Hearing Loss Treatment Report

www.HearingLossTreatmentReport.com

News

Neuracle Science Initiates Phase 1/2 Clinical Trial of NS101 for the Treatment of Hearing Loss

First details on NS101, a new pipeline candidate for sensorineural hearing loss (previously “undisclosed indication”), from Neuracle Science.

A new phase 1/2 clinical trial of NS101 for the treatment of hearing loss was added to clinicaltrials.gov on February 8, 2024. The trial, titled A Phase 1b/​2a, Study Evaluating the Safety, PK/​PD and Efficacy of NS101 in Healthy Volunteers and SSNHL Patients, lists a start date of January 19, 2024. The study record and public details only emerged more than a month later, however.

Here is what we know so far:

This new trial is currently recruiting participants and the sponsor, Neuracle Science, plans to enroll a total of 118 participants across 16 locations.

Important point: although the study is evaluating NS101 for SSNHL (sudden sensorineural hearing loss), the testing on healthy volunteers is not without significance. The drug’s potential applications extend beyond sudden/acute situation, and it is not limited to the “rescue therapy” category of treatment.

From the official clinical trial record (NCT06249919):

“NS101 is an anti FAM19A5 antibody expected to play as a synapse organizer and reversing synapse dysfunction in various neurological diseases.”

What else do we know about NS101—and its “regenerative” potential?

NS101 is an investigational new treatment that promotes nerve synapses and nerve regeneration. It’s being developed by Neuracle Science Co., Ltd., in collaboration with Samsung and Korean University. This broad applicability to nerve synapses and regeneration means that NS101 is also being researched to help with degenerative neurological diseases such as Alzheimer’s disease, ALS, and acute spinal cord injury. This means that NS101 may also help with other synaptopathies as well as different kinds of sensorineural hearing loss (not just the sudden sensorineural hearing loss being studied in this particular trial).

This is also supported by clues from the official trial record—note the provided keywords:

NS101 hearing loss indications trial record list
Specific keywords provided by Neuracle Science, relating to study and beyond “sudden” hearing loss.

Last year, on January 26, 2023, the company shared a press release outlining positive results of its first-in-human phase 1 clinical trial of NS101. That trial showed that the treatment had a good safety profile and “robust FAM19A5 target engagement.”

“Neuracle Science (CEO: Dr. Jae Young Seong) announced top-line results from the Phase 1 study of NS101, an investigational monoclonal antibody for the treatment of neurological diseases. NS101 binds to and neutralizes FAM19A5/TAFA5, a potential target for synaptopathy.”

At that time, Neuracle Science also shared that they planned “to initiate further clinical trials with an undisclosed indication…” Based on this phase 1/2 trial development, that undisclosed indication mentioned last year appears to have been hearing loss (plus tinnitus—but more about that later).

The Neuracle Science company website also has some more information, though its website has not yet been updated to cover the hearing loss indication(s). Note: This is not uncommon for small/private biotech companies, as they are usually too busy focusing on the research to update their pipeline snapshot. The company might post an update soon — hopefully one with a deeper dive into the mechanism of NS101 for various forms of sensorineural hearing loss.

The website has not yet been update to include the sensorineural hearing loss research angle.

http://www.neuracles.com/?version=135&spkey=5b3a3e4874f80210e3b655253439c7e702c29894&module=true&PageAccess=main/pipeline#sec01

Quick background on Neuracle Science, the company behind NS101:

According to last year’s press release, “Neuracle Science is a clinical-stage biotech company specializing in the development of new drugs for the treatment of neurological diseases.”

Here is some additional information about Neuracle Science:

Neuracle Science logo
Logo as it appears on the company website, neuracles.com.

http://www.neuracles.com/?version=135&spkey=5b3a3e4874f80210e3b655253439c7e702c29894&module=true&PageAccess=main/neuracle

What type of drug is NS101?

  • IV infusion
  • Doses = 15 mg/kg or 30 mg/kg
  • Frequency = Every second week over the course of 12 weeks
  • Participants will be followed for up to 20 weeks

In addition to testing for safety and tolerability, this study will look at whether NS101 is effective in improving hearing in people with sudden sensorineural hearing loss who have not benefited from treatment with oral steroids. This clinical trial is set up to be placebo-controlled and double-blinded.

Researchers will be looking for improvements in these outcomes:

  • Hearing capacity (via Pure Tone Audiometry, ABR, DPOAE, ECochG)
  • Speech discrimination (via SRT, SDS)
  • Tinnitus (via THI, VAS)

Looking further ahead, the anticipated completion date for the study is June 19, 2025.

Here is the link to the official study record for A Phase 1b/2a, Double-blinded, Placebo-controlled, Multiple Doses, 2 Step-up Study Evaluating the Safety, Tolerability, PK/PD and Efficacy of Systemic NS101 in Healthy Volunteers and SSNHL Patients—last updated on February 8, 2024:

https://clinicaltrials.gov/study/NCT06249919

How to get email updates on the development of NS101

If you want updates on NS101 from Neuracle Science — including the progress of this new clinical trial — sign up for the Hearing Loss Treatment Report email newsletter.

* indicates required

It’s free, your information is kept private, and you can unsubscribe at any time with a single click. As a subscriber, you get early access to “first look” updates like this one — before they are added to the front page of this website (or anywhere else).

Expect between 1-2 emails per week… but only if something interesting and treatment-related is happening.

References

https://classic.clinicaltrials.gov/ct2/show/NCT06249919

https://www.linkedin.com/feed/update/urn:li:activity:7024192632750829569/?updateEntityUrn=urn%3Ali%3Afs_feedUpdate%3A%28V2%2Curn%3Ali%3Aactivity%3A7024192632750829569%29

http://www.neuracles.com/?version=135&spkey=5b3a3e4874f80210e3b655253439c7e702c29894&module=true&PageAccess=main/neuracle

http://www.neuracles.com/?version=135&spkey=5b3a3e4874f80210e3b655253439c7e702c29894&module=true&PageAccess=main/pipeline#sec01

Phase 1b study of FX-345, new hearing loss drug candidate from Frequency Therapeutics, planned for second half of 2022

FX-345 program will “enable the company to clinically evaluate increased cochlear coverage across range of doses in multiple patient populations,” according to a recent presentation uploaded to the Frequency Therapeutics website.

Background:

FX-345 is Frequency Therapeutics’ second clinical program for sensorineural hearing loss, focused on the regrowth of sensory cells. The drug is being developed in addition to FX-322 (important distinction). Based on what we have been told so far, the big idea behind FX-345 — and its potential to restore hearing in SNHL patients — seems to be related to increased cochlear coverage. This particular aspect of the new drug candidate is repeated throughout the three-page FX-345 section of the presentation:

  • “Broad Exposure Through the Cochlea”
  • “Enables coverage of large portion of cochlea”
  • “Through Large Portion of Cochlea”

That’s the idea, anyway. But, as the presentation also points out:

  • “Clinical data will drive commercial positioning”

A good reminder and also a good reason to look forward to the second half of the year, when the phase 1 trial is slated to begin…

Sneak preview of the full presentation (pages 28 to 30):

FX-345 presentation preview

Below is a link to the full “Corporate Presentation – January 22” from Frequency Therapeutics. It is a 57-page PDF document but go to page 28 if you only want to read the FX-345 section (three pages, total):

https://investors.frequencytx.com/static-files/82a80eb8-8cd7-443b-a9c7-7c19d0d1b99d

What happens next?

