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crestline
 #1 
Here is something I think is new information posted by Auris Medical:


AM-101

Treatment of inner ear tinnitus

A large number of tinnitus cases may be due to single or repeated incidents of excitotoxicity in the cochlea, which can be provoked e.g. by exposure to excessive noise, fluctuations in the blood supply to the cochlea or certain ototoxic medications. Excitotoxicity leads through the excessive release of the neurotransmitter glutamate to neural degeneration, which may in turn lead to tinnitus. While the exact mechanisms responsible for the appearance of tinnitus following excitotoxicity remain to be elucidated, it seems highly likely that some dysregulation of cochlear NMDA receptors lies at the heart of the problem. Accumulating evidence suggests that the “phantom sound” is generated by dysregulated NMDA receptors which produce aberrant firing of the auditory nerve.

Frequently asked questions

How does AM-101 work?

AM-101 is a non-competitive antagonist of NMDA receptors which blocks the unwanted activity of NMDA receptors in the cochlea. According to our hypothesis, this can suppress the aberrant excitation of the auditory nerve that is perceived as tinnitus.

For which types of tinnitus could AM-101 work?

Animal studies with AM-101 were performed in a model of tinnitus induced by acoustic trauma, a condition known to trigger glutamate excitotoxicity in the inner ear. While it does not seem unlikely that AM-101 could also work in case of tinnitus provoked by other triggers of excitotoxicity, we do not know whether this holds true at this point.

Would AM-101 work only in acute tinnitus?

The animal studies with AM-101 were performed in a model of acute acoustic trauma with treatment shortly after tinnitus onset. At this point it is unknown whether there is a therapeutic window during which AM-101 is effective, and if yes, how long such window could last. It seems likely that after some time centralization of tinnitus sets in (i.e. the brain "memorizes" the phantom sound), and a pharmacological treatment of tinnitus in the inner ear may no longer be possible. This question is the subject of much scientific discussion. In general, brain plasticity tends to be more rapid in the type of animals tested than in humans.

How is AM-101 administered?

AM-101 is administered by intratympanic injection, a slightly invasive and safe procedure that has been known and practiced by ENT doctors for several decades. For the injection, the eardrum is first locally anaesthetized, then slightly perforated with a fine needle through which the drug is administered into the middle ear. During the procedure and for 30 minutes thereafter, patients are lying with their treated ear up. This shall allow for maximum contact of the drug product with the round window membrane - it is throgh this very small membrane that AM-101 then diffuses into the inner ear and reaches its target. After the resting period, patients get up and can go home.

How safe is AM-101?

Prior to the first clinical trial with AM-101, Auris Medical performed all mandatory toxicology tests in animals and performed further safety evaluations. They showed a good safety profile and local tolerance, in particular no effect on hearing or balance. IThanks to local administration of the drug, only tiny amounts need to be administered, and no systemic side effects are observed. As for any investigational drug, the evaluation of safety and local tolerance in humans is a very important part of all clinical trials.

When could AM-101 be available?

Like any other investigational drug, AM-101 first has to go through a certain number of clinical trials in order to thoroughly evaluate its safety and efficacy - in accordance with applicable regulations and laws. This process, involving an increasing number of participants at each subsequent study, is taking several years and a precondition for submitting a request for marketing approval. AM-101 will therefore even in the best case not be on the market shortly. It is also important to note that all drug development projects carry a substantial risk of failure, i.e. a great number of investigational products never make it to the market due to unacceptable side effects, lack of efficacy or other reasons. Therefore, market approval and general availability of AM-101 are not certain at this point.

How could I participate in a clinical trial with AM-101?

We are aware that many people are suffering very badly from their tinnitus and are eager to try out AM-101 by participating in a clinical trial. In fact, we are receiving quite many of such inquiries or requests. Please check first on our website whether a clinical trial is currently open for recruitment or not. In addition, a certain number of well-defined inclusion criteria have to be met for enrolment, while none of the various exclusion criteria are fulfilled.

Quite often, interested tinnitus patients are offering to travel very far in order to participate in a clinical trial. However, study documents may not be written in their mother tongue, which excludes them from participation - it is very important and mandatory that all study participants can read and fully understand the information provided by the clinical investigators and that they can express themselves to the investigators.

In no case can Auris Medical make any promises regarding the participation in a clinical trial with AM-101 to anyone who is contacting us for this purpose. Thank you for your understanding.

