CHALLENGES OF RECOGNIZING AND TREATING EXCESSIVE SLEEPINESS

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1 CHALLENGES OF RECOGNIZING AND TREATING EXCESSIVE SLEEPINESS Russell Rosenberg, Ph.D. Neurotrials Research and Atlanta School of Sleep Medicine DISCLOSURES Research grant funds from: Merck Jazz Pharmaceuticals Eisai Vanda Consulting agreement with Eisai Jazz Pharmaceuticals TECHNOLOGY=LESS SLEEP 1

2 PRIMARY CAUSES OF SLEEPINESS SECONDARY EXCESSIVE SLEEPINESS Chronic Sleep Deprivation Jet Lag Idiopathic Hypersomnolence Obstructive Sleep Apnea Narcolepsy Shiftwork Disorder Medical/Psychiatric and Neurodegenerative Disorders Brain injury Stroke Cancer Parkinson s Disease Kleine-Levin Syndrome Alzheimer s Disease Depression and Anxiety MEASURES OF SLEEPINESS OBSTRUCTIVE SLEEP APNEA: ICSD-3 Epworth Sleepiness Scale Karolinska Sleepiness Stanford Sleepiness Scale Visual Analog Scales Multiple Sleep Latency Test Maintenance of Wakefulness Test 2

3 OBSTRUCTIVE SLEEP APNEA SYNDROME (OSA) IS A RECOGNIZABLE AND TREATABLE DISORDER SHIFTWORK DISORDER: ICSD-3 Standard treatment for moderate-to-severe OSA is Continuous Positive Airway Pressure (CPAP) 1 Other treatments and strategies 2 Oral appliances Avoidance of alcohol Weight reduction Positional therapy Despite treatment of the underlying obstruction, patients with OSAHS may have residual excessive sleepiness (ES) % and 52.2% of patients who had subjective and objective pretreatment daytime ES, respectively, still had ES after 6 hours of CPAP use per night 3 1. Kushida CA et al. Sleep 2006;29: Mansfield DR et al. Med J Aust 2013;199:S Weaver TE et al. Sleep 2007;30: EVIDENCE RATINGS American Academy of Sleep Medicine (AASM) Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin provides evidence based treatment recommendations. Strength of Recommendation: Standard = This is a generally accepted patient-care strategy that reflects a high degree of clinical certainty. The term standard generally implies the use of Level 1 Evidence (high quality randomized controlled trial on well-characterized subjects or patients), which directly addresses the clinical issue, or overwhelming Level 2 Evidence (cohort study or flawed clinical trial). Guideline = This is a patient-care strategy that reflects a moderate degree of clinical certainty. The term guideline implies the use of Level 2 Evidence (cohort study or flawed clinical trial) or a consensus of Level 3 Evidence (case control study). Option = This is a patient-care strategy that which reflects uncertain clinical use. The term option implies either inconclusive or conflicting evidence or conflicting expert opinion. MORGENTHALER TI, ET AL. SLEEP. 2007;30: Thorpy MJ. J Fam Pract 2010;59(1 Suppl):S Adapted from Thorpy,

4 RECOMMENDATIONS FOR SHIFT WORK SLEEP DISORDER MORE RECOMMENDATIONS NARCOLEPSY: ICSD-3 TREATMENT OF NARCOLEPSY AASM recommends 1. An accurate diagnosis of a specific hypersomnia disorder of central origin should be established. The evaluation should include a thorough evaluation of other possible contributing causes of excessive sleepiness (Standard) 2. Treatment objectives should include control of sleepiness and other sleep related symptoms when present (Standard) 3. Treatment options for symptoms of narcolepsy: Daytime Sleepiness Cataplexy Disrupted Sleep Hypnagogic Hallucinations and Sleep Paralysis MORGENTHALER TI, ET AL. SLEEP. 2007;30:

