Otonomy Starting Phase 1 Trial in 2015 for Tinnitus

[attheedgeofscience]

Minor update on OTO-311...

IND filing and start of Phase 1 clinical trial for OTO-311 expected in 2015:Otonomy plans to file an Investigational New Drug (IND) application with the FDA for OTO-311 and to initiate a Phase 1 clinical trial in 2015. OTO-311 is a sustained-exposure formulation of the N-Methyl-D-Aspartate, or NMDA, receptor antagonist gacyclidine in development for the treatment of tinnitus. In November 2014, Otonomy announced the completion of an exclusive license agreement with Ipsen that enables Otonomy to use clinical and non-clinical gacyclidine data generated by Ipsen to support worldwide development and regulatory filings for OTO-311.

Source: http://www.nasdaq.com/press-release...te-and-product-pipeline-update-20150108-01027

I will try to get hold of some kind of information as to why the next step will be a phase I trial (and not a phase II trial) given that an initial trial had been conducted by another company already (i.e. "NeuroSystec"). I will also try to find out if the phase I trial is for healthy volunteers only.

 

[attheedgeofscience]

Update From Otonomy Regarding OTO-311

As promised, hereby a update regarding OTO-311. The information is directly from Otonomy Inc via their communications agency. There will an be opportunity to ask further questions as the clinical trial approaches. Otonomy is now aware of this thread (and forum) and takes an interest in keeping the information pertinent.

Dear Jakob,

Thank you for taking the time to outline your questions regarding Otonomy's OTO-311 product candidate for tinnitus. Please find information below regarding this effort that hopefully resolves any confusion amongst members of your TinnitusTalk forum.

• Otonomy expects to file an IND (Investigational New Drug) application with the FDA and initiate a Phase 1 clinical trial in the U.S. in 2015. The company expects this trial to enroll subjects with tinnitus rather than healthy volunteers but this is a point of discussion with the FDA.
• Details regarding this trial including the profile for eligibility for inclusion (such as time since tinnitus onset or potential cause of the tinnitus) will be disclosed in the future.
• While it is true that two small pilot clinical studies using gacyclidine in patients with tinnitus have already been conducted in Europe (one published by a group in Germany with lead author Wenzel and a second sponsored by NeuroSystec), both of these trials involved a different method of local drug delivery using a micro-pump and indwelling catheter. The goal of the OTO-311 program is to develop a sustained-exposure formulation of gacyclidine that will provide a full course of treatment from a single intratympanic injection (using Otonomy's proprietary thermosensitive gel technology). Given the difference in OTO-311's formulation profile from what was used in the previous pilot studies, Otonomy plans to conduct a full set of clinical trials for OTO-311 beginning with Phase 1.
• Finally, Otonomy announced in the Fall that the company acquired the rights to reference nonclinical and clinical data from Ipsen in our development and regulatory filings for OTO-311. Ipsen was the original developer of gacyclidine for the treatment of non-tinnitus disorders in the late 1990's and Otonomy views the information Ipsen generated in their program to be helpful for the development of OTO-311.

We apologize for the delay in responding to your questions and appreciate the interest by you and your forum members in our efforts. If interested, you and your members can sign-up to receive future communications from the company related to clinical trials and program updates by registering at the following website:

https://www.research.net/s/Otonomy_SignUp

If you would like to receive alerts of news announcements from the company, you can register for alerts on the Otonomy website:

http://investors.otonomy.com/phoenix.zhtml?c=234082&p=irol-alerts&t=&id=&

You can also follow the @otonomy Twitter handle and "Like" Otonomy on Facebook.

Finally, for information about other trials available for tinnitus patients, you can periodically check the clinicaltrials.gov website, searching for "tinnitus" to identify trials that are enrolling.

 

[valeri]

Thanks @attheedgeofscience

Unfortunately this is another one years away

 

[amandine]

So it is going to be an injection in the ear again just like am 101...........so how does that get to the brain I dont understand to calm the neurons down.....how can that be then without regard to date of onset?

 

[Robb]

So it is going to be an injection in the ear again just like am 101...........so how does that get to the brain I dont understand to calm the neurons down.....how can that be then without regard to date of onset?

Good question, mine is exactly similar

 

[Danny Boy]

Will phase 1 come to the UK?

 

[Karl28]

This kinda stuff never comes to Australia

 

[Danny Boy]

This kinda stuff never comes to Australia

The UK will cure tinnitus, you'll all see...You'll all see.