For updates on the development status of FX-345 — and other promising new treatments currently in development for sensorineural hearing loss — subscribe to the newsletter (email updates). It’s free, your information is kept private and not shared or sold to third parties… no spam or sponsored content… Instead, it’s a way to get “nothing but new treatment updates”, and only when something important happens.

Frequency Therapeutics Highlights Clinical Advancement of FX-322 and Unveils FX-345, a New Potential Restorative Treatment for Hearing Loss

Frequency Therapeutics Highlights Clinical Advancement of FX-322 and Unveils FX-345, a New Potential Restorative Treatment for Hearing Loss
November 9, 2021
https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-holds-virtual-rd-event-highlighting

Comments from the CEO:
“We will also unveil two new research programs that demonstrate the potential of our progenitor cell activation (PCA) approach. First, we will introduce FX-345, a new hearing restoration candidate designed for greater distribution through the cochlea, potentially enabling the treatment of expanded SNHL patient populations.”

Highlights from the press release, copy+pasted:

“FX-345
Introduction of new SNHL investigational therapeutic program, including a more potent GSK3 inhibitor designed to achieve broader exposure of the cochlea.

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study

https://www.businesswire.com/news/home/20211021005166/en/Frequency-Therapeutics-Announces-First-Subject-Dosed-in-FX-322-Phase-2b-Acquired-Sensorineural-Hearing-Loss-SNHL-Study-and-FDA-Agreement-on-Speech-Perception-as-Primary-Endpoint

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study and FDA Agreement on Speech Perception as Primary Endpoint

Eli Lilly-Backed Audion Therapeutics Initiates Phase 2 Clinical Trial of AUD1001 (LY3056480) in Patients with Sensorineural Hearing Loss

The official record for the study, “A Phase 2 Double Blind, Randomized, Placebo Controlled Trial inVEstigating the Effect and Safety of Several Dosing Regimens of LY3056480 in Patients With STAble Sensorineural Hearing Loss”, was added to ClinicalTrials.gov on September 30, 2021.

The name of this new study is “VESTA”, the name of the drug is “AUD1001” (also known as “LY3056480”), and it is sometimes referred to as the “REGAIN treatment” for hearing loss.

aud1001 study record phase 2 teaser

Official description from the new study record (9/30/2021):

VESTA is a double blinded, randomized, placebo controlled, multi center efficacy phase 2 study comparing three dosing regimens of 250 µg LY3056480. Adult volunteers with stable mild to moderately-severe SNHL will be recruited through Adult Otolaryngology – Head & Neck Surgery Services in the US. Four injections of 250µg LY3056480 or placebo administered trans-tympanically into one ear (worse hearing ear).

Source —link to the study record:

LY3056480 in Patients with Sensorineural Hearing Loss (NCT05061758)
https://clinicaltrials.gov/ct2/show/NCT05061758

More background and context — from Audion’s website:

AUD1001 was shown to be safe and well tolerated, and provided early indications of efficacy in speech in noise, a key clinical outcome parameter. Importantly, the efficacy signals persisted a year after the treatment.

[…]

Audion is preparing for initiation of new clinical trials of AUD1001 for sensorineural hearing loss at multiple sites in Europe and in the US in H2 2021. The planned Phase 2b double blind, placebo controlled trials will be conducted in adults with demonstrated loss of clarity, using a standardized local drug delivery.

Source: https://audiontherapeutics.com/development/

More details about the AUD1001 study:

  • phase 2 study will enroll 135 participants
  • recruitment has NOT started yet
  • three recruitment locations listed so far: Illinois, New York, Virginia
  • company website mentions sites in Europe but the study record says participants will be recruited through sites in the US
  • that does not rule out Europe sites (since the study record could be updated when new sites are added in the future)
  • so, right now there is a slightly confusing inconsistency — but nothing is contradictory or set in stone

As for timeline…

  • Start Date: September 2022
  • Primary Completion Date : September 2024
  • Study Completion Date : March 2025

Keep in mind, these are Estimated dates, and subject to change.

The key date here, for most people, is the September 2022 start date.

As for when RECRUITING will begin…

Not sure yet.

But I will send out an email when the status changes from “Not yet recruiting” to “Recruiting” — as soon as I find out. Nothing to report just yet and no estimates or opinions to share.

If you are not subscribed and want AUD1001 updates, I have a strongly-biased (and very good) recommendation: subscribe to the Hearing Loss Treatment Report email newsletter. Email updates for people who want “early access” to hearing loss treatment updates — like this one about AUD1001… in many cases, before the company has had time to issue a press release! (That is what happened here.) Expect between 1-3 emails per week, on average. Sometimes none. Sometimes four. It depends. But the important thing is, issues are only sent when something exciting and new is happening. No recycled stories or press releases. No blogspam. No advertorials or sneakiness. No spam, no nonsense. Unsubscribe instantly with one click.

More AUD1001 updates to follow… including an update whenever the trial opens its doors and begins recruiting. Which, hypothetically, could be any day now.

The Hunt for Drugs That Promote Ear Hair Cell Regeneration: Nanjing University researchers use cochlear organoids to identify drugs that can promote the regeneration of hair cells

https://www.technologynetworks.com/drug-discovery/news/treating-hearing-loss-the-hunt-for-drugs-that-promote-hair-cell-regeneration-353641

The Hunt for Drugs That Promote Ear Hair Cell Regeneration

“Nanjing University researchers use cochlear organoids to identify drugs that can promote the regeneration of hair cells”

Researchers at University of Maryland School of Medicine (UMSOM) launch new online tool to advance medical discoveries to reverse progressive hearing loss

https://www.news-medical.net/news/20210719/New-online-tool-launched-to-accelerate-discoveries-for-reversing-progressive-hearing-loss.aspx

New online tool launched to accelerate discoveries for reversing progressive hearing loss

Researchers at University of Maryland School of Medicine (UMSOM) launch a new tool to advance medical discoveries to reverse progressive hearing loss.

KCNQ4 Activators as a Potential Treatment for Hearing Loss

A recently published special issue of International Journal of Molecular Science reviewed a variety of therapeutic interventions currently being studied as novel strategies to restore hearing.

One of these strategies involves the use of “KCNQ4 activators” as a way to keep the inner ear functioning properly. And according to the paper, existing drugs (or combinations thereof) that are already approved could potentially be repurposed as therapies for sensorineural hearing loss.

From the May 26, 2021 paper titled, “Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics”:

The voltage-gated potassium channel KCNQ4 has an essential role in regulating auditory function in the inner ear, by contributing to potassium recycling and maintenance of cochlear homeostasis. Reduced activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss. Rim and colleagues presented a comprehensive review of 90 publications looking at the KCNQ4 as a potential therapeutic target for the treatment of hearing loss. In this review, the authors updated the current concepts of the physiological and pathophysiological roles of KCNQ4 in the inner ear and focused on the role of KCNQ4 activators in therapeutic management of different forms of hearing loss. They propose that the simultaneous application of two activators with distinct modes of action may result in synergistic effects and reduced off-target effects. It was also suggested that drug repurposing may be an attractive option for clinical development of KCNQ4 activators as therapies for hearing loss.

Another recent paper, from three months ago (published March 2, 2021) titled, “Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss”, stated:

Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss.

