Letter to the FDA (Dr. Janet Woodcock)

I had mentioned this in other threads, but I had been working on a letter to Dr. Woodcock of the FDA. Before I sent it to her, however, I was looking for member feedback. I know a few people have expressed interest in helping me with this letter. The mods suggested I put this post in this section and include the letter, so I will include it below.

First draft:

Dear Dr. Woodcock,

Hi. Thank you for your time. I am a former veterinarian who is writing for your help and guidance. About a year ago, I suffered a great loss to my functional hearing instantaneously and bilaterally after an extremely high and prolonged dose of Azithromycin.

While my audiogram only shows a moderately severe to severe loss at 12000 Hz and higher, my hearing is very distorted across all frequencies (even ones in which I have a normal audiogram) in ways that suggest that the audiogram is not detecting all of my cochlear damage. You may already know that audiograms only detect outer hair cell damage and do not detect other cochlear damage such as inner hair cells and synapses.

My hearing loss has resulted in me being unable to localize sound well anymore, unable to watch TV without captions and unable to listen to music at all (something I deeply and passionately loved). My hearing is bad enough where I could not hear well enough in the regular noise of my clinic to continue my job. I also have bilateral tinnitus which is loud enough to distract my concentration and it further adds to my stress/mental state hardship. I lost so much in an instant: the career I dedicated my life to, my husband (who left me for being “inconsolable”), the peace of quiet and music.

And yet, as bad as I have it, there are people who have it much worse. There are people who have “catastrophic tinnitus” as loud and unmaskable as a jet engine and hyperacusis so bad that the sound of typing this letter to you would send them into distress form either the loudness or the pain depending on their subtype. There are people who go days without sleep and are teetering on the point of full exhaustion and mental break down. People are literally ending their life over this torment. Adding to the difficulty is the fact that it is hard for the general public to understand how bad it can get because many people have more benign tinnitus or hearing issues that are mild or can be remedied with a hearing aid so they imagine that others just aren’t as “tough” as they are. Frequently the only “treatment” offered is counseling. The analogy I would use here is it is like trying to help a soldier get over PTSD while they are actively at war still.

We need treatments that address the underlying anatomy and physiology. We need actual relief. Some of us are dying from this. I’m on a very large and active online tinnitus forum and I have been on there less than a year and have already seen multiple members take their own life. And even those of us who are not immediately suicidal… waiting 10 years for a treatment means a 10-year gap in our careers and, in my case, since I’m already 42, it may mean the difference between getting to adopt and become a mother or not. For others who are already parents, some of them can’t even be around their own kids because of the noise kids make.

I know from reading op-ed pieces that you are personally very committed to FDA reform to make it work better for suffering patients. I ask that you consider us with debilitating hearing symptoms in these decisions, too. For the first time in history, regenerative medicine may help us. No matter which part of the cochlea is addressed: Outer hair cells, inner hair cells, cochlear synapse etc. I ask that, if any of these medications show efficacy in an important end point and are shown to be safe, I implore you and the FDA to help us get our lives back sooner.

Regardless, thank you so much for the work that you do. I know you fight for so many suffering people,

Sincerely,

name withheld, DVM

 

I could help with that, too, but @TuxedoCat and I determined this letter is sufficiently separate enough to work on this on my own first and then maybe I could offer any help (if I would be useful in that regard) on the political lobbying. Por que no los dos?!

 

Some thoughts on this:

1. Might we want to mention the precedent of granting conditional approval for drugs that have no known existing treatment by which to compare its efficacy?

2. Might we want to name-drop drugs like OTO-413/PIPE-505 & FX-322 and mention its fast track status in order to have a more direct request? I think if we were to leave her to her own devices, she may not possess the technological awareness as to what regenerative therapies you’re referencing.

 

I should definitely do 1. I'm on the fence about 2 but ultimately I suspect you are right.

