyperactivity/restlessness and ADHD index subscale scores. For pozanicline 40 mg b.i.d., the CAARS:selfimpulsive/emotional liability and problems with self-concept subscale scores as well as the CGI ADHD-S were improved. The overall incidence of AEs with pozanicline and placebo was comparable (70.4% pozanicline and 65.5% for placebo). There was no apparent relationship to dose of pozanicline. Three serious AEs included vasovagal syncope on pozanicline 5 mg q.d., cholelithiasis during washout from pozanicline 40 mg q.d. and a myocardial infarction that occurred 3 weeks after pozanicline 5 mg q.d. was discontinued. None were thought to be related to pozanicline by investigators. Insomnia occurred in 5.5% of pozanicline-treated subjects compared with 4.9% of placebo-treated subjects, and decreased appetite occurred in 0.5% of pozanicline-treated subjects compared with 1.9% of placebo-treated subjects. Irritability was the only common AE that occurred with pozanicline at twice the rate of placebo (5.5 vs 2.4%). Other AEs that did not occur at twice the rate of placebo included nausea, vomiting, dry mouth, diarrhea, dizziness, visual changes, anxiety, agitation and altered mood. Cholinergic and central nervous system adverse events are listed in (Table 1). Changes in heart rate and weight were similar in the drug and placebo groups. There were no clinically significant laboratory findings or significant changes in ECGs, vital signs or on physical examinations. Another randomized, double-blind, parallel-group study was conducted with pozanicline in 160 adults aged 18 -- 59 years [37]. The study consisted of a screening/washout period of up to 4 weeks and an 8-week double-blind treatment period. Subjects were randomized to pozanicline 40 mg once daily, pozanicline 80 mg once daily or placebo in a 1:1:1 ratio. The primary
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efficacy measure was the change from baseline to final visit in the CAARS Investigator-rated (CAARS-INV) total score in each active treatment group compared with placebo. Secondary measures included the CAARS inattentive and hyperactive/ impulsive subscales, the CAARS ADHD Index, CGI-ADHDS, AISRS, Conners’ Adult ADHD Rating ScaleSelf report, Time-Sensitive ADHD Symptom Scale, Behavior Rating Inventory of Executive Function-Adult Version, Adult ADHD Quality of Life Questionnaire and the Work Productivity and Activity Impairment scale. Nicotine use was also queried to determine the potential pozanicline effects on nicotine use. Drug safety was evaluated with AE queries, vital sign, laboratory and ECG measurements and physical examinations. Pharmacokinetic samples were also obtained at multiple study visits. Of the 160 subjects randomized, 159 took at least one dose of study medication and 137 (86%) completed the study. Mean age of study subjects was 35.9 years, and most subjects were white (84%) and male (62%). For nicotine use, 30% reported current use and 15% reported previous use. Type of ADHD included combined subtype 119/159 (75%) or inattentive subtype for 39/159 (25%) of subjects. One subject met criteria for hyperactive-impulsive subtype, and 40% of subjects were newly diagnosed with ADHD at screening. The mean (SD) CAARS-INV total scores were 36.9 (8.88) in the placebo group, 40.0 (7.40) in the pozanicline 40 mg daily group and 37.3 (7.79) in the pozanicline 80 mg daily group. No statistically significant improvement occurred in either drug treatment group compared with placebo on the primary efficacy measure or on any secondary efficacy measure. Pozanicline plasma levels were measured and were consistent with those found in previous trials. The most commonly reported treatment-emergent AEs, which occurred in at least 5% of subjects and were greater than in the placebo group, included nasopharyngitis (6.6%), upper respiratory tract infection (6.6%) and somnolence (5.7%). Two subjects had serious AEs. One subject was hospitalized with colitis not thought to be related to study drug, and a second subject had suicidal ideation requiring hospitalization. Because of stressors and previous psychiatric history, the suicidal ideation was thought to be probably not related to study drug. Three other subjects discontinued study drug secondary to AEs. The events were depression, irritability and erectile dysfunction. All of these were deemed possibly related to study drug. The reasons for the lack of positive results were examined for this trial and were not thought to be secondary to site selection. However, the study design using parallel groups was different from that of previous positive studies using a crossover design. The authors concluded that the withinsubject comparisons may be more sensitive in detecting pozanicline treatment effects. The safety and efficacy of pozanicline in children was also studied in two multicenter, randomized, placebo-controlled, double-blind, parallel-group trials [38]. Subjects were children aged 6 -- 12 years diagnosed with ADHD of at least moderate