The authors concluded by recommending that “KCNQ4 activators should be validated in clinical trials, as there is no ongoing clinical trial targeting hearing loss by KCNQ4 activators currently.”

But do not let the fact that KCNQ4 activators have not yet entered human clinical trials mislead you. Despite the current lack of trials, that does not automatically mean these drugs are far, far away.

Because, as the authors also pointed out earlier in the same paper: “Drug repurposing and optimization for applicable specific KCNQ4 mutation might also be an option for clinical application of KCNQ4 activators […] with advantages of reducing the cost and shortening the time when compared to de novo drug discovery.”

As far as what to keep an eye out for next, on the topic of KCNQ4, the researchers also tip us off as to which company is working on this mechanism most closely:

Acousia Therapeutics, which is a biotech company aiming for the development of small-molecule drugs for sensory neuronal hearing loss, has eight compounds targeting KCNQ4 in its pipeline.

Company website here (comment: Acousia seems to keep a low profile, so for now don’t expect to find any additional details about these eight compounds): http://www.acousia.com/

Last but not least, a fun fact.

Aside from the repurposed drugs that might hold hearing restoration potential, there is another compound related to KCNQ4 mentioned in the paper. An exotic one, as described in one of the cited papers: Subtype-Selective Activation of Kv7 Channels by AaTXKβ(2–64), a Novel Toxin Variant from the Androctonus australis Scorpion Venom.

Scorpion venom. Hmmm…

AUTHOR’S NOTE: There is something oddly reassuring about the thought of researchers from around the world leaving no stone unturned (and no tiny venomous creature unexamined) in search of a potential hearing loss cure.

A good reminder that we never know where (or from what) the next big discovery will arise. Nature is full of secrets and science is constantly uncovering these surprises…

KCNQ4 activators meme hearing loss scorpion

More updates to follow…

How to get KCNQ4 activator updates

  • Join the free email newsletter to get updates related to repurposed drugs targeting KCNQ4 (plus, news about other promising treatments in development for hearing restoration). Expect between 1 and 3 emails per week. But only when something interesting appears on the radar. No spam, no promotional emails, no third parties, and one-click unsubscribe. Privacy respected.

References

CMS121, a fatty acid synthase inhibitor, reduced hearing loss and increased preservation of ribbon synapses in the mid-range frequencies

A noteworthy abstract from The Association for Research in Otolaryngology (ARO) 44th Annual MWM held a few months ago:

Attenuation of Age-Related Hearing Loss in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated With Fatty Acid Synthase Inhibitor CMS121

Background

The senescence-accelerated prone strain 8 (SAMP8) mouse model provides opportunities to investigate potential therapies for age-related hearing loss (ARHL), the most common sensory disorder in older humans. In SAMP8 mice, oxidative stress leads to chronic inflammation, apoptosis, and premature senescence. CMS121 is a fatty acid synthase inhibitor previously shown to improve cognitive function in SAMP8 mice through anti-inflammatory and antioxidative effects in the hippocampus. Given the common cellular pathways leading to age-related dysfunction inthe hippocampus and cochlea, the aim of our study is to determine whether CMS121 is protective against ARHL in SAMP8 mice.

Methods

Auditory brainstem responses (ABRs) across six frequencies (4, 8, 12, 16, 24, and 32 kHz) were used to assess baseline hearing in sixteen 4-week-old SAMP8 mice, which were then split into age-matched groups with similar average hearing thresholds. The control group was then fed a vehicle diet, while the experimental group was fed a diet with CMS121. ABR measurements were repeated at seven, ten, and thirteen weeks of age. Cochlear immunohistochemistry was then performed using Ctbp2, GluR2, and Myo7a to analyze the number of paired ribbon-receptor synapses per inner hair cell (IHC). Descriptive statistics are provided with mean ±SEM (Standard Error of the Mean). Two-sample t-tests were performed to compare hearing thresholds and paired synapse count across the two groups, with alpha = 0.05.

Results

Baseline hearing thresholds across the six frequencies in the control group (77.5± 5.9, 59.0 ± 9.5, 44.2 ± 6.1, 47.5 ± 7.8, 36.8 ± 6.0, and 35.0 ± 7.2) were statistically similar to those of the CMS121 group (74.9 ± 2.3, 51.4 ± 3.7, 42.3 ± 3.3, 45.8 ± 5.0, 37.8 ± 4.6, and 33.3 ± 4.7.) While the control group showed progressive ARHL (hearing thresholds at 13 weeks were 84.0 ± 6.4, 63.8 ± 10.0, 56.5 ± 6.1, 64.8 ± 7.4, 37.0 ± 6.4, and 38.3 ± 6.1), the CMS121 group maintained stable hearing thresholds at 13 weeks (73.1 ± 4.0, 50.0 ± 4.5, 39.8 ± 3.8, 43.8 ± 4.4, 31.6 ± 4.3, and 35.8 ± 7.1). At that time, the control group had significantly worse hearing thresholds at 12 kHz (56.5 vs. 39.8, p = 0.044) and 16 kHz (64.8 vs. 43.8, p = 0.040) compared to the CMS121 group. Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014.

Conclusions

Our study shows a significant reduction in hearing loss and increased preservation of ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice. These findings support expanding the scope of current research on CMS121 to further investigate the promising role of this compound as a protective agent against ARHL.

Further study will be needed to explore whether CMS121 can reverse any pre-existing hearing loss. But considering how nearly all forms of hearing loss are progressive (albeit some are slower than others), a decibel saved is a decibel earned gained.

As far as mechanism is concerned, it seems to show potential in combating the damaging effects of noise-induced lipid peroxidation. But there’s likely a few things going on.

“But human trials must be years away.”

Fortunately this drug candidate has a bit of a head start, as it is being studied in Alzheimer’s disease:

https://www.sciencedirect.com/science/article/pii/S2213231720308533

That’s all for now. More information to follow.

These unfinished notes on CMS121 are for email subscribers. Sign up here.

Vinpocetine Improves Hearing in Patients with Sensorineural Hearing Loss: Results from a Phase 2 Study

New findings published in the Journal of Pharmacological Sciences outline the effectiveness of vinpocetine, a sodium channel blocker, as a treatment for sensorineural hearing loss.

“…with the use of vinpocetine, the hearing capacity improved. It is concluded that vinpocetine helps to stop hearing impairment and even improve hearing.”

Source: J Pharmacol Sci. 2021 Apr;145(4):313-318. doi: 10.1016/j.jphs.2021.01.010. PMID: 33712282.

Researchers conducted a phase 2 trial to determine if treatment with 30mg/day of vinpocetine could stop or reverse hearing deterioration in patients with sensorineural hearing loss.

Quick background from Wikipedia:

“Vinpocetine (ethyl apovincaminate) is a synthetic derivative of the vinca alkaloid vincamine. Vincamine is extracted from either the seeds of Voacanga africana or the leaves of Vinca minor (lesser periwinkle).”

Obligatory photo of the flowering plant:

periwinkle photo
“Lesser Periwinkle (Vinca minor)” (Photo credit: Ryan Kaldari)

More information:

The results, which were recently printed in the April issue of JPS, in a paper titled, “Evaluation of vinpocetine as a therapy in patients with sensorineural hearing loss: A phase II, open-label, single-center study”, appear promising.

