Intranasal betahistine for acute vertigo attacks
Acute vertigo/dizziness is one of the most common causes of visits to the ED. Vertigo is a condition described as a false sensation of spinning and unsteadiness often accompanied by nausea and vomiting that is thought to originate from vestibular (inner ear) disorders. Each year in the US, roughly 2.6m visits to the ED are associated with dizziness/vertigo. In adults aged 18–79, the annual incidence is approximately 1.4%; this substantially increases with age and is roughly 2 to 3 times more common in women than in men. Approximately 25% of those presenting with vertigo/dizziness symptoms are attributable to vestibular diagnoses. In the ED, acute vertigo due to BPPV (dislodged calcium carbonate ear crystals migrate to fluid-filled canals) is treated with vestibular rehabilitation (patterned head-trunk positioning manoeuvres or canalith repositioning therapy), which moves displaced canaliths to stop the symptoms and is effective about 80% of the time. In Europe, oral betahistine is the most commonly prescribed medication for treatment of MD (34.8%), BPPV (24.6%), peripheral vestibular vertigo of unknown origin (23.6%) and for other vertigo of peripheral vestibular origin (22.8%). Because oral betahistine is not approved in the US, alternative treatment regimens to alleviate acute vertigo symptoms include antihistamines such as Antivert (meclizine), Dramamine (dimenhydrinate), Phenergan (promethazine), and Benadryl (diphenhydramine), prescription anti-nausea medications including Reglan (metoclopramide) and Zofran (ondansetron), as well as prescription sedative medications such as Valium (diazepam), Ativan (lorazepam), or Klonopin (clonazepam). Unlike betahistine, these alternative regimens have drawbacks such as severe daytime drowsiness and targeting nausea relief as opposed to the underlying concern.
Betahistine dihydrochloride (betahistine), which is a structural analogue of histamine, is a neuromodulatory transmitter of the histaminergic system that regulates cerebral functions such as circadian rhythm, cardiovascular regulation, and food intake. Outside of the US, betahistine is approved and marketed (Serc, Betaserc, Hiserk) in the oral form for the management of vertigo. Vertigo may affect patients differently depending on the underlying cause of the condition including BPPV, MD, and vestibular neuritis. Although betahistine is not approved by the FDA, it can be obtained through compounding pharmacies with a prescription in the US.
Histamine receptors (H1, H2, and H3) are found diffusely throughout the central vestibular system (ie the brain and brain stem) and pharmacological evidence suggests these histamine receptors also exist in the peripheral vestibular system (the inner ear and pathways to the brainstem). Betahistine dually acts as a partial postsynaptic H1 receptor agonist and potent presynaptic H3 receptor antagonist, and as previously demonstrated in preclinical animal models and clinical trials, leads to increased cerebrovascular blood flow via dilatation of precapillary arterioles and improves microcirculation of the cochlear and vestibular systems. Nonetheless, several studies examining the efficacy of oral betahistine for the management of vertigo attacks have reported inconsistent outcomes.
In a recent post-marketing observational study investigating the effectiveness of oral betahistine in 305 patients with vestibular vertigo prescribed the recommended dose (ie 48 mg/day) in Russia and Ukraine, the frequency of monthly vertigo attacks decreased significantly from baseline to day 60 of treatment (p<0.001). Similarly, a review of 17 studies comprising a total of 1,025 patients with vertigo of multiple aetiologies suggests there may be a positive effect of betahistine in reducing vertigo symptoms; however, the authors also highlight that quality of evidence available is weak. Although studies have demonstrated mixed results, we assume efficacy must be seen at least in acute indications as results are seen rather quickly and European physicians continue to prescribe the drug with an average 26% market share across all types of vertigo.
Because orally administered betahistine is readily and almost completely absorbed by the gastrointestinal tract on its first pass and its metabolites (ie 2-pyridylacetic acid, or 2-PAA) are pharmacologically inactive, higher doses of the drug have been investigated to increase effectiveness. A trial demonstrated that the recommended dose of 48mg/day of betahistine was not effective and higher doses between 192mg/day (eight tablets per day at 24mg each) to 960 mg/day (40 tablets per day at 24mg each) of betahistine were needed to minimize the frequency of vertigo attacks in patients with severe MD over six months. However, the efficacy of high-dose treatment plans for MD and symptoms of vertigo have not been validated. Because the efficacy of oral betahistine is highly dose and time dependent, it is postulated that bypassing the catabolism of the compound at the digestive barrier could significantly improve its effectiveness and convenience.
IP, previous studies and the AM-125 clinical program
As per the agreement with Otifex Therapeutics, Auris Medical purchased several assets related to intranasal betahistine including preclinical and clinical data and intellectual property rights for an upfront payment and future development milestone payments totalling approximately $500,000. The development work for AM-125 details the composition matter for the intranasal delivery of betahistine over a range of doses for the treatment of otological and neurological disorders. The patent application (US patent application no. 15/887,388) is pending in the US with a priority filing date of February 2017, which would provide coverage in the US through 2037. Similarly, the international patent (international publication no. WO 2018/141922) should provide coverage in Europe through 2037. Aside from patent coverage, there may be data exclusivity of up to five and 10 years in the US and in Europe, respectively.
