Clinical outcomes with betahistine in vestibular disorders

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1 Clinical outcomes with betahistine in vestibular disorders Michael Strupp MD, FRCP, FANA, FEAN Department of Neurology, German Center for Vertigo and Balance Disorders University of Munich

2 Role of betahistine in the treatment of vertigo - 4,294 patients with vertigo (REVERT registry) international centers: 13 countries over 28 months 1 Diagnosis Treatment 0% 10% 20% 30% 40% 50% 60% 70% 20,5% 37,2% 15,4% 26,9% Betahistine Piracetam Ginkgo biloba Other vertigo therapy Diuretics Benzodiazepines Antihistamines Meniere's disease BPPV Other vertigo of peripheral vestibular origin Peripheral vestibular vertigo of unknown origin Neuroleptics Calcium antagonists Homeopathics 1 Agus S, et al. Front Neurol 2013;4:48

3 Betahistine for the treatment of - Acute vertigo - Menière s disease - animal and clinical studies - limitations and perspectives

4 Animal models of Unilateral Labyrinthectomy (UL) Surgical labyrinthectomy Chemical labyrinthectomy irreversible Arsenilat/Bupivacain irreversible Bupivacain reversible repetitive Zwergal et al. Klinik und Poliklinik für Nuklearmedizin - LMU

5 Behavioural compensation after unilateral labyrinthectomy Postural asymmetry Klinik und Poliklinik für Nuklearmedizin - LMU

6 Animal model of unilateral labyrinthectomy

7 Effects of betahistine in unilateral labyrinthectomy on BALANCE BETAHISTINE iv. versus SHAM treatment i.v. injection (1mg/kg BID day 1-3) Behavioral scoring postural asymmetry Mean of score Range 0-10

8 Effect of betahistine in unilateral labyrinthectomy on GAIT: day 8 Control Betahistine

9 Effects of betahistine in unilateral labyrinthectomy on GAIT VELOCITY OPEN FIELD osmotic pump Velocity 5x Betahistine NaCl

10 Micro-FDG PET of the rat brain - challenges anatomy Klinik und Poliklinik für Nuklearmedizin - LMU

11 Micro-FDG-PET data processing 3D statistical parametric maps group maps 3 individual µpet data 2 1 FDR p<0.05 Zwergal et al Klinik und Poliklinik für Nuklearmedizin - LMU

12 Betahistine in unilateral labyrinthectomy: Double effect: acute and on central compensation Zwergal et al.

13 Menière s disease new diagnostic criteria Consensus document of the Bárány Society, the Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), AAO-HNS and the Korean Neurotology Society J.A. Lopez-Escamez, J. Carey, W.-H. Chung, J.A. Goebel, J. Magnan, M. Mandala, D.E. Newman-Toker, M. Strupp, M. Suzuki and A. Bisdorff 1861 Definite Menière s disease: two or more attacks of vertigo, each lasting 20 min to 12 h audiometrically documented hearing loss in at least one examination (< 2000 Hz, > 30dB) and related to the attacks fluctuating tinnitus or aural fullness in the affected ear not better accounted for by another vestibular diagnosis J Vest R 2015 OPEN ACCESS

14 Efficacy and safety of betahistine treatment in patients with Menière s disease: primary results of long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial) Adrion C, Fischer CS, Wagner J, Gürkov R, Mansmann U, Strupp M (2016) BMJ 221 pts, 14 centers: incidence of attacks related to Menière s disease did NOT differ between the three treatment groups (placebo, 16 mg tid, 48 tid mg (p=0.759)).

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16 Observational study on 11 patients with MD who did not sufficiently respond to 144 mg betahistine per day - dosage: mg per day - mean treatment period: 4.1 ± 1.4 years - side effects: 4 mild gastrointestinal 1 fatigue 1 altered taste none had to stop the treatment F. Lezius, C. Adrion, U. Mansmann, K. Jahn, M. Strupp (2011) Eur Arch Otorhinolarngol

17 Nmber of patients > 6 months no attacks Clinical practice: pharmacotherapy of Menière s disease: > 144 mg/d betahistine > 6 months free of attacks Daily dosage of betahistine (mg) Strupp et al. Frontiers Neuro-otol (2017)

18 The effect of betahistine on cochlear microcirculation in guinea pigs in vivo F. Ihler, M. Bertlich, M. Canis, M. Strupp