5 Approved by the FDA for the treatment of cataplexy in patients with narcolepsy Not approved by the FDA or discontinued in the United States 11/13/2017 TREATMENT OF EXCESSIVE SLEEPINESS ASSOCIATED WITH NARCOLEPSY Treatment objectives should include control of sleepiness and other sleep related symptoms when present (AASM Standard) 1 Pharmacologic Interventions Modafinil (AASM Standard) 1 Armodafinil (AASM practice parameters preceded its availability) 2 Sodium Oxybate (AASM Standard) 1 Amphetamine, methamphetamine, dextroamphetamine, and methylphenidate (AASM Guideline) 1 Selegiline (AASM Option) 1 Ritanserin (AASM Option) 1 Mazindol 3 Bupropion 3 Caffeine 3 TREATMENT OF CATAPLEXY Pharmacologic interventions Sodium Oxybate (AASM Standard) 1 Selegiline (AASM Option) 1 Tricyclic Antidepressants 1 (Imipramine, Desipramine, Protripyline, Clomipramine) 2 (AASM Guideline) 1 Selective serotonin reuptake inhibitors 1 (Fluoxetine, Fluvoxamine) 2 (AASM Guideline) 1 Venlafaxine 1,2 (AASM Guideline) 1 Reboxetine (AASM Guideline) 1 Mazindol 2 Atomoxetine 2 Approved by the FDA to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy Not approved by the FDA or discontinued in the United States The physician who elects to prescribe either modafinilor armodafinil should be familiar with the risks discussed in the full prescribing information, including a bolded warning for serious or lifethreatening rash, including Stevens-Johnson syndrome, which has been reported in adults in association with the use of armodafinil and children taking modafinil, a racemicmixture of S and R modafinil (the latter is armodafinil). Modafinil and armodafinil are not approved for use in pediatric patients for any indication. 1. MORGENTHALER TI, ET AL. SLEEP. 2007;30: ; 2. HARSH JR, ET AL. CUR MED RES OPIN. 2006;22: ; 3. NISHINO S, ET AL. EXPERT OPIN EMERG DRUGS. 2010;15(1): MORGENTHALER TI, ET AL. SLEEP. 2007;30: ; 2. NISHINO S, ET AL. EXPERT OPIN EMERG DRUGS. 2010;15(1): TREATMENT OF HYPNAGOGIC HALLUCINATIONS AND SLEEP PARALYSIS MODAFINIL MECHANISM Pharmacologic interventions 1 Sodium oxybate (AASM Option) Tricyclic antidepressants, selective serotonin reuptake inhibitors and venlafaxine (AASM Option) Modafinil selectively activates wake-generating sites in the hypothalamus. Fos immunoreactivity is increased in the tuberomammillary nucleus and in the hypocretin neurons in the perifornical area of the hypothalamus. MORGENTHALER TI, ET AL. SLEEP. 2007;30:

6 ARMADOFANIL: PHARMACOKINETIC PROFILE ARMODAFINIL: PHARMACODYNAMIC PROFILE 37% higher C max and 69% higher area under the curve (AUC 0-T ) with armodafinil vs. modafinil (P<0.001) NUVIGIL has wake-promoting actions Similar to sympathomimetic agents Pharmacologic profile not identical to sympathomimetic amines NUVIGIL is an indirect dopamine receptor agonist Binds in vitro to the dopamine transporter (DAT) and inhibits dopamine reuptake For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals In genetically engineered mice lacking the DAT, modafinil lacked wake-promoting activity, suggesting DATdependence suggesting that this activity was DAT dependent Adapted from Darwish M et al A multicentre, randomised, open-label, cross-over study comparing pharmacokinetic (PK) properties of armodafinil and modafinil at equal doses in 42 patients with residual excessive sleepiness associated with obstructive sleep apnoea (patients were compliant with CPAP). Primary endpoint was to compare systemic exposures after 10 days of armodafinil (200 mg/day) or modafinil (200 mg/day) Darwish M et al. Clin Ther 2010;32: NUVIGIL Approved Product Information, 26 November Animal data does not necessarily predict clinical effects. ARMODAFINIL: WAKEFULNESS ARMODAFINIL : CLINICAL STUDIES Dopamine receptors are necessary for wakefulness D 2 R-deficient mice combined with D 1 R and D 2 R-specific antagonists, clarified the role of dopamine receptors in the arousal effects of modafinil D 1 R and D 2 R both contributed to the arousal effects D 2 R was found to be the receptor of primary importance Qu W-M et al. J Neurosci 2008;28: Animal data does not necessarily predict clinical effects. Four 12-week, randomised, double-blind, placebo-controlled studies in patients with excessive sleepiness associated with narcolepsy, OSAHS or SWSD (N=1108) NUVIGIL 150 mg/d NUVIGIL 250 mg/d Narcolepsy OSAHS I OSAHS II SWSD TOTAL Patients who received at least 1 treatment dose, had a baseline and at least one postbaselinemwt/mslt, and at least one postbaselinecgi-c assessment. MWT, Maintenance of Wakefulness Test; MSLT, Multiple Sleep Latency Test; OSAHS, Obstructive Sleep Apnoea/Hypopnoea Syndrome; SWSD, Shift Work Sleep Disorder. 1. NUVIGIL Approved Product Information, 26 November Harsh JR et al. Curr Med Res Opin 2006;22: Roth T et al. Clin Ther2006;28: Hirshkowitz M et al. Respir Med 2007;101: Czeisler CA et al. Mayo Clin Proc 2009; 84:

7 ARMODAFINIL CLINICAL STUDIES: PRIMARY OUTCOME MEASURES Improvements in wakefulness: MWT and MSLT 1 4 Narcolepsy and OSAHS: Change from baseline to final visit in mean MWT sleep latency (average of 4 tests, 9 AM 3 PM) SWSD: Change from baseline to final visit in mean MSLT sleep latency (average of 4 tests, 2 AM-8 AM) Improvement in overall clinical condition: CGI-C 1 4 Percent of patients with at least minimal improvement on the CGI-C at final visit 7-point physician-completed assessment of patient s overall clinical condition Ranges from 1 (very much improved) to 7 (very much worse) MWT, Maintenance of Wakefulness Test; MSLT, Multiple Sleep Latency Test; OSAHS, Obstructive Sleep Apnoea/Hypopnoea Syndrome; SWSD, Shift Work Sleep Disorder; CGI-C, Clinical Global Impression of Change. 1. Harsh JR et al. Curr Med Res Opin2006;22: Roth T et al. Clin Ther 2006;28: Hirshkowitz M et al. Respir Med 2007;101: Czeisler CA et al. Mayo Clin Proc 2009; 84: Mean (SEM) change from baseline in sleep latency (min) at final visit ARMODAFINIL SIGNIFICANTLY IMPROVED WAKEFULNESS 5 (MWT/MSLT) IN ALL PATIENT P<0.01 GROUPS P<0.001 vs VS placebo. PLACEBO P< I OSAHS I (MWT) 1, P= I OSAHS II (MWT) 1,3-1.9 Adapted from: 1. NUVIGIL Approved Product Information, 26 November Roth T et al. Clin Ther 2006;28: Hirshkowitz M et al. Respir Med 2007;101: Harsh JR et al. Curr Med Res Opin 2006;22: Czeisler CA et al. Mayo Clin Proc 2009;84: Narcolepsy (MWT) 1, SWSD (MSLT) 1,5 NUVIGIL 150 mg NUVIGIL 250 mg NUVIGIL combined % Improved on CGI-C at final visit OVERALL CLINICAL CONDITION (CGI-C) IMPROVED IN SIGNIFICANTLY MORE ARMODAFINIL PATIENTS VS PLACEBO P<0.001 P= P< OSAHS I 1,2 OSAHS II 1,3 Narcolepsy 1,4 SWSD 1,5 I Very much, much, or minimally improved. OSAHS, Obstructive Sleep Apnoea/Hypopnoea Syndrome; SWSD, Shift Work Sleep Disorder. Adapted from: 1. NUVIGIL Approved Product Information, 26 November Roth T et al. Clin Ther2006;28: Hirshkowitz M et al. Respir Med 2007;101: Harsh JR et al. Curr Med Res Opin 2006;22: Czeisler CA et al. Mayo Clin Proc 2009;84: P< NUVIGIL 150 mg NUVIGIL 250 mg NUVIGIL combined Mean (SEM) change from baseline to final visit ARMODAFINIL IMPROVED PATIENTS REPORTS OF SLEEPINESS (ESS/KSS) IN ALL PATIENT GROUPS VS PLACEBO OSAHS 1 I (ESS) 1,5 OSAHS II (ESS) 2,5 Narcolepsy (ESS) 3,5 ) SWSD (KSS) 4, P< ESS, Epworth Sleepiness Scale. KSS, Karolinska Sleepiness Scale; OSAHS, Obstructive Sleep Apnoea/Hypopnoea Syndrome; SWSD, Shift Work Sleep Disorder. P< P= vs placebo; P= vs placebo; P= Adapted from: 1. Roth T et al. Clin Ther2006;28: Hirshkowitz M et al. Respir Med2007;101: Harsh JR et al. Curr Med Res Opin 2006;22: Czeisler CA et al. Mayo Clin Proc 2009;84: Data on File, Teva Pharma Australia. P<0.001 Armodafinil150 mg Armodafinil250 mg Armodafinilcombined 28 7