Here is the abstract (emphasis ours):

Abstract
The progressive degeneration of the excitable cells of the ear depends on the sustained excitation of the voltage-sensitive sodium channels, so the negative pharmacological modulation could be a rational therapeutic strategy against the damage of these cells. The objective was to demonstrate the effectiveness of Vinpocetine (VPC), a potent sodium channel blocker, as a treatment for acquired sensorineural hearing loss. A phase II, longitudinal and prospective open clinical study, was conducted over a period of 12 months with patients older than 18 years, to demonstrate the effectiveness of Vinpocetine (VPC) as a treatment for acquired sensorineural hearing loss, using evoked potentials, otoacoustic emissions, audiometry and logoaudiometry, analyzing the results at 6 and 12 months of treatment with Vinpocetine (30 mg/day in 3 doses). It was observed that from 0 to 6 months there was hearing impairment (which was already expected due to the age of the patients). From 6 to 12 months and from 0 to 12 months there were significant differences with a tendency towards improvement, indicating that the aforementioned deterioration not only stopped, but that with the use of vinpocetine, the hearing capacity improved. It is concluded that Vinpocetine helps to stop hearing impairment and even improve hearing.

Link to the full-text version of the paper plus a backup link to the entry on PubMed:

Journal of Pharmacological Sciences front cover
Journal of Pharmacological Sciences (JPS) is an international open access journal that publishes research on “novel and exciting pharmacological findings.” (Source: ScienceDirect)

More information on vinpocetine will follow.

For now, here are some quick notes followed by links to further reading:

  • semisynthetic natural product
  • derived from the periwinkle plant
  • has anti-inflammatory properties
  • has the ability to modulate sodium and channel channels
  • is used as a vasodilator for cerebrovascular and age-related memory disorders
  • regulates levels of toll-like receptors
  • subject of debate, controversy, and FDA activity/memos [comment: to anyone reading this, be very careful of vinpocetine for sale on the internet. This article is not meant to suggest any treatment and especially not a do-it-yourself vinpocetine regimen. Furthermore, one of the studies I read tested supplement products that listed  vinpocetine as an ingredient… and found that many of these products actually contained no vinpocetine (and/or worse, “replacement” ingredients that were not listed on the bottle).]
  • a search for vinpocetine on PubMed shows a lot of results, quite recent too… hmmm…

Some interesting articles on vinpocetine [author’s note: this “drug” keeps getting more interesting the more I read about it…]:

Two more scientific papers, related to vinpocetine and the auditory system:

That’s all for now.

Michael Sutton

P.S. This article is a DRAFT COPY (work in progress). An early access link is provided to HearingLossTreatmentReport.com email subscribers. Not signed up? It’s free. Subscribe to the newsletter here »

P.P.S. You can email me at michael@urgentresearch.com if you have feedback/comments or just want to say hello.

Discovery of new hearing loss gene in humans [GAS2]

https://medicalxpress.com/news/2021-05-discovery-genetic-loss-illuminates-ear.html

Discovery of new hearing loss gene in humans – the first one known to affect the mechanical properties of inner ear support cells

FGF signaling system for hearing restoration

Researchers at the University of Utah’s Mansour Lab are studying the Fibroblast Growth Factor signaling pathway with the long-term goal of harnessing developmental signals to drive hearing restoration.

“Our results will contribute new knowledge to the long-term goal of harnessing developmental signals to drive hearing restoration.”

The project has received funding from the National Institute on Deafness and Other Communication Disorders (NIDCD) and will continue through January 2022.

According to investigators, the results “will facilitate future efforts to manipulate the FGF signaling system for hearing restoration.”

First, they will use mouse models to investigate the role of the Fibroblast Growth Factor signaling pathway and its critical role in the inner ear.

But the findings could uncover key development signals that could potentially be commandeered to restore hearing function.

Dr. Mansour photo
TEAM LEADER a.k.a. Professor Mansour (Photo credit: University of Utah website)

The team is being led by Dr. Suzanne L. Mansour (Molecular Biology Program – FGFs and Inner Ear Development, Mouse models of hearing loss and restoration), who has been studying these FGF signals since the early 2000s.

Here is the full abstract and public health relevance statement:

Regulation of inner ear development by FGF signals and effectors

Mansour, Suzanne L.
University of Utah, Salt Lake City, UT, United States

Abstract

Morphogenesis of the inner ear epithelium requires coordinated deployment of several signaling pathways and disruptions cause abnormalities of hearing and/or balance. With the advent of cochlear implantation to treat hearing loss even in cases of inner ear malformation, it is critical to understand exactly how such malformations affect the auditory ganglia and innervation. Also, in light of the intense focus on in vitro generation of inner ear cell types for transplantation and in vivo manipulation of developmental signaling molecules to promote differentiation of various inner ear cells for hearing restoration, elucidating the roles and regulation of such signals and their effectors governing otic differentiation and morphogenesis are necessary to advance treatment. The genes encoding FGF3 and FGF10, ligands that signal through FGFR2b and FGFR1b, are expressed dynamically throughout otic development in both epithelial and ganglion domains. Studies conducted by the Mansour Lab of both conventional Fgf3 and Fgf10 conditional knockout mice and those expressing a doxycycline-inducible ligand trap (dnFGFR2b) that rapidly inhibits signaling through both FGFR1b and FGFR2b, showed that Fgf3 and Fgf10 are not required in the placode lineage for otocyst formation, but are required subsequently for otocyst patterning, neuroblast maintenance, epithelial proliferation and both vestibular and cochlear morphogenesis. Furthermore, the first genome wide analyses of otocyst mRNA revealed FGFR2b/1b signaling targets that define novel candidates for genes involved in otic morphogenesis and function. This proposal has two Aims addressing the hypotheses that 1) FGFR2b/1b signaling is required continuously for both otic neuroblast specification and maintenance, and that at later stages, mesenchymal signaling, as well as that in the epithelial and ganglion domains, is required for cochlear epithelial differentiation and ganglion maintenance and 2) FGFR2b/1b downstream target genes mediate some or all of the effects of FGFR2b/1b signaling on otic morphogenesis and gangliogenesis. To determine the early role of FGFR2b/1b signaling in otic ganglion formation and its later role in epithelial differentiation and ganglion maintenance, DOX-induced ubiquitous and CRE-limited expression of dnFGFR2b will be employed and morphology and molecular markers of otic patterning, proliferation and survival in both tissues will be assessed. To determine the roles of downstream targets of FGFR2b/1b signaling, two genes encoding transcription factors that are activated by FGFR2b/1b signaling and one gene encoding a BMP signaling regulator that is repressed by FGFR2b/1b signaling will be studied. Otic conditional mutants will be generated for each gene, and their morphologic and functional development will be assessed. In addition, the extent to which the BMP regulator contributes to the dnFGFR2b phenotypes and the effects of overexpressing the BMP regulator will be assessed. The results will contribute new knowledge that will facilitate future efforts to manipulate the FGF signaling system for hearing restoration.

Public Health Relevance

Permanent hearing loss caused by malformation of the inner ear or congenital or progressive loss of its sensory or neural cells affects up to one third of individuals by the age of 80 and generates significant social and healthcare costs. In this proposal, we use mouse models to investigate the role of the Fibroblast Growth Factor signaling pathway in forming the inner ear epithelium and neurons. Our results will contribute new knowledge to the long-term goal of harnessing developmental signals to drive hearing restoration.

For updates on Mansour’s FGF signaling system (and other hearing restoration research/treatments) sign up for free email updates (our newsletter) here.