19 Animal model Canis et. al Eur Arch Otorhinolaryngol

20 Previous studies Dziadziola et. al Otolaryngol Head Neck Surg mg/kg b. w. Laurikainen et. al Acta Otolaryngol ca mg/kg b. w.? Lamm & Arnold 2000 Hear Res 0.15 mg/kg b. w. Meyer et. al Laryngorhinootologie 0.11 mg/kg b. w. Strupp et. al Acta Otolaryngol und BEMED 2x 24 mg versus 3x 48 mg calculated corresponding dosage for equivalent peak concentration when administered orally mg/kg KG Current study treatment group 1: 1.0 mg/kg b. w. treatment group 2: 0.1 mg/kg b. w. treatment group 3: 0.01 mg/kg b. w treatment group 4: mg/kg b. w. control group: Placebo (NaCl 0.9%)

21 Results Dose-response curve: Cochlear cochlear blood flowblood flow (CBF) peak fold change from basal value 1,5 1,4 1,3 1,2 1,1 48 mg 24 mg 16 mg 160 mg * * Calculated corresponding single dosages when administered orally (Chen et al. 2003) 1,0 0,0001 0,001 0,01 0, dosage [mg/kg b. w.] (treatment group) mean +/- SEM; *: p < 0.05 vs. placebo (ANOVA on ranks/dunn s) F. Ihler, M. Bertlich, M. Canis, M. Strupp (2012) PLoS ONE

22 Betahistine metabolites aminoethylpyridine and hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo Mattis Bertlich, Fritz Ihler, Kariem Sharaf, Bernhard Weiss, Michael Strupp, Martin Canis Int J Audiol (2014)

23 Mode of action of betahistine: increase of cochlear blood flow via its action as an inverse agonist of the H3 heteroreceptors (blocking of the H3 receptor with proxyfan or thioperamide caused a suppression of betahistine effects on cochlear blood flow) M. Bertlich, F. Ihler, S. Freytag, B.G. Weiss, M. Strupp, M. Canis. Int J Audiol (2015)

24 Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menières disease M. Nue Møller et al (2016) Eur Arch Otorhinolaryngol Immuno-histochemical demonstration of histamine H1 receptor (HRH1) expression in the human endolymphatic sac: epithelial lining with an intense labeling in most cells both apically and basally (* endolymphatic sac). Histamine H3 receptor (HRH3) expression in the subepithelial capillary network of the human endolymphatic sac.

25 Mode of action of betahistine: Dilatation of precapillary arterioles Bertlich et al. Life Sci (2017)

26 Treatment of Menière s disease Betahistine-dihydrochloride: BEMED trial: (221 pts, 16 mg tid, 48 mg tid vs plac.) negative, therefore: 96 mg tid 12 months ( much and long-term ) up to 1920! mg/d, i.e. 80 tablets per day (Strupp et al. 2017) observational study: 11 pts 288 mg to 480 mg per day rarely: intratympanic gentamicin not effective: - endolymphatic sac operation (Pullens et al. (2013) Cochrane Rev) - salt-free diet (no state of the art clinical trial) - diuretics (Thirlwall AS, Kundu S (2006) Cochrane Rev) - Meniett device (Russo et. (2017) Laryngoscope) - intratympanic dexamethasone (Otonomy press release, )

27 Basic problem: betahistine pharmacokinetics Orally-administered betahistine: rapidly and almost completely metabolized into 2-pyridylacetic acid (2-PAA; no known pharmacological activity) The two other metabolites: pharmacologically active, but short half-life time Absolute bioavailability of oral betahistine: ~1% Plasma levels of betahistine are very low: high inter-subject variability Challenge to increase plasma exposure

28 Relative to C max oral administration Intranasal delivery: superior systemic exposure C max Betahistine in Plasma Oral Întranasal Intranasal Reference = 3x maximum approved oral dose Single-dose phase 1 study with intranasal delivery in healthy volunteers: - dose-dependent betahistine concentration in blood plasma (T max ~10 min post-dose) - significantly higher plasma concentrations C max than with oral dosing Auris Medical

29 Betahistine for the treatment of acute vertigo and Menière s disease: It is effective all a question of the dosage or application form due to the 99% first-pass effect Next step: randomized controlled trials