ContactJobsImpressumDeutsch
Key points about AM-101
 Treatment for tinnitus
originating in the inner ear
 Excitotoxicity due e.g. to
noise trauma, long noise
exposure, cochlear ischemia,
ototoxic medications
 Phase I/II clinical trial ongoing

pt
 #2 
so what happens to the eardrum after it is perforated with a fine needle? that sounds potentially risky, and could maybe bring on a bad side effect, like hearing loss or hyperacusis.
crestline
 #3 
AM 101 Results:

 

August 21, 2008

Auris Medical reporting results of phase I/II clinical trial with AM-101

Auris Medical reported the results of the first clinical trial with AM-101, its investigational drug for the treatment of inner ear tinnitus. The double blind, randomised clinical trial with placebo control involved four study sites in Germany and had the evaluation of AM-101’s safety as primary objective. As a secondary objective, the potential efficacy of AM-101 was evaluated. The study results show that intratympanically injected AM-101 was well tolerated by study participants, and provided first indications of therapeutic efficacy.

The first clinical evaluation of AM-101, an investigational medicinal product under development by Auris Medical for the treatment of inner ear tinnitus, was conducted from March 2007 to March 2008 in a phase I/II study in Germany. A total of 24 patients suffering from persisting moderate to severe tinnitus following acute noise trauma or sudden deafness were enrolled at 4 study centres (3 clinics of the German Bundeswehr and 1 private ear, nose and throat practice). Their tinnitus had been refractory to a first-line corticoid treatment prior to study inclusion, and was not older than 3 months (i.e. still at an acute stage).

Study participants were randomized to receive either AM-101 or placebo in a single dose intratympanic injection, whereby a total of 4 dose concentrations were tested under a dose escalation scheme. Follow-up visits were performed 7, 30 and 60 days after treatment administration. The primary objective of the study was to evaluate the safety of AM-101 delivered by intratympanic injection. Secondary objectives were a preliminary evaluation of the potential therapeutic benefit of AM-101 in the treatment of acute inner ear tinnitus as well as the determination of the systemic exposure from local drug administration. The study’s lead investigator was Professor Heinz Maier, Head of the Otorhinolaryngology and Head and Neck Surgery Department of the Bundeswehr clinic of Ulm (Germany).

At baseline, i.e. before administration of AM-101, study participants on average had had tinnitus for 62 days. In 19 cases, tinnitus had been provoked by acute acoustic trauma, in 5 cases it had been related to sudden deafness. A slight majority of patients suffered from bilateral tinnitus (13 out 24), in which case only the worse affected ear was treated. The average audiogram was downward sloping with a maximum hearing loss at 6 kHz.

Overall, AM-101 was well tolerated by study participants, irrespective of the administered dose. Adverse events occurred in only few patients and were either unrelated or considered unlikely related to the pharmaceutical treatment. AM-101 and its primary metabolite could be found in plasma samples obtained in the first hours following treatment in traces only, which confirmed the favourable safety profile of intratympanic injection. This minimally invasive procedure allows for a highly site specific treatment with low doses and only minimal systemic exposure.

In terms of efficacy, the clinical trial provided first indications for the potential efficacy of AM-101 in the treatment of inner ear tinnitus. The clinical data suggest that AM-101 has a positive effect on the perceived loudness of tinnitus as well as on its maskability; in addition, a positive trend was observed in the overall tinnitus handicap as measured by the TBF-12 questionnaire. Further details of the clinical trial and its outcomes shall be published later in a scientific journal.

Thomas Meyer, Auris Medical’s founder and Managing Director, commented: “We are very pleased with the positive results from this first clinical evaluation of AM-101. The trial not only confirmed the presumed good safety profile following local application, but also provided encouraging early indications of potential efficacy.” He added that the successful conclusion of the study represented an important milestone for Auris Medical and the development of a treatment for inner ear tinnitus, an area of great unmet medical need. In a next step, Auris Medical is planning to test AM-101’s efficacy in a phase IIb clinical trial with a substantially larger number of participants

stringplayer
 #4 
This is a very instructional thread.

Here is what we have in persective ...

It is pilot study with numbers too small to be statistically significant.  Moreover, the study is unpublished - so we have no assurances of the quality of the controls, the data collection methodology, etc.

Keeping in mind that most "favorable" pilot studies ultimately do not pan out, there are two things that the cautious reader would want to see before getting excited about this particular treatment approach.

One, of course, is a large scale blinded properly controlled study published in a juried scientific journal.

Can anybody think of the second?

sp
stringplayer
 #5 

Hmm.  It seems that we have some sort of software issue.

I am going to request that it be continued HERE.

sp

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