References

Project #: 1R01DC019127-01

UC-Irvine researchers studying nicotine-like drugs to improve hearing and restore auditory function

Researchers at University of California-Irvine are testing the effects of nicotine to see if it will reduce or reverse auditory decline.

The research is part of a new project funded by the NIA division of the U.S. National Institutes of Health.

The project was recently awarded $640,473 in grant money for 2021 to determine, in humans and mice, whether nicotine’s effects can restore auditory function.

It began a few months ago and will continue until at least the end of 2021. (If successful, it could continue to receive more funding every year, until the end of 2025.)

Worth pointing out: nicotine, in this context, is NOT related to tobacco, smoking, or vaping. This is some sort of pharmaceutical nicotine, apparently:

“Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs … These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally.”

And, according to the project description, a positive outcome “will facilitate the translation of nicotine-based therapeutic treatments for hearing loss to clinical populations.”

Here is a shortened version of the project Abstract and Public Health Relevance Statement (formatting and emphasis ours):

Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing.

The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits.

Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking.

We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline.

We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics).

  • Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms.
  • Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG.

This project features a multifaceted, parallel approach in mouse and human. Each Aim will:

  1. examine auditory processing at multiple adult ages;
  2. use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms;
  3. test the effects of nicotine.

A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.

nicotine for hearing improvement grant screenshot
Image source: HHS Tracking Accountability in Government Grants System (TAGGS), 5/1/2021

Public Health Relevance Statement

Nicotine enhances auditory and cognitive functions because it mimics the brain’s system for “paying attention” to important sounds amid distractions (for example, understanding speech in a noisy environment). In part, nicotine does this by activating inhibitory neurons in the auditory cortex. Since age-related hearing deficits result in part from the loss of inhibitory neurons, this project will determine, in humans and mice, whether nicotine’s effects can compensate for reduced inhibition in aging and thereby restore auditory function.

For some more background on the science and theory behind nicotine and hearing, here is a good paper from last year:

Nicotine Enhances Auditory Processing in Healthy and Normal-Hearing Young Adult Nonsmokers March 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039769/

Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

The UC Irvine project described in this post is part of the story. There is also a separate project, also at UC Irvine, titled, “Nicotinic enhancement of auditory-cognitive processing.” (Also awarded a grant worth over $600,000.)

From the project narrative section of the description:

The drug nicotine enhances auditory-cognitive function because it “hijacks” the brain’s endogenous system for directing attention to important sounds (for example, understanding speech in a noisy environment). This project seeks to determine if one kind of nicotine receptor (a2 subtype) and one kind of neuron (VIP) in two key regions of the cerebral cortex (auditory cortex and prefrontal cortex) play essential roles in nicotine’s effects. The long-term goal is to understand brain mechanisms of auditory processing and guide development of novel drug treatments for auditory-cognitive disorders.

We will be following this research and these nicotine/hearing improvement projects and posting updates as important milestones are met.

This article is an unfinished draft and a work in progress. You are accessing it early because this not-yet-public link is sent to email subscribers.

References

Exported on 05/01/2021 from the HHS Tracking Accountability in Government Grants System (TAGGS), http://taggs.hhs.gov, Project Number 1R01AG067073-01A1

DB-301: Update on Decibel Therapeutics’ cochlear hair cell regeneration program for hearing loss

An unofficial update on Decibel Therapeutics’ secretive gene therapy program to treat sensorineural hearing loss by regenerating cochlear outer hair cells…

First, the official story, followed by a big “unofficial” update on “DB-301″…

Officially:

Laurence Reid, CEO of Decibel Therapeutics, had this to say during a recent presentation at the 20th Annual Needham Virtual Healthcare Conference – from April 15, 2021:

Laurence Reid: We have an earlier stage program with respect to the cochlea. The goal is to drive differentiation of the supporting cell, through an immature hair cell, and then on particularly to either generate the outer hair cell or potentially the inner hair cell – for treating different types of patient populations with different cellular bases for their hearing loss.

Here is a slide from the presentation:

Officially, we also have some background information thanks to a recent Decibel Therapeutics, Inc SEC filing (emphasis ours):

Cochlear Hair Cell Regeneration

Age-related hearing loss and noise-induced hearing loss affect millions of people in the United States and Europe. Research has shown that the degree of hearing loss in these populations is best predicted by the amount of outer hair cell loss. We believe that restoring outer hair cells could restore hearing in these individuals. In our cochlear hair cell regeneration program, we are designing an AAV-based gene therapy that utilizes cell-selective expression of reprogramming factors to convert supporting cells into outer hair cells. We are currently conducting preclinical in vitro and in vivo rodent studies to evaluate the cell-selectivity of certain proprietary promoters and the ability of certain reprogramming factors that may drive an outer hair cell fate.

In that same filing, we learn that Decibel Therapeutics plans to announce the targets for this cochlear hair cell regeneration program in 2022. Excerpt and pipeline snapshot:

In addition, we are advancing our cochlear hair cell regeneration program to treat acquired hearing loss by regenerating cochlear outer hair cells. We plan to announce the targets for our cochlear hair cell regeneration program in 2022.

Deceibel Therapeutics 2022 cochlear hair cell regeneration program target date

However, we might not need to wait until 2022 for that update, because…

Unofficially:

Our independent research has uncovered what appear to be details related to Decibel’s “Cochlear Hair Cell Regeneration Program” (a.k.a. the gene therapy program which could potentially be given the name “DB-301”)…

“DB-301”?

That’s our unofficial code name, inferred from Decibel’s naming scheme (“AAV.RF301” or “AAV.301” + “DB” = DB-301).

From a Decibel Therapeutics corporate overview presented during Citi’s 15th Annual BioPharma Virtual Conference:

Possibly DB-301 Decibel Therapeutics

As you can see, this slide looks like a perfect match for the cochlear hair cell regeneration program. (Which is why we’re calling this an “early update” on the program.)

Confidential?

The presentation has the word “confidential” written on page 19.

However, the source of this information – a PDF document – is currently available on Decibel’s website. (It is indexed by search engines and accessible to the public. We have archived it digitally as well, for record-keeping purposes.)

But Wait There's More meme
Was the information below included in the presentation on purpose? or accidentally? Hmmm…

Intentional?

Furthermore, within this PDF – on page 19, in very, very, very tiny text – is a list of what appear to be outer hair cell candidate targets (copy+pasted):

