NervGen Pharma’s NVG-291-R Demonstrates Significant Functional Recovery in DoD-Sponsored Preclinical Models of Traumatic Hearing Loss

[vttbx]

NervGen Pharma's NVG-291-R Demonstrates Significant Functional Recovery in DoD-Sponsored Preclinical Models of Traumatic Hearing Loss

About NVG-291

NervGen holds exclusive worldwide rights to NVG-291, a first- and potential best-in-class neuroreparative therapeutic peptide targeting nervous system repair. NVG-291's technology is licensed from Case Western Reserve University and is based on academic studies that demonstrated the preclinical efficacy of NVG-291-R, the rodent variant of NVG-291, in animal models of spinal cord injury. These studies implicated multiple potential molecular and cellular mechanisms by which NVG-291-R promotes neurorepair and functional improvement in both central and peripheral nervous system injury models. The implicated mechanisms include the promotion of neuronal sprouting, or plasticity, remyelination, and promotion of a non-inflammatory phenotype in the microglial cells. NervGen has received Fast Track designation from the FDA and Orphan Designation from the EMA for NVG-291 in individuals living with spinal cord injury.

• Demonstrated significant hearing restoration in blast-induced sensorineural hearing loss models
• Promoted significant functional recovery and axonal regeneration in peripheral nerve injury models
• Reinforced NVG-291's broad therapeutic potential with new data across three distinct injury models

 

[Joeseph Stope]

Hey! Is this my birthday, Christmas, or what? I never thought they would arrive in the height of summertime!

Before and after my first encounter with tinnitus, I was pretty much in perfect health. That made me believe there must be some simple cause, like a tiny screw loose in my ear that just needed tightening. If only those egghead, nerdy doctors could figure out which one, then I'd be back in shipshape again.

Thirty-three years on, I've learned to be careful with euphoria. While it would be beyond wonderful if the medical community had come up with a simple quick fix for tinnitus and hyperacusis, I'm not celebrating just yet.

Recent findings suggest that the first damage from noise or acoustic trauma occurs to the synapses and maybe the stereocilia. Sorry, I've forgotten the link. More serious damage would be to the hair cells.

This would suggest that the first attempt at a cure might target the synapses, followed by attempts to rejuvenate, regrow, or repair the hair cells.

Maybe I think too logically. But it would be beyond wonderful if your post is heralding the arrival of the cavalry.

 

[Street Novelist]

Good find! What is the delivery method?

 

[PhillyBill]

This seems to be for "acute" hearing injury. Is there any research for applications to chronic cases?

 

[gracepixie]

Good find! What is the delivery method?

From their website:

Novel Preclinical Findings in Blast-Induced Sensorineural Hearing Loss

Conducted by the U.S. Air Force's 59th​ Medical Wing in collaboration with the Uniformed Services University, Brooke Army Medical Center, NVG-291-R was investigated as a potential novel treatment for blast-induced sensorineural hearing loss.

• Significant Hearing Restoration: In a rat model exposed to shock waves, either a single high-pressure blast or a series of low-pressure blasts, daily subcutaneous NVG-291-R treatment led to statistically significant improvements in hearing thresholds across all frequencies by end-of-study at Day 30, preventing the profound and permanent hearing loss observed in untreated animals

It was given as subcutaneous daily injections, but the press release doesn't mention when treatment was started or how long it lasted. Their ongoing clinical trial for Spinal Cord Injury includes two cohorts: A) injury occurring more than one year but no later than ten years ago, and B) injury occurring between 20 and 90 days ago.

They announced positive phase 2 results from cohort A earlier this summer, which suggests it could also be effective for cases of chronic hearing loss. So far, I haven't found any direct references to tinnitus, but it's hard to imagine they aren't considering it.

 

[Street Novelist]

Subcutaneous injections? So, behind the ear or somewhere around the ear?

 

[withintention]

From their website:

It was given as subcutaneous daily injections, but the press release doesn't mention when treatment was started or how long it lasted. Their ongoing clinical trial for Spinal Cord Injury includes two cohorts: A) injury occurring more than one year but no later than ten years ago, and B) injury occurring between 20 and 90 days ago.

They announced positive phase 2 results from cohort A earlier this summer, which suggests it could also be effective for cases of chronic hearing loss. So far, I haven't found any direct references to tinnitus, but it's hard to imagine they aren't considering it.

@gracepixie, the article did say how soon the intervention was done for hearing loss. Within 30 days.

 

[Jinx]

It looks promising, but they are measuring over a time span. I wonder if it will also be helpful for people who have already had it for a long time.

 

[Furetto]

Subcutaneous injections? So, behind the ear or somewhere around the ear?