 

[valeri]

This kinda stuff never comes to Australia

Australia as usual is just too far behind the rest of the world, in many things

 

[Danny Boy]

Australia as usual is just too far behind the rest of the world, in many things

Let's swap passports lol

 

[valeri]

Let's swap passports lol

Any day!!!
But you can't be serious right????

 

[NiNyu]

Gacyclidine for the treatment of non-tinnitus disorders in the late 1990's

Late '90s .. that says it all. Waste of time.

Gacyclidine is a psychoactive drug. It's a derivative of tenocyclidine (TCP). TCP was discovered by a team at Parke Davis in the late 1950s. It's a dissociative anesthetic drug with psychostimulant and hallucinogenic effects.

So basically LSD for T. Yeah, I can see how that's going to solve T.

 

[attheedgeofscience]

Late '90s .. that says it all. Waste of time.

Gacyclidine is a psychoactive drug. It's a derivative of tenocyclidine (TCP). TCP was discovered by a team at Parke Davis in the late 1950s. It's a dissociative anesthetic drug with psychostimulant and hallucinogenic effects.

So basically LSD for T. Yeah, I can see how that's going to solve T.

An astute analysis from someone who - in the same breath of air - states the following two contradictory statements:

Yes! Honestly, I think HIFU is the only treatment with potential here; now. All those meds won't resolve anything.

Still, where is the proof for HIFU? Where is T-patient X that has been cured by HIFU?
All we know is that it's utterly overpriced. Just an appointment cost big money.. and in the end the prof. can easily tell you that your brainwave activity isn't significant enough to justify a procedure. Of course..

With the above in mind, I can see how members of TinnitusTalk can feel assured of your wisdom and your ability to convey it.

attheedgeofscience
16/APR/2015.

 

[Danny Boy]

Any day!!!
But you can't be serious right????

For sure, England isn't that great, now, is it?

 

[NiNyu]

@attheedgeofscience , quoting two statements taken out of context make little to no sense. But as a pioneer in experimental medicine and with essentially no knowledge of the (human) brain I suppose you should have known that.

I have essentially no knowledge of the (human) brain.

With that in mind,

Nothing wrong with questioning the facts - I do it myself all the time in my line of work.

 

[Danny Boy]

@attheedgeofscience , quoting two statements taken out of context make little to no sense. But as a pioneer in experimental medicine and with essentially no knowledge of the (human) brain I suppose you should have known that.



With that in mind,

The true cure will be potassium channel modulators, specifically ones that target the kv3.1 channels, as we can repolarize the neurons back to their natural state. Or scratch that, regeneration of hair cells. Now the only potential tinnitus treatment before Autifony's drug is brivaracetam, as that targets the KV3.1 channels, same as keppra but is 10x more potent.

 

[NiNyu]

regeneration of hair cells.

The endless optimist and knight on his continuing quest.^^

 

[Danny Boy]

The endless optimist and knight on his continuing quest.^^

Regeneration of hair cells is possible, after all, birds can and we will soon.

 

[NiNyu]

Indeed, birds can. They can also fly. Let me say this, if we humans ever grew wings and fly, then yes, hair cell regeneration could be in our reach as well.

You know, I went to the future. And there was nothing for us. Not until we enter the nano-technology century, where they can put ultra tiny robots inside your body to fix whatever is broken.

 

[Zechariah]

Indeed, birds can. They can also fly. Let me say this, if we humans ever grew wings and fly, then yes, hair cell regeneration could be in our reach as well.

You know, I went to the future. And there was nothing for us. Not until we enter the nano-technology century, where they can put ultra tiny robots inside your body to fix whatever is broken.

Nanotech is already used in the field of medicine.

btw, most of your counter-arguments against @attheedgeofscience arguments are kind of ridiculous. And you keep writing them without any self criticism. I'm not saying that ATEOS's habit to dig up old quotes will produce anything useful while arguing with you but still...

Instead you could have admitted that there was a time when you didn't believe in HIFU but you have changed your mind and now you think that the HIFU is the most promising treatment...

 

[attheedgeofscience]

@attheedgeofscience , quoting two statements taken out of context make little to no sense. But as a pioneer in experimental medicine and with essentially no knowledge of the (human) brain I suppose you should have known that.

Why don't you just be happy that there are:

1. People like myself and @Zimichael who track down important and accurate information directly from researchers and pharmaceuticals - and who do so at no expense to yourself.
2. Pharmaceuticals actually involved in research of hearing disorders (and who are willing to engage in a dialogue with the patient group(s) - remember the pharmas are by no means obligated to do so...).

You represent the type of person who consistently feels the need to share with the world what your opinions are. Trouble is: opinions (rather than facts) are not terribly important to anyone in science. Especially when those opinions are stated by non-professionals. You think that what you have to say is so terribly important. But it isn't.