Hdac3 Kdm4a Mtpn Htatip2 Dnmt3a Mlxip Foxo3
oxn3 Prnp Sall1 Pknox2 Klf9 Rora Six2 Trps1 Actn4 Mef2a Pdcd11 Nfkb1 Hlcs Zfp410 Banp Zbtb7b Esrra E2f3 Zfp740 Zkscan3 Creb3l1 Ighm Zfp324 Arnt Lig1 Elk3 Zbtb40 Crem Smarca2 Nfatc2 Rest Nfib Zfp608 Nfix Smad7 Mafk Adarb1 Irf6 Nacc2 Rorb Bhlhe40 Ikzf2 Jun Zfp423 Nr3c1 Tppp Cat Zfp637 Zfp777 Kmt2a Nr2f2 Zfp592 Pura Zfp365 Zbtb46 Zfp654 BC005561 Zfp516 Cic Zhx3 Rxra Zfp106 Zfp277 Thra Tmem33 Zc3h7a Srrm3 Pds5a Zbtb4 Ube2k Ctbp2 Id4 Srebf1 Nfat5 Ddit3 Sall3 Mdm2 Srebf2 Gtf2i Prdx5 Smap2 Zbtb7a Zfp618 Gata3 Irf9 Mef2d Taf1 Zfp523 Kdm2a Abcf2 Zfp398 Zfp638 Hmg20a Msi2 Nmral1 Tead1 ead2 H2afy Irx3 Ezh2 Rfxap Sox9 Tgif2 Egr4 Egr3 Npas4 Sox11 Fhl2 Prox1 Sox2 Cers2 Gm10093 Dazap1 Dnajc21 Isl1 Ran Ebf1 Atoh1 Hes6 Rpl35 Rps10 Psma6 Akr1a1 Barhl1 Smarca5 Ruvbl1 U2af1 Gtf2a2 Zfp428 Ssbp3 Zfp326 Nuak1 Pknox1 Cyb5r1 Tceal5 Msra Cers6 Zmat4 Bcl11b Npdc1 Bcl2 Ybx1 Stub1 Zmat2 Zfp667 Yeats4 Tfdp2 Hnrnpa1 Tfdp1 Rbm17 Hmgn3 Lhx3 Cers4 Ugp2 Bax Mrps25 H1fx Nap1l1 Pax2 Traf4 Mcm6 Neurod6 Rab2a Cd59a Ptcd1 Klf7 Las1l Cdk2ap1 Mycl Nono Zfp330 Insm1 Irx2 Id1 Id2 Magoh Nr2f6 Zbtb20 Diablo Gar1 Snrpb2 Rps4x Zmiz1 Hnrnpc Nr2f1 Rbpj Lsm6 Hmgb2 Tbpl1

Is this a short list of targets that Decibel is planning to choose from and announce in 2022?

Time will tell.

But, taken together, all this information leads us to believe that Decibel Therapeutics could have an earlier update for us about all these “unofficial” details (including the name “DB-301”, which is just one possibility).

References

https://wsw.com/webcast/needham107/deci/2205522

http://www.decibeltx.com/wp-content/uploads/ARO-2021_Inner-Ear-Tropism_Poster-1.pdf

https://www.sec.gov/Archives/edgar/data/1656536/000156459021016167/0001564590-21-016167.txt

http://www.decibeltx.com/wp-content/uploads/Decibel-Corp-Overview-Q320-CITI-conference.pdf

COMMENT: This article was made available to email subscribers several days early. If you want early access to updates like this one, join the email updates list. It’s free, no spam, and your information is kept private.

AOK-1 for hearing loss: a new regenerative drug from Hough Ear Institute

Hough Ear Institute is developing a new drug that uses RNA technology to regenerate inner ear hair cells and restore lost hearing.

AOK-1 siRNA therapeutic from Hough Ear Institute slide
The source of this information is a video recording of a meeting between Hough Hearing Institute CEO Dr. Richard Kopke and members of the Central Oklahoma Chapter of the Hearing Loss Association of America. The recording was uploaded to YouTube and shared with the public on April 15, 2021.

The name of the drug is AOK-1.

Unlike Hough’s first drug, NHPN-1010, AOK-1 is not a pill.

Instead, it is an injection.

And the way it works is equally different.

New: Breakthrough Number Two from Hough Crew

The Hough pill aims to restore hearing by repairing and reestablishing the connections to hair cells. It is designed to rescue or salvage “stranded” sensory cells.

This AOK-1 injection, on the other hand, aims to restore hearing by regenerating, repairing and regrowing the sensory cells themselves. Perhaps even from virtually scratch.

The dream? That AOK-1 could someday give hearing to people affected by even the most severe forms of noise-induced hearing loss.

“…like releasing a ‘parking brake’ on the regenerative process”

Hough Ear Institute CEO Dr. Richard Kopke recently shared the first details on AOK-1, including the big idea behind its mechanism.

From the video (transcribed and lightly edited for clarity and brevity):

The next technology is the one that is injected into the ear and we call it AOK-1. And it’s a regenerative therapeutic. It’s a regenerative drug and it’s an RNA technology. It’s an RNA molecule that eliminates a protein that keeps the hair cells from regenerating in the cochlea. So it’s like a parking brake on the whole regenerative process in the cochlea. When we get rid of that protein, then the hair cells can generate.

In short, AOK-1 is being developed to awaken the human body’s innate ability to repair and regrow its lost or damaged inner ear hair cells. The same way many animals, including birds, frogs, and fish, can naturally regenerate lost sensory cells and hearing. AOK-1, a small interfering RNA achives this by interfering with the protein that is responsible for keeping this regenerative power “asleep” in humans.

A “same-day” hearing restoration procedure?

Dr. Richard Kopke also explained how the drug is being designed as an outpatient “same-day” procedure. It does not require an overnight stay at the hospital. Rather, you get it and go home shortly after. The procedure involves some numbing drops for the ear drum, followed by a minimally invasive injection of thermosensitive hydrogel that contains the active drug.

This delivery method is discussed during the presentation:

AOK-1 injection delivery method photograph

Importantly, the science appears to be getting there. In vivo animal model experiments are showing lots of promise. (The research behind AOK-1, by the way, is supported by a $1.9 million Department of Defense CDMRP grant.)

AOK-1 before and after

And although AOK-1 is still in preclinical development, Dr. Richard Kopke concluded his presentation with a “hint” at the possibility of upcoming human clinical trials…

His exact words:

Currently we’re under talks and negotiations with another pharmaceutical company that would like to take this technology, license it, and bring it to the clinic. It seems to be a robust, reproducible technology that restores hearing.

The full presentation from Dr. Richard Kopke is available on YouTube: March 2021 – Hough Institute Breakthrough – Member Meeting (uploaded on April 15, 2021). The AOK-1 part of the presentation starts at the 33 minutes, 56 seconds (33:56) timestamp.

For updates on the progress of AOK-1 and its progress toward human studies, subscribe to our free email newsletter (updates).

For those of you who are eager to dive deeper into the science behind AOK-1, here are links to the original research papers:

References:

Source: Hearing Loss Association of America – Oklahoma Central Chapter. (2021, April 15). March 2021 – Hough Institute Breakthrough – Member Meeting [Video]. YouTube. https://www.youtube.com/watch?v=WCed87H92S4

Acknowledgements: Credit belongs to reddit user u/filleorange for finding and sharing the link to this informative video. (When it was first posted to reddit, the video only had a measly 4 views!)

Comments? Questions? Feedback?

Send an email to:

michael@hearinglosstreatmentreport.com

… and say hello!

Rinri Therapeutics Raises £10 million to Advance its Novel Stem Cell Therapy to Reverse Sensorineural Hearing Loss

https://www.prnewswire.com/news-releases/rinri-therapeutics-raises-10-million-from-existing-investors-and-uk-future-fund-to-advance-its-novel-stem-cell-therapy-to-restore-hearing-loss-301271469.html

Rinri Therapeutics Raises £10 million from Existing Investors and UK Future Fund to Advance its Novel Stem Cell Therapy to Restore Hearing Loss

Rinri Therapeutics Raises £10 million to Advance its Novel Stem Cell Therapy to Reverse Sensorineural Hearing Loss

The proceeds will support the development of the Company’s novel stem cell therapy to reverse sensorineural hearing loss (SNHL).

