Chemistry:AM-102
AM-102 (also known as AM102) is an investigational small molecule drug candidate being developed by Altamira Therapeutics for the treatment of tinnitus.[1]
Development
According to company statements and patent filings, AM-102 acts as an inhibitor of the sodium–potassium–chloride co-transporter 1 (NKCC1), a mechanism thought to modulate neuronal chloride homeostasis involved in tinnitus perception.[2]
The compound was developed by Altamira Therapeutics (formerly Auris Medical) in collaboration with King’s College London as part of a program to identify small-molecule drugs for tinnitus.[3]
As of February 2024, there have been no publicly announced clinical trials or active development updates for AM-102 in tinnitus.[4]
Mechanism of action
AM-102 is reported to act via inhibition of the Na⁺K⁺2Cl⁻ co-transporter 1 (NKCC1), a transporter involved in chloride homeostasis in auditory cells.[2]
By inhibiting NKCC1, it is hypothesised that the excitatory-inhibitory balance in inner-ear sensory neurons may be restored, potentially reducing the perception of tinnitus.[2][5]
A relevant patent application describes the concept of NKCC1 antagonists for tinnitus, citing a link between injury-induced down-regulation of KCC2 (the chloride–potassium co-transporter) and tinnitus.[2]
Preclinical and clinical data
Preclinical studies
In animal models of noise-induced tinnitus (Mongolian gerbils), compounds of the NKCC1 inhibitor class significantly reduced behavioural markers of tinnitus and preserved inner hair-cell ribbon synapses.[6]
Clinical development
While AM-102 specifically has limited disclosed trial data, a related compound AM‑101 (also from Auris Medical/Altamira) underwent a Phase-2 intratympanic study in tinnitus after noise trauma or otitis media.[7][8]
The AM-101 study (0.81 mg/ml) showed statistically significant improvements for tinnitus loudness, annoyance, sleep disturbances and tinnitus impact, though the primary endpoint (minimum masking level) was not met.[7][9]
Patent and intellectual property
A patent application (ES2862673T3) describes the use of NKCC1 modulators (including bumetanide derivatives) for tinnitus treatment via chloride-transport modulation in auditory sensory cells. An allowed European patent application (NKCC1 inhibitor for tinnitus) was noted in Switzerland for Auris Medical in January 2020.[10]
Current considerations and outlook
Tinnitus remains a condition with high unmet medical need and no widely approved pharmacotherapy. Although AM-102 represents a mechanistically novel approach, its public development status appears stalled or undisclosed. Potential hurdles include demonstrating robust clinical efficacy, safety in humans, target engagement, and obtaining regulatory approval. Researchers also caution that preclinical models of tinnitus may not always predict human outcomes, so translation into meaningful patient benefit remains uncertain.[11][12][13]
See also
References
- ↑ "Auris Medical Collaborates with King's College London on AM-102 Tinnitus Treatment". Hearing Review / Medqor Media. 2015-01-12. https://hearingreview.com/hearing-loss/tinnitus/tinnitus-therapy/auris-medical-collaborates-kings-college-102-tinnitus-treatment.
- ↑ 2.0 2.1 2.2 2.3 Knipper M, Ruettiger L, "Treatment of tinnitus through modulation of chloride co-transporter NKCC1", US patent 2016/0271098, published 22 September 2016, assigned to Otolanum AGand Auris Medical AG
- ↑ "Auris Medical Collaborates with King's College London on AM-102 Tinnitus Treatment". Hearing Review / Medqor Media. 2015-01-12. https://hearingreview.com/hearing-loss/tinnitus/tinnitus-therapy/auris-medical-collaborates-kings-college-102-tinnitus-treatment.
- ↑ "Altamira Therapeutics Ltd. Annual Report 2021". Altamira Therapeutics Ltd.. 2022-04-12. pp. 72. https://www.annualreports.com/HostedData/AnnualReportArchive/a/NASDAQ_CYTO_2021.pdf.
- ↑ "Hemin acts as CD36 ligand to activate down-stream signalling to disturb immune responses and cytokine secretion from macrophages". Immunology Letters 243 (3): 1–18. March 2022. doi:10.1016/j.tins.2022.01.007. PMID 35104496.
- ↑ "Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils". The European Journal of Neuroscience 54 (3): 4768–4780. August 2021. doi:10.1111/ejn.15334. PMID 34061412.
- ↑ 7.0 7.1 "Efficacy and safety of AM-101 in the treatment of acute inner ear tinnitus--a double-blind, randomized, placebo-controlled phase II study". Otology & Neurotology 35 (4): 589–597. April 2014. doi:10.1097/MAO.0000000000000268. PMID 24603353.
- ↑ "Positive results in Phase II clinical trial for Auris Medical tinnitus treatment". 2015-12-02. https://hearingreview.com/hearing-loss/tinnitus/positive-results-in-phase-ii-clinical-trial-for-auris-medical-tinnitus-treatment.
- ↑ "Corrigendum: Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers". Frontiers in Aging Neuroscience (Frontiers) 13. 2021. doi:10.3389/fnagi.2021.730758. PMID 34434102.
- ↑ Knipper M, Ruettiger L, "Tratamiento del tinnitus mediante la modulación del cotransportador de cloruro NKCC1 en el sistema auditivo [Treatment of tinnitus by modulating the NKCC1 chloride cotransporter in the auditory system]", ES patent 2862673T3, issued 7 October 2021, assigned to Zilentin AGand Auris Medical
- ↑ "Emerging pharmacotherapy of tinnitus". Expert Opinion on Emerging Drugs 14 (4): 687–702. December 2009. doi:10.1517/14728210903206975. PMID 19712015.
- ↑ "Why Is There No Cure for Tinnitus?". Frontiers in Neuroscience 13. 2019. doi:10.3389/fnins.2019.00802. PMID 31447630.
- ↑ "The Current State of Tinnitus Diagnosis and Treatment: a Multidisciplinary Expert Perspective". Journal of the Association for Research in Otolaryngology 25 (5): 413–425. October 2024. doi:10.1007/s10162-024-00960-3. PMID 39138756.
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