severity. Other significant diagnoses, including bipolar disorder, psychotic disorder, autism spectrum disorders, tics and Tourette syndrome, were excluded. Other current psychiatric disorders that required treatment were also excluded as were subjects who had failed to respond to two or more prior trials of ADHD medication. The demographic characteristics did not differ between studies or between treatment groups within studies. In both trials, 66% of subjects were male. The mean age was 8.6 years in Study 1 and 8.5 years in Study 2. In Study 1, 80% of subjects were diagnosed with ADHD combined subtype and in Study 2, 76% were diagnosed with ADHD combined subtype. The first study lasted 8 weeks and contained six treatment groups (n = 274) dosed once daily. Four groups were dosed with pozanicline: 0.085, 0.260, 0.520, 0.700 mg/kg [38]. A fifth group was given ATX at 1.2 mg/kg, and the last group received placebo. A total of 278 subjects were randomized, 274 received at least one dose of study drug and 236 subjects (86%) completed the study. Study 2 included a 2-week screening period and 6 weeks of double-blind treatment [38]. Subjects were randomized to pozanicline 0.7 mg/kg, pozanicline 1.4 mg/kg or placebo in 1:1:1 ratio. For this trial, 121 subjects were randomized, 119 received at one dose of study drug and 96 (81%) completed the trial. For both trials, the primary efficacy measure was mean change in the ADHD rating scale (ADHD-RS-IV) Total Score administered by trained raters from baseline to final evaluation. Secondary efficacy measures included the CGIADHD-S, ADHD-RS-IV total score assessed at every visit, the ADHD-RS-IV attention and hyperactivity/impulsivity subscale scores, the Conners’ Global Index-Parent Version, Behavior Rating Inventory of Executive Function-Parent Questionnaire, Child’s Sleep Habits Questionnaire the Child Health Questionnaire and ADHD Impact Module-Child. Steady-state plasma concentrations of pozanicline were also assessed. There were no statistically significant differences between any pozanicline dose and placebo on the primary efficacy measures for either study. However, there was a statistically significant treatment effect between ATX and placebo at each evaluation during Study 1. There were no statistically significant differences between any pozanicline dose and placebo for the mean changes from baseline to final evaluation for the CGI-ADHD-S. There were no statistically significant differences between subjects who had received prior treatment for ADHD and treatment naı¨ve subjects. 4.
Conclusion
Pozanicline is an a4b2 NNR agonist developed after finding that nicotine improved cognition in animals and in humans with ADHD. Pozanicline has been shown to be effective in animal models by improved cognitive performance in rats and monkeys.
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In mice, pozanicline was found to enhance inhibitory avoidance. For older monkeys, memory was improved with pozanicline after a long delay. Pozanicline was much less potent than nicotine in causing unwanted effects such as seizures, ataxia, hypothermia and decreased locomotor activity. It also had minimal gastrointestinal and cardiovascular effects. Pozanicline has also been found to protect cells against multiple cytotoxic insults in vitro. Pozanicline showed promise in initial crossover pilot study in adults with ADHD. The drug was found to be effective compared with placebo with tolerable side effects. The initial findings in the small crossover trial in adults were encouraging; however, larger randomized trials in children and adults yielded disappointing results. In the first trial, effect sizes of 0.92, 0.76 and 0.71 were seen with doses of 2, 4 and 20 mg b.i.d. pozanicline doses. This trial had some serious limitations. The sample size was small because the trial was ended while further preclinical data were collected, time on treatment was only 2 weeks and there was no washout between treatments. In another larger adult trial, there was no significant difference between pozanicline and placebo. In a third larger trial in adults, the effect sizes were small. In two trials in children and adolescents, pozanicline was not significantly better than placebo. 5.
Expert opinion
Acetylcholine receptors are established therapeutic targets for Alzheimer’s disease, schizophrenia, Parkinson’s disease, smoking cessation, pain, attention-deficit hyperactivity disorder, epilepsy, autism and depression [39-41]. Based on the effectiveness of nicotine in the improvement of attention in animals and healthy human volunteers and the reduction of ADHD symptoms in early studies, multiple nicotinic receptor agonists have been developed. Pharmacological and genetic studies have demonstrated that the a4b2 subunits of NNRs play an important role in attention. Agonists selective for the a4b2 subunits have improved sustained attention and vigilance, decreased distractibility and improved accuracy in animals. ABT-418 was the first NNR agonist studied in humans with ADHD [42]. It was found to be effective in a small placebo-controlled, randomized trial of adults with ADHD. However, because of its short half-life the drug had to be delivered transdermally. It also caused nausea and dizziness, similar to nicotine. Side effects and a short half-life made the drug unsuitable for larger trials. Further research identified pozanicline, which had a longer half-life and fewer potential side effects. Based on the effectiveness of pozanicline in improving cognitive functioning in animal models, this NNR was thought to be a good candidate for extensive study in patients with ADHD. NNR compounds were among the first to utilize animal models for early target validation and proof of concept. Models including the 5-CSRTT and the operant signal detection 1590