NLRP3 inhibitors such as Oridonin may provide new treatment strategy for noise-induced hearing loss

Some research that appeared on our radar recently: “Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 – NEK7 mediated inflammasome activation” (March 23, 2021).

Link to the paper:

https://www.sciencedirect.com/science/article/pii/S1567576921002125

Excerpt:

Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.

see it's simple toy story meme hearing loss oridoninWhat does that mean?

Here is an extremely loose – but simple – explanation of what this means:

  • inflammation is involved in noise-induced hearing loss (NIHL)
  • we aren’t sure how, exactly
  • but it seems that… sometimes… inflammation can go way too far
  • which might actually make things worse, or interfere with healing
  • this could be what happens in the ear after acoustic trauma
  • we aren’t sure about that either
  • but according to this theory…
  • maybe a drug that keeps the inflammation process from going way too far…
  • … might also help with the healing process and prevent further damage
  • (by making sure inflammation does not get carried away)
  • this might apply in the context of noise-induced hearing loss
  • Oridonin, anakinra are two drugs worth studying for this
  • but we aren’t sure… yet

Now, for those of you who prefer the nitty gritty details… diving deep into the science… and the technical side of things…

Here is some further reading about Oridonin – “a covalent NLRP3 inhibitor with strong anti-inflammasome activity” – from Nature:

https://www.nature.com/articles/s41467-018-04947-6

From that paper:

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases.

Hmmm…

(I wonder if it has anything to do with osteoclasts…)

That’s all for now.

Estimated PIPE-505 Phase 2a Study Completion Date: June 12, 2021

Short but sweet update:

We now have an estimated completion date for the PIPE-505 phase 2a clinical trial: June 12, 2021.

Details below:

  • The PIPE-505 study record was updated on March 29, 2021.
  • The study completion date was changed from March 2021 [Anticipated] to June 2021 [Anticipated].
  • The June 12, 2021 date [Estimated] was calculated using information found within the study record and its history of changes, including: a) the submission date on which the Study Status was changed from “Recruiting” to “Active, not recruiting” and, b) the maximum follow-up Time Frame (“3 months after drug administration”) as detailed in the Outcome Measures section.
  • For a more conservative completion date, replace the last submitted update to Study Status date with the more recent last submitted update date of March 26, 2021. This gives us June 24, 2021.
  • Taken together, we are looking at a range of June 12 – June 24, with June 12th as the one to mark on your calendar.

PIPE-505 phase 2 completion date

Source: History of Changes for Study: NCT04462198 (Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss)

That’s all for now.

We will probably have the next PIPE-505 update for you before June 15th (and/or whenever Pipeline Therapeutics makes an announcement).

For ongoing PIPE-505 updates and news of other upcoming hearing loss treatments, sign up for the free email newsletter. No spam, no promotional emails, privacy respected. Between 1-3 emails per week (but only when something interesting is happening).

BREAKING: CGF166 Clinical Trial Results Posted Online…

CGF166 update: Results from the phase 1/2 study of the hearing loss drug are now available.

Developing story…

CGF166 has results clinical trial update

Two days ago, on March 30, 2021, the official study record of CGF166 was updated on ClinicalTrials.gov.

This update was not accompanied by a press release from Novartis nor any media coverage.

However, this “surprise” update had two important words: has results.

An unexpected update

These results came out of nowhere…

For anyone learning about CGF166 for the first time, here is some quick background info on the “mysterious” Novartis gene therapy drug candidate for hearing loss:

A Case Study: Using Regenerative Medicine to Treat Hearing Loss

In 1999, scientists singled out a gene called atonal as a “master switch” for turning on the growth of inner ear hair cells, which pick up sound waves and translate them into electrical signals in the brain. Humans are born with hair cells, but the atonal switch flips off at birth. Any subsequent damage to hair cells is permanent.

In collaboration with a biotech company, GenVec Inc, NIBR researchers have developed an experimental gene therapy called CGF166 to restore hearing function by regenerating hair cells. It consists of a viral vector carrying the atonal gene. The vector has been altered with the aim of making it harmless and is injected directly into the inner ear. CGF166 is now being tested in a limited number of patients with severe-to-profound hearing loss.

SOURCE: an old brochure from the Novartis Institute for Biological Research (NIBR), circa 2016.

Sounds promising, right?

Absolutely.

But that material was written 5 years ago and… since then – aside from the early buzz and media coverage on this holy grail treatment – CGF166 updates have been incredibly rare.

In fact, before today… the last credible update we got on CGF166 was from over a year ago when, on February 21, 2020, BioCentury pointed out that Novartis had “yet to publicly report data from its Phase I/II trial of gene therapy CGF166.”

SOURCE: Regenerative medicine for hearing loss makes quiet progress, BioCentury, https://www.biocentury.com/article/304491, dated February 21, 2020.

Well, now it looks like they (quietly) have.

The results were uploaded to the study record of the phase I/II clinical trial. Here is the official description:

The goal of the study was to evaluate the safety, tolerability, and the potential ability of CGF166 delivered through IL-infusion to improve hearing. CGF166 is a recombinant adenovirus 5 (Ad5) vector containing a cDNA encoding the human Atonal transcription factor (Hath1).

This study evaluated the safety, tolerability, and potential efficacy of CGF166 and the associated delivery procedures in patients with severe-to-profound unilateral or bilateral hearing loss. Eligible patients were required to have documented, non-fluctuating hearing loss.

SOURCE: https://clinicaltrials.gov/ct2/show/NCT02132130, last updated March 30, 2021.

CGF166 study results: Part 1

These results do not show all the data and numbers, but we expect to post a follow-up once we have some experts review them.

Here is the direct link to the study results that were uploaded on March 30, 2021: ClinicalTrials.gov Identifier: NCT02132130 – Study Results

It’s important to keep in mind that these results are NOT the same thing as an announcement or press release from the company. For that reason, there is no accompanying commentary or explanation of what these results mean.

CGF166 results sneak preview confusion emojiThis can be frustrating, but here at Hearing Loss Treatment Report we are currently working on a follow-up post that will provide a clear idea of what these numbers mean for people with hearing loss.

This is a developing story…

I wish we had more for you.

This is all we have, for now.

We will continue to monitor what is happening with CGF166 and post an update as soon as we know more. (The best way to get updates is by subscribing to our email newsletter – which we’ll be sending out very soon!)

cgf166 trial results meme

For now, we decided to share the link to these “raw” results because we believe in sharing early and sharing often. Information ASAP. Before the official press releases, before company Twitter announcements, before the media outlets, before before before.

And so, for that reason, we didn’t want to sit and wait on this long-awaited study result update just so we could organize it into a neatly-wrapped package with in-depth commentary.

That’s not our style.

“First”

The reason we believe in this post-first-question-later approach is because an increasingly large number of patients, organizations, and industry professionals use this site as a shortcut to the very latest hearing loss treatment updates.

Think of this site like a secret source of some of the fastest, earliest updates in the world of hearing loss drug development. And it’s meant to help inform people in situations like this: where this CGF166 phase I/II results story was missed, ignored, or simply too early (and thus unknown) to the mainstream media.

Which is also why you might want to subscribe to our email updates list… so you can get as-fast-as-we-can-find-them updates on experimental hearing restoration drugs and milestones… plus, sneak previews of what potential “cures” are really around the corner in 2021, 2022, and beyond…

But it’s not for everyone.

Questions? Comments? Corrections? Feedback:

Send an email to michael@urgentresearch.com and say hello.