8 Mean (SEM) BFI change (units) from baseline to final visit ARMODAFINIL SIGNIFICANTLY IMPROVED FATIGUE (BFI SCORES) 1.0 IN PATIENTS WITH OSA AND NARCOLEPSY VS PLACEBO P<0.05 vs placebo; P< OSA I 1,4 I OSA II 2, OSA, Obstructive Sleep Apnea Syndrome; SWD, Shift Work Disorder. Adapted from: 1. Roth T et al. Clin Ther2006;28: Hirshkowitz M et al. Respir Med2007;101: Harsh JR et al. Curr Med Res Opin 2006;22: Data on File, Teva Pharma Australia.5. Czeisler CA et al. Mayo Clin Proc 2009;84: P<0.05 Narcolepsy P= P= vs placebo; P= Armodafinil150 mg Armodafinil250 mg Armodafinilcombined Mean (SEM) % sleep efficiency ARMODAFINIL : NO SIGNIFICANT CHANGES IN NIGHTTIME SLEEP (MEAN % SLEEP EFFICIENCY) OCCURRED WITH ARMODAFINIL OR PLACEBO Armodafinil150 mg Armodafinil 250 mg No significant differences for final visit versus baseline were observed Armodafinilcombined Baseline Final visit Baseline Final visit Baseline Final visit OSAHS I 1 OSAHS II 2 Narcolepsy 3 Time asleep as a percent of the total time in bed. OSAHS, Obstructive Sleep Apnoea/Hypopnoea Syndrome; SWSD, Shift Work Sleep Disorder. Adapted from: 1. Roth T et al. Clin Ther2006;28: Hirshkowitz M et al. Respir Med 2007;101: Harsh JR et al. Curr Med Res Opin2006;22: Czeisler CA et al. Mayo Clin Proc 2009;84: Baseline Final visit SWSD ADVERSE EFFECTS OF ARMODAFINIL Headache Rash Nausea Anxiety Dizziness Depression Increased suicidality Tachycardia Hallucinations Reduction in oral contraception efficacy PITOSILANT In preclinical studies, pitolisant acted as a high-affinity competitive antagonist and as an inverse agonist at the human histamine H3 receptor subtype. Pitolisant showed high selectivity for H3 receptors compared with the other histamine receptor subtypes (H1, H2, and H4 subtypes) and showed a lack of interaction with other human receptors or channels. 8

9 MORE ON PITOLISANT The recommended dose of pitolisant is between 4.5 and 36 mg per day, depending on the patient s response. Peak plasma C-max ~1 3 hours after oral administration and has a plasma half-life of hours. Further studies are needed to gage the long-term efficacy of pitolisant to treat EDS and cataplexy in narcolepsy. AEs include insomnia headache, nausea anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo and dyspepsia. SOLRIAMFETOL Solriamfetol (JZP-110) is a selective dopamine norepinephrine reuptake inhibitor that exhibited robust wake-promoting effects in two phase 2 trials in narcolepsy patients and is being further evaluated for the treatment of ES in patients with OSA. The most common treatment emergent adverse events (TEAEs) were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), and anxiety (7%), and among the solriamfetol patients, these side effects increased with dosage. TEAEs and discontinuation of therapy due to adverse events was most common in the 300-mg solriamfetol group. OSA TRIAL: CHANGE FROM BASELINE MWT MORE IN DEVELOPMENT AND FINAL THOUGHTS Nonhypocretin therapies Histamine receptor H3 antagonists/inverse agonists GABA modulation Slow-wave sleep enhancers Hypocretin-based therapies Cell transplantation and stem cells Gene replacement therapy Hypocretin peptide replacement 9