In Auris Medical’s non-clinical pharmacokinetic study in Beagle dogs, concentrations of betahistine were measured in blood plasma following intranasal administration of the compound at doses up to 120mg and oral administration up to 48mg/kg, which is the maximum approved daily dose. The study demonstrated that the absolute bioavailability of oral betahistine reached 2% to 6% (Exhibit 2), while it reached 27% to 82% with intranasal betahistine. This suggests a relative increase of bioavailability of five to 35 times over oral administration (Exhibit 3).
Moreover, Auris Medical compared human pharmacokinetic outcomes of intranasal betahistine from a previous Phase I trial in eight healthy volunteers per dose group (single dose, volume of 100 µl per dose) conducted by Otifex Therapeutics to data from an independent Phase I clinical trial in 20 healthy female volunteers dosed with 48mg oral betahistine three times daily. Although the juxtaposition of these data suggests the relative bioavailability of intranasal betahistine is 20 to 40 times higher (NB: this is dose adjusted) than with oral administration (Exhibit 4), a controlled clinical trial is the only way to establish superior clinical efficacy of intranasal administration over oral administration of the drug.
Exhibit 2: Oral administration of betahistine in Beagle dogs
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Exhibit 3: Intranasal administration of betahistine in Beagle dogs
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Exhibit 4: Comparison of previous Phase I trials in healthy human volunteers
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Auris Medical recently completed its randomized, placebo-controlled Phase I clinical trial in 72 healthy volunteers (Exhibit 5) and reported top-line data including pharmacokinetics and maximum tolerated does with single and repeated dosing on 17 October 2018. The trial was divided into three parts: the first included the administration of escalating doses of oral betahistine to 384 mg, the second included intranasal betahistine administration to determine the maximum tolerated dose with single and repeated dosing, and the third included dose escalation of repeated doses of AM-125 three times daily for three days.
Exhibit 5: AM-125 Phase I in 72 healthy volunteers
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Dose |
Group 1 |
Single dose intranasal betahistine (10, 20, 40, 60 mg, 100 µl) or placebo |
3x daily intranasal betahistine (5, 10, 20, 40 mg, 100 µl) or placebo for three days |
Group 2 |
Oral betahistine (48mg) or placebo |
Dose |
Single dose intranasal betahistine (10, 20, 40, 60 mg, 100 µl) or placebo |
3x daily intranasal betahistine (5, 10, 20, 40 mg, 100 µl) or placebo for three days |
Oral betahistine (48mg) or placebo |
Single doses (10, 20, 40, 60 mg) of intranasal betahistine demonstrated 6 to 29 times superior relative bioavailability (0.056<p<0.0001) over a single 48mg oral dose of oral betahistine as illustrated by the median betahistine plasma concentration (Exhibit 6). The company did not present data on repeated doses, but explained the profile was similar. Adverse events (AE) were mild to moderate, described as transient and included sneezing and nasal congestion, which corresponded to dose. One patient withdrew from the trial due to an AE, however no serious AEs were reported. According to Auris, the maximum tolerated repeated dose based on local tolerability in the nose was identified and set at 40 mg; the maximum tolerated single dose was not reached at 60mg.
Exhibit 6: Single-dose AM-125 demonstrates superior bioavailability to oral betahistine
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Following these encouraging Phase I data, Auris expects to initiate its Phase II clinical trial in 138 patients with surgically-induced acute vertigo following the removal of vestibular schwannoma (ie a noncancerous tumour located on the main nerve leading from the inner ear to the brain, also known as acoustic neuroma). Vestibular schwannoma surgery triggers acute vertigo which can leave patients with the loss of peripheral vestibular input on one side. Surgical complications may include vision or hearing problems as well as nausea. Patients spend approximately three days in the hospital following the surgery and recovery time may take anywhere from six to 12 weeks, though this varies from patient to patient. Previous studies have demonstrated the ability of oral betahistine to shorten the time required to achieve vestibular compensation in patients who underwent unilateral vestibular neurectomy.
Auris Medical’s randomized, controlled double-blind Phase II trial, called TRAVERS, will be divided into two parts (Exhibit 7). Part A of the trial, which the company plans to initiate in Q119, will include 50 patients who will be administered 5 steps with AM-125 three times daily and 16 patients who will receive 48mg three times daily. The company anticipates top-line data readout in Q319, expects to determine a dose response curve and select a low dose and a high dose of AM-125 for the second part of the trial, which will be measured against placebo. The company plans to enrol 72 patients in part B of the trial. Furthermore, Auris expects to receive EMA feedback on the TRAVERS trial in Q418 and plans to initiate Part A of trial thereafter.
Exhibit 7: TRAVERS Phase II trial outline
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No. patients |
Dose (3x daily) |
Time frame |
Primary endpoints |
Secondary endpoints |
Part A |
50 (experimental) |
5 doses up to 40 mg with AM-125 |
4 weeks |
Standing on foam, tandem Romberg test |
Tandem gait, subjective visual deviation and subjective questionnaires |
16 (placebo) |
48mg oral betahistine |
Part B |
72 |
High dose and low dose (determined by interim analysis) vs placebo (48mg oral betahistine) |
4 weeks |
Standing on foam, tandem Romberg test |
Tandem gait, subjective visual deviation and subjective questionnaires |