So stop clogging up this thread with your daily crap. Your type of person is the #1 reason why other TT-members will have a hard time finding the relevant information - because for every important post in a thread such as this one, there are +10 other posts which are not. Try to understand. Just try.

attheedgeofscience
16/APR/2015.

 

[Sharpfire]

Indeed, birds can. They can also fly. Let me say this, if we humans ever grew wings and fly, then yes, hair cell regeneration could be in our reach as well.

Stem cells might, in the future (no promises), be able to be induced into differentiating into functioning cochlear hair cells.

 

[Silvio Sabo]

Indeed, birds can. They can also fly. Let me say this, if we humans ever grew wings and fly, then yes, hair cell regeneration could be in our reach as well.

You know, I went to the future. And there was nothing for us. Not until we enter the nano-technology century, where they can put ultra tiny robots inside your body to fix whatever is broken.

Well, we can also fly. There are airplanes, helicopters, gliders and so on. We don't have to be able to to it the exact same way as the birds and as with regeneration of hair cells we might never be able to do it ourselves the way the birds can but there's always drugs and surgeries.

We can grow a whole new body based on our own cells with organs and everything but there is an issue with ethics. It is theoretically possible today. We were able to clone sheep 20 years ago and we can do the same with humans. We could make a whole new body for you and transplant whatever you want that is broken but there are some tremendous ethical issues and becouse of that we might never accually do it.

However there is research going on where they are trying to just grow specific organs and not whole bodies (clones). In wich case we in the future might be able to take a few cells from a person, grow them whole new chocheas (or whatever other organ is malfunctioning) and transplant it into them and VOILA! Cured!

Late '90s .. that says it all. Waste of time.

Gacyclidine is a psychoactive drug. It's a derivative of tenocyclidine (TCP). TCP was discovered by a team at Parke Davis in the late 1950s. It's a dissociative anesthetic drug with psychostimulant and hallucinogenic effects.

So basically LSD for T. Yeah, I can see how that's going to solve T.

Well not necessarily. There are some pretty big similarities between tinnitus and chronic pain disorders. And lidocaine administered intravenously is known to eliminate tinnitus for a while. It is however not a viable treatment. The same goes for deep brain stimulation and HIFU wich when applied on patients with chronic pain dissorders have at the same time brought them relief from tinnitus (if they also had it).

Cyclidine are drugs that generally treat the brain and different brain dissorders such as depression, parkinson, epilepsy, chronic pain and so on. So don't say it won't work just becouse it resembles something already known. It might not work for you but for someone else, but then it might work for you also, you never know. Tinnitus is a complex dissorder with more then one cause so don't say there's only one possible cure.

The true cure will be potassium channel modulators, specifically ones that target the kv3.1 channels, as we can repolarize the neurons back to their natural state. Or scratch that, regeneration of hair cells. Now the only potential tinnitus treatment before Autifony's drug is brivaracetam, as that targets the KV3.1 channels, same as keppra but is 10x more potent.

The same goes here. There will probably not be a single one cure for T but a veriety of cures depending on the root of the problem for that specific patient.

 

[NiNyu]

Nanotech is already used in the field of medicine.

Nano tiny robots that they inject intravenously that can fix whatever is damaged inside your body? What movie was that?

..you could have admitted that there was a time when you didn't believe in HIFU but you have changed your mind and now you think that the HIFU is the most promising treatment...

I still do not know if HIFU really works on T patients. That's why I did suggest a clinical trial to investigate the efficacy of HIFU for T. However, apparently HIFU does work on tremor, cancer etc.

Source,
http://www.fusfoundation.org/for-pa...linical-trial-for-conditions-seeking-approval

If HIFU is essentially a non-invasive lobotomy, then yes, it could be the most promising treatment for neurological symptoms like T. Again, quoting my statements taken out of context make little to no sense.

~
@atheedgeofscience, to be honest, I actually do respect your and @Zimichael efforts in tracking down relevant information regarding a genuine treatment for T.

Indeed, I do feel the need to share how I feel. You know, with the onset of debilitating T +H my health has dropped to rock bottom. I'm in a very bad condition (emotionally and physically) and that's even an understatement; an euphemism if you wish.

I never claimed that my view is terribly important to anyone in science. Nonetheless, I believe my view is quite logical and reasonable. I like to question things. I'm a realist, not an optimist. Also I like to tease and at times I can be very cynical and harsh.