 

I definitely don’t want to come off as a homer (even though I am) for these regenerative therapies. I think there’s a way to tactfully reference these so that it doesn’t appear to push one over the other. Once I get home from the gym I’m going to cut and paste some parts of the section titled “Promising Curative Treatments” I wrote up for a veterans brochure. It’s succinct and understandable to the layman.

 

Thanks. I would welcome your suggestions on adding this.

 

Hopefully these passages with references will help bolster your letter. I more or less cut & pasted this from the veteran's brochure, so you can certainly trim this down a fair amount. I do think referencing specific citations that give this community hope could lend some credibility to the letter.

Inner Ear Hair Cell & Cochlear Regeneration Therapies

1. Frequency Therapeutics has formulated a first-in-class drug in "FX-322," which is “designed to treat the underlying cause of sensorineural hearing loss (SNHL) by regenerating hair cells through activation of progenitor cells already present in the cochlea.(13)” Since tinnitus is thought to be a consequence of hearing loss, logic follows that treating hearing loss will improve or remove tinnitus symptoms. Frequency Therapeutics’ phase 1/2 results determined that four of fifteen participants who had been administered a single dose of FX-322 experienced 10dB improvements in thresholds at 8khz(14). Further, those same four participants had clinically significant improvements in clarity of sound, doubling their word scores in a quiet background and experiencing a 20% improvement in word scores in a noisy background at 90-days post-administration(14). What’s even more exciting is that not only has the FDA has granted FX-322 fast-track status for the treatment of sensorineural hearing loss (SNHL)(15), but that Frequency Therapeutics has added a tinnitus experimental arm to their phase 2 experiment(16), which is set to be complete by late 3Q 2020. Speculation: phase 3 of drug testing “compare(s) the safety and effectiveness of the new treatment against the current standard treatment,(17)” and considering FX-322 is a first-in-class drug, it is conceivable that FX-322 could be granted conditional approval upon proving significant efficacy in phase 2 trials. If this is at all a possibility it may require effort on behalf of the sufferers to contact the FDA about this possibility.

2. Two drugs are being formulated for the treatment of cochlear synaptopathy—a condition that concerns the degradation of auditory nerve fibers termed “hidden hearing loss,” which chiefly manifests as a lack of clarity upon hearing speech-in-noise.

a. Otonomy, Inc. are currently phase 1/2 trials with their sustained-release BDNF (brain-derived neurotrophic factor) drug, “OTO-413” with results expected in the second half of 2020(18). Non-clinical studies by Otonomy “have demonstrated that local administration of BDNF repairs ribbon synapses damaged due to noise trauma or exposure to ototoxic chemicals and restores hearing function.”(19)

b. Pipeline Therapeutics has developed “PIPE-505”—a gamma secretase inhibitor that aims to regenerate “the cochlear synapse, [which] should augment signal-to-noise processing and manifest as improved speech-in-noise comprehension.”(20) Their phase 1b/2a study commenced in 4Q 2019 and the company is expecting results of the trial to be reported by late 2020.(21)

c. Of the 73 Hearing Research Program applicants vying for a Congressionally Directed Medical Research Programs (CDMRP) grant—only one company, Hough Ear Institute, was awarded the $1.9 million grant.(26) Their drug—a free radical scavenger pill ”HPN-07" passed phase 1 for safety in 2015(27) and a paper published in 2018(28) reported some remarkable findings. In a study wherein Sprague Dawley rats were induced to have permanently shifted their auditory thresholds via an open field acoustic blast insult, rats that were treated with HPN-07 plus N-acetylcysteine four weeks after the initial trauma exhibited restoration of inner hair cell (IHC) ribbon synapses.(28) Hough Ear Institute has been extremely open with their communications with tinnitustalk, with an ambassador of theirs informing us that they’ve reached a major obstacle regarding funding for entry into phase 2 trials.

