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Tinnitus Hopes Put to Sleep by Latest Auris Failure

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Tinnitus Hopes Put to Sleep by Latest Auris Failure March 14, 2018 Tinnitus hopes put to sleep by latest Auris failure Madeleine Armstrong Ketamine is best known as a horse tranquiliser or a recreational drug, but it has also been proposed as a treatment for various disorders from depression to Alzheimer’s. Hopes of developing the drug in tinnitus have been dashed by the failure of Auris’s Keyzilen in a second phase III trial. As well as leaving Auris’s future looking bleak – Keyzilen is the second of its phase III candidates to flunk in four months – the setback could also be bad news for the sparse tinnitus pipeline. According to EvaluatePharma there is only one other candidate in active clinical development, Otonomy’s OTO-313, and this uses the same mechanism of action as Keyzilen (see table below). Tinnitus pipeline Generic Project Company Pharma class Trial(s) Notes name Phase III Auris Esketamine TACTT2 Keyzilen NMDA antagonist Failed Aug 2016 Medical hydrochloride (NCT01803646) TACTT3 Failed Mar 2018 (NCT02040194) Phase I OTO- Phase I/II trial to OTO-311 abandoned in Otonomy NMDA antagonist Gacyclidine 313 start H1 2019 favour of this formulation Preclinical Auris AM-102 Undisclosed - - Medical KCNQ2 Knopp Kv7 potassium - - Program Biosciences channel modulator Source: EvaluatePharma. Both projects are psychoactive drugs targeting the NMDA receptor. Tinnitus is commonly caused by loud noise and resulting damage to the sensory hair cells in the cochlea. Initial trauma to the inner ear has been shown to trigger excess production of glutamate, which leads to the hyperactivation of NMDA receptors and, in turn, cell death. Blocking the NMDA receptor could therefore have a protective effect – but it is unclear how this mechanism would work once the damage to hair cells had been done. Keyzilen is a “biocompatible and fully biodegradable” gel formulation of esketamine, an enantiomer of ketamine, which is administered via three injections into the middle ear over three to five days. All that Otonomy will say about OTO-313 is that it is a “sustained-exposure formulation of gacyclidine” that can be given via a single middle ear injection. Perhaps it is the formulation of Keyzilen that is at fault, rather than its mechanism. However, it will take data on OTO-313 to prove this, and according to Otonomy’s website a phase I/II trial of ’313 will not begin until the first half of 2019. Otonomy was previously developing a different formulation of gacyclidine, OTO-311. This completed a phase I trial, but the company switched to OTO-313, which it believes could be better. So far, the signs for drug development in this indication are not auspicious. As well as the failure of Keyzilen in two pivotal trials – TACTT3 yesterday and TACTT2 in August 2016 – Merz appears to have abandoned its own NMDA antagonist, neramexane, which had been in phase III for tinnitus and Alzheimer’s. Auris has a preclinical tinnitus candidate, AM-102, but has not disclosed its mechanism. The only novel agent in development appears to come from Knopp Biosciences, which is targeting the KCNQ2 voltage-gated potassium ion channel family; this company also has related projects in seizures, epilepsy and pain. Auris is not the only group looking at esketamine for a novel use – Johnson & Johnson is developing an intranasal formulation for treatment-resistant depression, and marked it out last year as one of its potential blockbusters (Johnson & Johnson lays out its battle plan, May 18, 2017). Phase III data are due soon, and J&J plans to file for approval this year. One for 10 Despite the failure of Keyzilen and another phase III project, AM-111, in November, Auris is limping on. The company reacted to yesterday’s news with a one for 10 reverse stock split; taking this into account, shares were down 43% this morning to $1.54. It looks like Auris has not given up on AM-111, a JNK inhibitor. Despite the failure of the Healos trial in sudden hearing loss in November, the company hopes to have a discussion with the regulatory authorities in the second quarter. It appears that the group plans to focus on a subpopulation of patients with profound hearing loss, who performed better in a post-hoc anlaysis of Healos. Auris expects more data from this subgroup towards the end of the first quarter from the prematurely terminated Assent trial. The company has one more clinical candidate standing: AM-125, an intranasal betahistine in development for vertigo, and had said it wanted to start a second phase I trial in the current quarter. Still, with funds running short – Auris only had SwFr20.2m ($21m) in the bank at the end of September, and raised another $5.5m in January – the company might have a problem continuing for long enough to find out if AM-125 can turn into a success. To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter More from Evaluate Vantage Evaluate HQ 44-(0)20-7377-0800 Evaluate Americas +1-617-573-9450 Evaluate APAC +81-(0)80-1164-4754 © Copyright 2021 Evaluate Ltd..
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