You know, I used to believe what doesn't kill you simply makes you stranger. Now, in respect to T I believe it just kills your sanity slowly.
~

Well, we can also fly. There are airplanes, [..] We don't have to be able to to it the exact same way [..] but there's always drugs and surgeries.

So basically you are referring to CIs, which side effect is T.

We can grow a whole new body based on our own cells with organs and everything but there is an issue with ethics.

You mean a new human being. An individual just like you but with the same DNA.

We could make a whole new body for you and transplant whatever you want that is broken..

In a book, yes. In reality, no. We can't even fix paraplegics. Nerve damage is irreversible. At least that's what science teachs us.

There are some pretty big similarities between tinnitus and chronic pain disorders.

I not only agree but say it's the very same thing. Both are neurological symptoms. It's all in the brain.

Cyclidine are drugs that generally treat the brain and different brain dissorders such as depression, parkinson, epilepsy, chronic pain and so on.

Just like morphine. Still it ain't a cure.

 

[Silvio Sabo]

You mean a new human being. An individual just like you but with the same DNA.

Basically, yes. However if that person is never allowed to wake up and form any sort of consciousness then it would be more or less a body that could be used for spare parts. Only with ones DNA, wich would simplify a lot of things that are otherwise attached to transplantations of organs.

In a book, yes. In reality, no. We can't even fix paraplegics. Nerve damage is irreversible. At least that's what science teachs us.

Not entirely true, otherwise we would not be able to reattach severed limbs.

The problem with the spine is that it's complex, much like the brain. There are lots of nerves and when people do have an accident and end up as paraplegics the nerves are not severed cleanly, there is lots of other damage that prevents the nerves from being able to heal. If you severe a nerve cleanly and have both ends meet that nerve will heal and regain function. And there are those who have been able to walk again, sometimes after several years despite the prognosis initially made. I myself have had surgery where nerves had been severed which led to loss of sensation in that area but after a few months it came back when the nerves had healed.

And another problem with paraplegics is that when nerves are not stimulated for a while they simply moulder away and can never regain function again. This is why in modern therapies where people have been paralyzed they do electric stimulation of the nerves so that those people might have a chance to recovery in the future.

I not only agree but say it's the very same thing. Both are neurological symptoms. It's all in the brain.

Well, it depends. But you shouldn't simplify a complicated issue. There are so many things that can go wrong that can cause tinnitus.

A part of it surly is in the brain but I don't think it's not only a brain issue. Perhaps we can get rid of the T. with treating the brain with HIFU in absence of other treatments. And maybe that's enough. But I also think it's an inner ear issue since it starts there.

Perhaps if we could fix the inner ear the tinnitus would disappear as well but since we can't do that yet we can't know for sure. We know that it effects the brain. But how, and why? Is it reversable if the chochlea or the auditory nerve is repared? Maybe it is and maybe it's not. What if there is a timeframe in wich the T. can be cured if the inner ear is fixed. And maybe after some time when the pathways have been set it wouldn't matter if the ear is healed anymore. That would explain why tinnitus vanishes after a while in some people. For most it accually does. We are the unlucky few that get to have it as a chronic condition. And there are reports of people where their tinnitus vanished after 30 or so years!

Questions like these will hopefully be answered in the next few years.

 

[NiNyu]

Basically, yes. However if that person is never allowed to wake up and form any sort of consciousness

Did you know that hearing is one of the first things a fetus develops?

Interesting what you wrote about the nerves.

Perhaps if we could fix the ear the tinnitus would disappear as well but since we can't do that yet we can't know for sure.

I presume it's the very same like with the spinal nerves. If the nevers in the cochlea don't get stimuli from the sensory cells they either send crazy stuff to the neurons in the brain, or the neurons in the brain go apesh*t 'cause they don't get any input. Moreover, maybe if the nerves in the cochlea are not stimulated for a while they even simply molder away and can never regain function again. Perhaps if they are completely moldered T ceases.

Questions like these will hopefully be answered in the next few years.

Or centuries.

 

[Silvio Sabo]

Did you know that hearing is one of the first things a fetus develops?

Yes it develops shortly before midway through the pregnancy. Around week 18-19 I think. I think the development before that is cool. The brain and the whole CNS is formed from a tube (the neural tube) and the face accually grows from the top down. Cells migrate down the top of the head, later on the forehead and then downwards to form the nose, the mouth and so on. Sadly there are people where this goes a bit wrong and depending on in wich phase parts of the face can be missing. I know of one girl in the US (I think) that had no lower jaw.