That just means "under the skin." It's the same as the COVID vaccine.

 

[Street Novelist]

That just means "under the skin." It's the same as the COVID vaccine.

Yes, I know. But where would they give the injection?

 

[IYIiKe]

Still waiting for the day they do tests on the rats that have tinnitus symptoms longer than a week.

 

[gracepixie]

@gracepixie, the article did say how soon the intervention was done for hearing loss. Within 30 days.

No, the improvement was noticeable within 30 days. However, the article does not specify how much time passed between the blast injury and the first injection. Obviously, that implies the dose was given within 30 days, but it almost certainly began sooner.

If I were to guess, I would say it was started sometime between one hour and one day after the injury, with daily injections continuing until day 30. But the article does not clarify this.

Yes, I know. But where would they give the injection?

In mice, a subcutaneous injection is usually done by scruffing the mouse and injecting into the flap of skin that collects behind the neck. It is meant to introduce a medication into circulation in a slow and sustained release model.

This method has lower risk and causes less pain than intramuscular (IM) or intravenous (IV) injections, which are both faster acting, have a shorter half-life, and are more painful.

Subcutaneous delivery is the preferred method when you want a medication systemically delivered over a long period of time, when side effects are not a concern, and when the duration of drug exposure matters more than a single large dose.

That just means "under the skin." It's the same as the COVID vaccine.

No, the Covid vaccine (and most vaccines) is intramuscular. This method allows faster uptake and reaches more immune cells in the muscles.

Subcutaneous injection is given under the skin into the fat layer. It allows for slower but more sustained release over a longer period of time. For example, GLP-1 medications such as Ozempic are given subcutaneously, and you only need to dose weekly because the drug is slowly released throughout that entire time.

 

[Furetto]

No, the Covid vaccine (and most vaccines) is intramuscular. This method allows faster uptake and reaches more immune cells in the muscles.

Subcutaneous injection is given under the skin into the fat layer. It allows for slower but more sustained release over a longer period of time. For example, GLP-1 medications such as Ozempic are given subcutaneously, and you only need to dose weekly because the drug is slowly released throughout that entire time.

You are right, I stand corrected.

 

[Joeseph Stope]

No, the improvement was noticeable within 30 days. However, the article does not specify how much time passed between the blast injury and the first injection. Obviously, that implies the dose was given within 30 days, but it almost certainly began sooner.

If I were to guess, I would say it was started sometime between one hour and one day after the injury, with daily injections continuing until day 30. But the article does not clarify this.

In mice, a subcutaneous injection is usually done by scruffing the mouse and injecting into the flap of skin that collects behind the neck. It is meant to introduce a medication into circulation in a slow and sustained release model.

This method has lower risk and causes less pain than intramuscular (IM) or intravenous (IV) injections, which are both faster acting, have a shorter half-life, and are more painful.

Subcutaneous delivery is the preferred method when you want a medication systemically delivered over a long period of time, when side effects are not a concern, and when the duration of drug exposure matters more than a single large dose.

No, the Covid vaccine (and most vaccines) is intramuscular. This method allows faster uptake and reaches more immune cells in the muscles.

Subcutaneous injection is given under the skin into the fat layer. It allows for slower but more sustained release over a longer period of time. For example, GLP-1 medications such as Ozempic are given subcutaneously, and you only need to dose weekly because the drug is slowly released throughout that entire time.

Bowled over by your scholarship in this specialized area of medicine.

I recall one post from @Nick47, not so far back, I believe from this year, where he mentioned that some form of delivery method, specifically injection, had fallen into disrepute. Was it the intra-tympanic delivery or the round window? I am shockingly ignorant of these things, regrettably.

Who would have thought that the delivery method would be so important for the outcome! I am delighted for the lab rats or guinea pigs and their improvement. Now the human trials?

Of course, testing rats or guinea pigs with medications for chronic tinnitus has limitations. They do not live all that long.

Still, I await with anticipation the results of the human trials for chronic tinnitus. There are good reasons to test the medication also on chronic patients. That is where the money is.

 

[gracepixie]

lol, @Furetto and @Joeseph Stope, sorry for my tart responses. My PhD research is in vaccine design, so I'm very familiar with that field and loosely familiar with biotech in general.

Joeseph, some people doubt that intratympanic (IT) injections will result in effective drugs for hearing loss and tinnitus because many have tried and failed. Intratympanic injections go through the eardrum and fill the middle ear space, where they are eventually drained via the Eustachian tube. However, before the medicine is drained, the active ingredient must diffuse through the windows of the inner ear to enter the cochlea, where it can have an effect. A major challenge with IT injection is that many drugs are too large to diffuse across this barrier. Notably, Brain-Derived Neurotrophic Factor (the main ingredient in some of the Otonomy drugs) was not seen to diffuse far enough into the cochlea to be effective.