References:

13. Frequency Therapeutics. (n.d.) Our Sensorineural Hearing Loss Program. Retrieved from https://www.frequencytx.com/pipeline-programs/hearing-program/

14. Frequency Therapeutics. (2020). Corporate Overview. 25-29. Retrieved from https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1

15. Park, B. (2019). FDA Grants Fast Track Status to FX-322 for Sensorineural Hearing Loss. Retrieved from https://www.empr.com/home/news/drug...tus-to-fx-322-for-sensorineural-hearing-loss/

16. U.S. National Library of Medicine. (2020). FX-322 in Adults With Stable Sensorineural Hearing Loss. Retrieved from https://clinicaltrials.gov/ct2/show/NCT04120116

17. American Cancer Society. (n.d.). What Are the Phases of Clinical Trials? Retrieved from https://www.cancer.org/treatment/tr...u-need-to-know/phases-of-clinical-trials.html

18. Otonomy. (n.d.) OTO-413. Retrieved from https://www.otonomy.com/pipeline/

19. Otonomy. (2019). Otonomy Initiating Phase ½ Clinical Trial of OTO-413 in Hearing Loss. Retrieved from https://investors.otonomy.com/news-...-phase-12-clinical-trial-oto-413-hearing-loss

20. Pipeline Therapeutics. (n.d.). Synaptogenesis. Retrieved from https://www.pipelinetherapeutics.com/science/synaptogenesis.html

21. BusinessWire. (2019). Pipeline Therapeutics Completes $30 Million Series B Financing. Retrieved from https://www.businesswire.com/news/h...peutics-Completes-30-Million-Series-Financing

26. Hough Ear Institute. (n.d.). Otologic Pharmaceutics and Hough Ear Institute Awarded Grant to Advance Cochlear Hair-Cell Regeneration Treatment. Retrieved from https://houghear.org/hei-awarded-grant-from-u-s-dept-of-defense/

27. U.S. National Library of Medicine. (2015). Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC. Retrieved from https://clinicaltrials.gov/ct2/show/NCT02259595

28. FPO. (2018). Methods For Enhancing Synaptogenesis and Neuritogenesis. Retrieved from http://www.freepatentsonline.com/y2018/0117115.html

 

Clear and concise. You rock!

 

@FGG I definitely do think you should do 1 and 2 from @mrbrightside614's suggestions, especially with number 2 as you are letting Dr. Janet Woodcock at the FDA know about the fast track status of FX-322 unless she already knows about it.

But so far your draft letter to the FDA is very good.

 

Should we attach some personal stories? Or do you guys think that would weaken the letter outside of what FGG has shared?

 

I think it would weaken the letter outside of what FGG has shared. I think her letter is detailed enough.

 

Hey guys, I haven't really looked at the letter. Will do this week. I'm not real sure where FDA reform fits in with trying to increase government funding for research. It's really downstream, but that doesn't mean that Janet Woodcock should not be informed sooner rather than later. TC

 

I think @FGG has an incredibly compelling story, and more cases may not be needed. If we do include more, we should curate carefully.

 

@mrbrightside614

I really like this quote. If there is any chance of the drug getting released into the market at Phase 3 that would be good.

 

I didn’t include Audion’s Regain because I know very little about it and wasn’t even sure if this is going through the FDA or EU regulations. Phase 2 is supposed to be wrapped in April, so this could be a legitimate contender for therapy of the year considering there’s nothing to compare it against—Shore will have phase 2 done in summer but I foresee great complications with distribution, and Frequency will have just wrapped up phase 2 by the end of the year. I know the content I provided is dense and don’t want to complicate the letter at all but I thought I should mention Audion.

As for those asking about attaching more personal stories, I think @Markku validated that there would be a way to attach co-signers to this letter instead. It would demonstrate far-reaching solidarity and not bog down the letter IMO.

Once @FGG decides what to make of my suggestion and the final draft, we can perhaps begin to formulate more letters (pending Woodcock’s response).

 

Hi everyone,

So I go back and forth on one issue with the letter and have surveyed most everyone I know and still can't decide if I should name the investigational drugs by name. I could name Otonomy and Frequency but Pipeline seems premature to mention before they have even started phase 1, since my letter mentions ("If they have shown to be safe...").