The developmental biology course I went to during the time I studied for my degree was one of the more interesting ones

I presume it's the very same like with the spinal nerves. If the nevers in the cochlea don't get stimuli from the sensory cells they either send crazy stuff to the neurons in the brain, or the neurons in the brain go apesh*t 'cause they don't get any input. Moreover, maybe if the nerves in the cochlea are not stimulated for a while they even simply molder away and can never regain function again. Perhaps if they are completely moldered T ceases.

Everything is possible. From what I've read recently it might be the other way around. In a paper I read recently they did experiments with mice and studied the effects of a protein called Neurotropin-3 (NT3). In the paper they stated that it's the connection between the hair cells and the nerve cells that is damaged by noise, drugs or other reasons. The connection is called a ribbon synapse. They were able to restore hearing in mice with noise induced hearing loss by enebling the mice to produce extra NT3 through gene therapy.

The nature of T. tells me that it might not be a problem of nerves moldering away but the opposite. That they are overstimulated. It seems that there is a code for silence. A pattern of neuron firing that the brain translates to silence. And that is screwed up in us T. sufferers. So our nerves might be ok. We just need to form that connection again.

This is where the ion channel modulators work, they might not restore the link but they might reduce the activity of the nerves back to a somewhat normal state.

The hair cells stimulate opening/closing of ion channels wich regulates the flow of calcium and potassium ions across the membrane of the neuron and an impulse is formed. If that link is broken then everything gets screwed up. This is why ion channel modulators might work on tinnitus. There seems to be an increased activity (wich creates the sound of T.) and not absence of activity.

Or centuries.

Let us hope not!

 

[NiNyu]

This is where the ion channel modulators work, they might not restore the link but they might reduce the activity of the nerves back to a somewhat normal state.

The hair cells stimulate opening/closing of ion channels wich regulates the flow of calcium and potassium ions across the membrane of the neuron and an impulse is formed. If that link is broken then everything gets screwed up. This is why ion channel modulators might work on tinnitus. There seems to be an increased activity (wich creates the sound of T.) and not absence of activity.

That sounds like,

'Low-Threshold Calcium Spike (LTS) Bursts
Bursting discharges produced by thalamic and reticular cells, when their membranes are hyperpolarized by either disfacilitation or overinhibition. They are due to the deinactivation of calcium T-channels causing the appearance of a large calcium spike, itself inducing a burst of sodium action potentials.'

What are these ion channel modulators?

 

[Silvio Sabo]

That sounds like,

'Low-Threshold Calcium Spike (LTS) Bursts
Bursting discharges produced by thalamic and reticular cells, when their membranes are hyperpolarized by either disfacilitation or overinhibition. They are due to the deinactivation of calcium T-channels causing the appearance of a large calcium spike, itself inducing a burst of sodium action potentials.'

What are these ion channel modulators?

Well nerve impulses are being transfered by ions traveling across the cell membrane. More closely Sodium, Calcium and Potassium ions.

When a neuron is stimulated, usually by the release of some neurotransmitter like acetylcholine or norepinephrine by a neigbouring cell, normally Sodium channels are being opened (I think in some cells it might also be Calcium but I'm not sure, I haven't studied this stuff for years). When Sodium ions move across the membrane to the inside of the cell a polarization occurs. This is called an action potential. Becouse now the charge is larger on one side of the membrane then on the other. If it's strong enough neigbouring sodium channels will open and the same thing occures through the length of the axon like a chain reaction. This is how an electric impulse travels.

In response to the inflow of sodium ions, potassium channels open and potassium ions rush from inside of the cell.

However more potassium will move out of the cell then is necesary and the membrane will become hyperpolarized.

Then a refractory period starts when the cell will not respond to new stimulus becouse the sodium and potassium ions are on the wrong side of the membrane. You have sodium on the inside and potassium on the outside. To restore the original distribution of these ions sodium/potassium pumps in the cell membrane move potassium from the outside of the cell to the inside and sodium from the inside to the outside. When the levels are restored the cell is ready for new stimuly.

In T. sufferers there seems to be something wrong with these channels. So that nerves fire even thouogh there is no stimuly.

 

[Zechariah]

Nano tiny robots that they inject intravenously that can fix whatever is damaged inside your body? What movie was that?

I still do not know if HIFU really works on T patients. That's why I did suggest a clinical trial to investigate the efficacy of HIFU for T. However, apparently HIFU does work on tremor, cancer etc.

Yes, it is a common misunderstanding that nanotech = little robots.

And you seem to be much more optimistic about HIFU than you were couple of months ago. Atleast you can draw that conclusion of your writings even though you feel that they are taken off context. But nvm, you will keep twisting things and I don't want to be part of that conversation.