Therefore, my current theory is that only small molecules will be viable for IT drug delivery. The Frequency Therapeutics drugs were small molecules, but still failed in trials. Then again, the Frequency Therapeutics drugs were very different from the small molecules being developed for hearing loss today, such as CilCare's formulation of Xaliproden, which restores synapses. So the failure of those IT drugs does not really imply that IT injections as a whole will not work, and I disagree with people who claim those failures as evidence that we should abandon IT delivery.

NervGen's drug is a peptide, a very small chain of amino acids similar to a protein but much smaller. There is a chance that this could diffuse past the windows of the inner ear and therefore succeed in IT delivery. However, the primary development of this drug is for CNS injury, and it is being delivered via subcutaneous injection. To me, this is a good sign. Subcutaneous injections can have many side effects, and the main benefit of IT injection is that it limits drug exposure to the inner ear rather than the whole body. NervGen's drug is already being tested in humans and has not shown any worrisome side effects so far. This means they can choose the delivery method that is most effective, rather than focusing on minimizing systemic exposure. They might still go for IT, but from the clinical studies so far, it sounds like they do not have to.

One more note about mouse-to-human trials: mice do not live as long as humans, but they age on a similar scale. Much like how one year of dog aging equates to about seven years of human aging, the conversion for mice is roughly one year equating to 30 years of human aging. So if you want to study chronic models in a mouse, you only need the mouse to experience a disease or condition for about a week or two. CilCare's drug delayed treatment in mice by two days, which equates to about six months in a person, making it the longest delayed model I've seen. Many companies are also working on longer treatment delays and are treating two-year-old mice, so the models exist.

 

[Emao]

I noticed that NervGen's pipeline page currently shows nothing related to hearing loss. Could we assume that if their current trial on treating spinal cord injury with NVG-291 goes well, there will likely be efforts to investigate the same drug for other uses?

 

[Joeseph Stope]

lol, @Furetto and @Joeseph Stope, sorry for my tart responses. My PhD research is in vaccine design, so I'm very familiar with that field and loosely familiar with biotech in general.

Joeseph, some people doubt that intratympanic (IT) injections will result in effective drugs for hearing loss and tinnitus because many have tried and failed. Intratympanic injections go through the eardrum and fill the middle ear space, where they are eventually drained via the Eustachian tube. However, before the medicine is drained, the active ingredient must diffuse through the windows of the inner ear to enter the cochlea, where it can have an effect. A major challenge with IT injection is that many drugs are too large to diffuse across this barrier. Notably, Brain-Derived Neurotrophic Factor (the main ingredient in some of the Otonomy drugs) was not seen to diffuse far enough into the cochlea to be effective.

Therefore, my current theory is that only small molecules will be viable for IT drug delivery. The Frequency Therapeutics drugs were small molecules, but still failed in trials. Then again, the Frequency Therapeutics drugs were very different from the small molecules being developed for hearing loss today, such as CilCare's formulation of Xaliproden, which restores synapses. So the failure of those IT drugs does not really imply that IT injections as a whole will not work, and I disagree with people who claim those failures as evidence that we should abandon IT delivery.

NervGen's drug is a peptide, a very small chain of amino acids similar to a protein but much smaller. There is a chance that this could diffuse past the windows of the inner ear and therefore succeed in IT delivery. However, the primary development of this drug is for CNS injury, and it is being delivered via subcutaneous injection. To me, this is a good sign. Subcutaneous injections can have many side effects, and the main benefit of IT injection is that it limits drug exposure to the inner ear rather than the whole body. NervGen's drug is already being tested in humans and has not shown any worrisome side effects so far. This means they can choose the delivery method that is most effective, rather than focusing on minimizing systemic exposure. They might still go for IT, but from the clinical studies so far, it sounds like they do not have to.

One more note about mouse-to-human trials: mice do not live as long as humans, but they age on a similar scale. Much like how one year of dog aging equates to about seven years of human aging, the conversion for mice is roughly one year equating to 30 years of human aging. So if you want to study chronic models in a mouse, you only need the mouse to experience a disease or condition for about a week or two. CilCare's drug delayed treatment in mice by two days, which equates to about six months in a person, making it the longest delayed model I've seen. Many companies are also working on longer treatment delays and are treating two-year-old mice, so the models exist.

Many thanks for taking the time and effort to explain things. It lifts our spirits to have a member who is on top of their game in auditory matters.