I'm also not sure about mentioning Hough because it doesn't look like they are seeking FDA approval outside of their cochlear implant indication and then hope to use it off label for tinnitus. I can't rightly plead with the FDA for quicker approval of the Hough pill for an unrelated indication in the hopes I can use it later or I don't know how to make that sound right. And just mentioning Otonomy and Frequency seems weird because they both happen to be publicly traded companies (but maybe that doesn't matter).

I'm leaning towards pushing for the general idea of safe, effective drugs being pushed through Breakthrough and Fast Track status without mentioning specific drugs by name.

This is, accordingly, how I have edited the last paragraph:

"I know from reading op-ed pieces that you are personally very committed to FDA reform to make it work better for suffering patients. I ask that you consider us with debilitating hearing symptoms in these decisions, too. For the first time in history, regenerative medicine may help us. No matter which part of the cochlea is addressed by an investigational drug: Outer hair cells, inner hair cells, cochlear synapse etc (I would be happy to discuss with you the drugs I am most optimistic about if you would like). I ask that, if any of these medications show efficacy in an important end point for hearing disorders (or surrogate endpoint) and are shown to be reasonably safe, I implore you and the FDA to help us get our lives back sooner. Many cancer drugs are approved after phase 2 through Breakthrough and Fast Track designations and for many of us, this is a matter of life or death. Please help us.

Regardless, thank you so much for the work that you do. I know you fight for so many suffering people."

 

“No matter which part of the cochlea is addressed by an investigational drug: Outer hair cells, inner hair cells, cochlear synapse etc (I would be happy to discuss with you the drugs I am most optimistic about if you would like). I ask that, if any of these medications show efficacy in an important end point for hearing disorders (or surrogate endpoint) and are shown to be reasonably safe, I implore you and the FDA to help us get our lives back sooner.“

Needs a rewrite, restructuring, ...

Probably the result of adding more and more.

I would drop the parts in parentheses.

I would not list the elements of the cochlea or various drug treatments to avoid the letter becoming too long.

Suggestion:
“If any of the hearing regeneration medications currently in clinical trials shows efficacy, irrespective of which part of the cochlea is addressed (e.g. hair cells), I implore you and the FDA to be instrumental in providing us access to this medication or making this medication available as soon as possible.”

Feel free to do as you like.

I think this is an excellent initiative. Great work

 

@FGG

You could still mention Frequency Therapeutics, maybe you can talk about FX-322 being in Phase 2a at the moment.

 

I was focusing on all hearing distortions including: tinnitus, hyperacusis, hearing loss, etc because regenerative medicine will help all 3 and all 3 are a reason for faster approval.

My gut tells me to send this letter as an individual based on the fact that it was a single Duchenne's mom who got Dr. Woodcock to help her son (and children like him) with DMD to get exon skipping drugs faster. The DMD organizations did not seem to have the same influence on Dr. Woodcock in that case. I concluded that she may respond better to personalized approaches but that's just based on my knowledge of one drug that she assisted with.

If we want a bigger umbrella, including things like bimodal devices, we can definitely follow up with a petition to maybe to the FDA at large but Dr. Woodcock is only in charge of pharmaceuticals, not medical devices.

While not being 100% of the cause of all tinnitus, hearing loss is *greatly* associated with tinnitus in the majority of cases. Even in the latest podcast, Kopke goes into that briefly.

This letter is specifically about regenerative medicine's ability to help cases of cochlear origin (the majority of cases). Is there a drug in trials you feel would be left out by this approach?

Perhaps, I should just send this one and then help with a separate petition to the FDA more generally that includes things like bimodal stimulation and brain therapies. Thoughts?

Forgot the mention, this has nothing to do with research. The FDA does not dictate research. I was just pushing for faster approval of regeneration drugs.

 

I think sending an individual letter is better because it’s more personal. Let us know when you send it. Hopefully she replies ASAP.

 

It's still not proven fixing hearing loss fixes tinnitus. I think you might be sorely disappointed if you put too much faith in that. Dr. Rauschecker knows a lot about this.