task (SDT) are used to assess sustained attention while selective attention is often measured using a novel object recognition (NOR) task and sand-digging test. A limitation of these models is that attention is not measured directly but surmised based on behavior. Some of the tests, such as the 5-CSRTT and SDT, require extensive animal training, while the NOR and sand-digging do not. However, the NOR and SDT are not as specific in assessing attention as the other models. Humans are given little practice for cognitive testing in trials. Based on the failure of pozanicline to dramatically improve attention in humans, one may conclude that animal models employed to assess cognitive effects of the cholinergic system do not appear to translate to efficacy for ADHD symptoms in humans. The models for attention have not always correlated even between strains of the same species. For example, nicotine has been shown to improve attention in some strains of rats but not others [43]. There may be subtle critical differences in the neural systems associated with the expression of nicotinic receptors even within species that make extrapolation to humans difficult. Other factors that make it difficult to extrapolate efficacy from animals to humans include the complexity of the nervous system. The exact mechanism by which nicotinic agonists exert cognitive effects is not clear. Initially, only stimulatory effects were thought to be important in enhancing cognition; however, compounds such as pozanicline also desensitize receptors [44]. Nicotinic systems interact with multiple neurotransmitter systems promoting the release of many neurotransmitters including acetylcholine, dopamine, serotonin, g-aminobutyric acid and glutamate, all of which are involved in cognitive functioning [43]. Due to the complicated interactions of nicotinic agonists with other transmitter systems, development of specific targets based on animal models is difficult. Despite the lack of positive evidence associated with pozanicline, the continued development of non-stimulant therapies to treat ADHD is warranted. However, to be useful clinically, these drugs need to have effect sizes at least comparable to those of medications currently used to treat ADHD. Stimulants have an effect size close to 1.0, and all of the non-stimulants have an effect size of ~ 0.7. Effect sizes for pozanicline in an initial small crossover trial in adults were good with effect sizes of 0.71 -- 0.92. In a second trial in adults, the effect sizes of 0.29 and 0.30 for pozanicline were quite small compared to the effect sizes of currently available medications to treat ADHD. In a third adult trial, there were no significant differences between pozanicline and placebo. Although the exact reasons for the failure of pozanicline are not clear, it does not appear to be secondary to design flaws in the trials. The first double-blind clinical trial in children used ATX as an active comparator and ATX separated from placebo as expected. The results of other NNRs in large human clinical trials found to improve cognition based on animal models have also been disappointing. Another a4b2 NNR agonist, AZD
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3480 or ispronicline, also showed promise in a small trial of 24 adults with ADHD [45]. The study included a Stop Signal Task to measure response inhibition, and the CAARS:Inv was the primary efficacy measure. Subjects showed greater improvement on inattention than hyperactivity/impulsivity. Subjects with higher baseline cognitive impairment and not greater clinical ADHD symptoms had a greater treatment response. Ispronicline also had a beneficial effect on cognition in subjects with age-associated memory impairment [46]. However, it failed to demonstrate improvement in cognition in a large study of stable patients with schizophrenia treated with an atypical antipsychotic [47]. A third a4b2 NNR agonist, AZD1446, improved attention and memory in rodents [48]. Although it was well tolerated in humans, it failed to show improvement in cognitive functioning in subjects with ADHD [49]. It was unclear why the drug failed to separate from placebo. The authors postulated that the selectivity and affinity for b2 subunits, different agonism profiles, and potential for dopamine release may impact clinical effect. Because the nicotinic acetylcholine system is so complex, it is unclear which attributes for NNR agonists are needed for efficacy in ADHD. Furthermore, ADHD is a complex disorder that has been shown to be highly heritable but the cause is unknown. The diversity of symptoms in ADHD comprising both cognitive and behavioral components makes the development of specific receptor targets even more difficult. Additionally, there may be differences in the maturation of the attentional control system between juveniles and adults Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest A Childress has consulted for Shire Pharmaceuticals, Inc., Novartis, NextWave Pharmaceuticals and Ironshore Pharmaceuticals. She has also received research support from Shire Pharmaceuticals, Inc., Novartis, Pfizer, Inc., Somerset Pharmaceuticals, NextWave Pharmaceuticals, Abbott Pharmaceuticals, Eli Lilly & Co., Ortho-McNeill Janssen Scientific Affairs, Johnson & Johnson, Otsuka, Shionogi, Sunovion, Noven Pharmaceuticals, Ironshore Pharmaceuticals and Rhodes Pharmaceuticals, Purdue Pharma, Forest Laboratories, Arbor Pharmaceuticals and Tris Pharma. She has received speaker fees from Shire Pharmaceuticals, Novartis and Shionogi and is also on the advisory board of Shionogi. FR Sallee is a consultant of Ironshore Pharma, AstraZeneca, Impax Laboratories, Inc., Purdue Pharma, Otsuka Research and Development, as well as Reckitt Benckiser. They also have received research support from Shire PLC. FR Sallee only is a stockholder and on the board of P2D Bioscience.
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Affiliation
Ann Childress†1,2 MD & Floyd R Sallee3 MD PhD † Author for correspondence 1 President, Center for Psychiatry and Behavioral Medicine, Inc., 7351 Prairie Falcon Road, Suite 160, Las Vegas, NV 89128, USA 2 Clinical Assistant Professor, University of Nevada School of Medicine, Department of Family Medicine, Reno, NV, USA; Tel: +1 702 838 0742; Fax: +1 702 838 6749; E-mail: [email protected] 3 Professor of Psychiatry, University of Cincinnati, 260 Stetson Street, Suite 3200, Cincinnati, OH 45219, USA
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