It doesn't matter if tinnitus is originally from cochlear origin, after a while the brain will remember the sound. There is no evidence plasticity will work in our favor when hearing is fixed.

 

There actually is some evidence. Cochlear implant studies for instance. And in the latest podcast, Dr. Kopke talked about tinnitus improvements in half to 2/3 of his hearing aid patients. He's a clinical otologist as well as a researcher so he actually treats patients.

On top if that, Hough says their pre clinical studies suggests in works in rodents. Frequency also mentioned in their Q and A that they saw trends (implied positive) for tinnitus in their phase 1 patients.

On top of that, people who have acute SSHL that respond to steroids find their tinnitus reduces or is eliminated too.

I would say we have a ton of evidence, actually.

 

@FGG

Definitely worth sending this letter on an individual basis. Individual stories can often have more impact. This may be one of those situations.

I, personally, would name the current drugs under development. They may end up helping only some tinnitus patients, but that is better than waiting years while no tinnitus patients are being helped. Plus, if we can get these drugs onto the market sooner rather than later, we will soon know if they work or not and for how many people and whether researchers need to go back to the drawing board. Not only this, but other people may have already contacted her already about the same subject and named the drugs.

It seems sending a letter via email in PDF format may be the best option. I'm sure you have seen the best way to layout such a letter.

Keep up the good work.

 

It's funny, I think the opposite: it's better to send this letter on behalf of 30,000 tinnitus sufferers. That makes me wonder: so far what did all organizations like ATA, Hearing Loss Association of America... do with FDA in terms of lobbying? I made a quick search, I found nothing.

 

@FGG should send her personal letter as she pleases. Entirely her effort and her decision.

Tinnitus Hub and the community can send an additional separate and more formal letter. Though it’s probably best to wait for promising results in regards to tinnitus (e.g. after FX-322 phase 2a) as this community letter would be in direct relation to tinnitus.

I think both angles are important. Personal more intimate angle and then the more general angle from a large community.

 

I really think we owe it to ourselves and the community to push full throttle at lobbying to label FX-322 “Breakthrough Therapy” if phase 2 shows the results we all hope for. I don’t have years of patience in me; these last 7 months have felt like 7 years.

How is the letter going @FGG? Could you PM me her email perhaps? When I press email on the FDA website it doesn’t register an appropriate recipient address.

Since the focus of the letter is on hearing disabilities, I think there is no harm in name-dropping NHPN-1010 and FX-322. Since the FDA has already fast-tracked FX-322 it would seem reasonable to pry as to whether conditional approval/Breakthrough Therapy labeling would be on the table if phase 2 goes well.

I truly think this drug holds more promise for treating tinnitus than it does hearing loss for a few reasons:

1. The participants who were administered the drug in phase 1 had more significant hearing loss (25-60dB @ 250Hz-8kHz) than do most tinnitus-sufferers. This would suggest:

• They probably had more support-cell depletion than people with little-to-no hearing loss.
• They likely experienced improvement in the untested frequencies above 8kHz where I believe the comparatively more intrusive/troubling tinnitus resides.

2. The drug better penetrates the base of the cochlea where HF- and UHF-associated HC’s are located.

3. A gel would not discriminate against treating the untested notches of which I believe all tinnitus is composed. I believe the reason why tinnitus sufferers have difficulty matching the exact notch wherein the bulk of their tinnitus resides is because tinnitus is a composite of many untested regions of hearing loss. The bulk of my “loss” is at 16kHz, where there is a 25dB difference in pure tone audiometry between my R & L ear, so 16kHz is my dominant tone; however, when I try to sleep I can better hear the little nuances in the sound of my tinnitus—untested damage of HC’s corresponding to 11kHz, 13,455kHz., etc. Indiscriminately sweeping all of these areas with the gel solution should correct the HC’s that its surface area contacts.

 

I agree with everything you said. I want this affliction to be over as soon as possible, for myself and all of us. We need to work together and take action in order to get the ball rolling for these therapies. I am standing by and ready to help in any way that I can!