HLAA to Hold Patient-Focused Drug Development Webinar for People and Families Living with Sensorineural Hearing Loss (April 8)

HLAA Webinar: Externally-Led Patient-Focused Drug Development Meeting for People and Families Living with Sensorineural Hearing Loss

Patient-Focused Drug Development Meeting led by HLAA

This one-hour webinar will provide an overview of the FDA drug development process as well as the value of Patient-Focused Drug Development (PFDD) meetings. We hope this webinar will spike your interest in being part of this important virtual meeting for the hearing loss community taking place on Tuesday, May 25, 2021.

HLAA to Hold Patient-Focused Drug Development Webinar and Meeting

Externally-Led Patient-Focused Drug Development Meeting for People and Families Living with Sensorineural Hearing Loss

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies

https://www.businesswire.com/news/home/20210323005208/en/Frequency-Therapeutics-Releases-New-Data-from-Two-FX-322-Clinical-Studies-Plans-to-Advance-Single-Dose-Regimen

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies; Plans to Advance Single-Dose Regimen
Interim FX-322 Phase 2a Results Show Four Injection Schedule Had No Discernible Hearing Benefit

Separate FX-322 Phase 1b Study Confirms Hearing Improvement from Single Injection

Conference call at 8:30am ET today

VEGF-A165 restores vascular function to the inner ear and could potentially reverse common forms of hearing loss…

Could improving poor blood supply to the damaged inner ear reverse noise-induced and/or age-related hearing loss?

Yes, according to some fascinating new research from Zhang et al, published yesterday on March 9, 2021, that describes a unique approach to hearing restoration that is backed by “clear-cut evidence”…

VEGF-A165 article screenshot
This VEGF-A165 research paper is hot off the press!!!

Here is a link to a full-text PDF copy of the paper (and all the science-y details):

VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss [PDF]

Sneak preview of the abstract:

When hearing loss is caused by noise or aging, it is often associated with breakdown of the barrier between the cochlea and its blood vessels. Pericytes populate many small vessels in the adult inner ear, however, their role in different forms of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model, we show that loss of pericytes leads to marked changes in vascular structure, resulting in poor blood circulation and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models in combination with exogenous donor pericytes, we show pericytes, signaled by endothelial growth factor isoform A165 (VEGF-A165), vigorously drives new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1 (AAV1)-mediated VEGF-A165 viral vector to pericyte depleted animals regenerated lost pericytes, improved blood supply, reduced loss of sensory hair cells, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for adult hearing and can regenerate cochlear vasculature. The restoration of vascular function in the damaged inner ear with AAV1-mediated VEGF-A165 gene therapy is a new strategy for ameliorating vascular associated hearing disorders, including common forms of age-related hearing loss.

SOURCE: Zhang et al. Published March 9, 2021. JCI Insight 2021. https://doi.org/10.1172/jci.insight.143285.

That’s all for now.

The Hearing Loss Treatment Report system will be monitoring the scientific literature and news for any further mentions of VEGF-A165… including any progress it makes toward that first big milestone: human clinical trials.

We don’t have a timeline for you (yet)… but you can expect some follow-up coverage in the coming weeks/months.

Stay tuned.

RE: how to get VEGF-A165 updates

To follow what’s happening with VEGF-A165 (as well as other treatments such as FX-322, OTO-413, PIPE-505), I encourage you to sign up for Hearing Loss Treatment Report email updates. These updates are 100% free… your information is kept private, and… you won’t get any spammy marketing emails or promotional emails. That’s a promise. Instead, you will only receive important (and often exclusive) updates related to up-and-coming hearing loss treatments and scientific breakthroughs.

Questions? Comments? Feedback?

Send an email to michael@urgentresearch.com and speak your mind.

I read every email and try my best to reply (thoughtfully) within 1-2 days.

P.S. Do you like these “exclusive” update posts?
Kindly share them with people you know who might find them interesting.

Research center at Creighton University awarded $10.8 million NIH grant to help researchers discover new drugs for hearing loss

https://www.newswise.com/articles/translational-hearing-center-awarded-largest-nih-grant-in-creighton-university-history

Translational Hearing Center awarded largest NIH grant in Creighton University history
NIH grant to help researchers translate basic hearing loss research into practical therapies

Research center at Creighton University awarded $10.8 million NIH grant to help researchers discover new drugs for hearing loss

Frequency Therapeutics Announces Publication of FX-322 Phase 1/2 Data Showing Hearing Improvements in Sensorineural Hearing Loss Patients

https://www.businesswire.com/news/home/20210222005818/en/Frequency-Therapeutics-Announces-Publication-of-Phase-12-Data-Showing-Hearing-Improvements-in-Acquired-Sensorineural-Hearing-Loss-Patients-Receiving-FX-322

Frequency Therapeutics Announces Publication of Phase 1/2 Data Showing Hearing Improvements in Acquired Sensorineural Hearing Loss Patients Receiving FX-322
Results Published in Leading Peer-Reviewed Otolaryngology Journal, Otology & Neurotology

Statistically Significant Improvements Observed in Word Recognition Tests in Quiet and in Noise; Suggests Potential to Improve Speech Intelligibility, a Major Unmet Need for Individuals with Hearing Loss

Company Expects Interim FX-322 Phase 2a Study Data Later this Quarter

https://journals.lww.com/otology-neurotology/Abstract/9000/Improved_Speech_Intelligibility_in_Subjects_With.95768.aspx

Sensorion Presents New Preclinical Data on SENS-401 at ARO 2021: significant treatment benefits in rats with severe hearing loss when initiated within 7 days of acoustic trauma

https://www.businesswire.com/news/home/20210218006082/en/Sensorion-Presents-New-Preclinical-Data-on-SENS-401-at-ARO-2021

Sensorion Presents New Preclinical Data on SENS-401 at ARO 2021
SENS-401 yields significant treatment benefits in rats with severe hearing loss when initiated with a delay up to 7 days after the initial acoustic trauma
Sensorion presenting three posters at Association for Research in Otolaryngology (ARO) meeting
ARO will be hosted virtually on February 20-24, 2021

OTO-413 Phase 1/2 trial expansion in hearing loss expected to start in Q2 2021 with results anticipated in mid-2022

https://www.globenewswire.com/news-release/2021/02/11/2174562/0/en/Otonomy-Reports-Fourth-Quarter-and-Full-Year-2020-Financial-Results-and-Provides-Corporate-Update.html

Otonomy Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Corporate Update

February 11, 2021 16:17 ET | Source: Otonomy, Inc.
OTIVIDEX® Phase 3 trial results in Ménière’s disease expected by end of February
OTO-313 Phase 2 trial in tinnitus planned to start in first quarter of 2021 with top-line results expected in mid-2022
OTO-413 Phase 1/2 trial expansion in hearing loss expected to start in second quarter of 2021 with results anticipated in mid-2022

New pill [SPI-1005] that may help improve age-related hearing loss by protecting delicate hair cells in the inner ear

https://www.dailymail.co.uk/health/article-9238361/New-pill-help-hear-clearly-protecting-delicate-hair-cells-inner-ear.html

New pill that may help improve age-related hearing loss by protecting delicate hair cells in the inner ear
A new drug, SPI-1005, aids hearing by protecting delicate hair cells in inner ear
It is also being tested in U.S. as a potential treatment for patients with Covid-19
The number of auditory hair cells declines due to age, disease and loud noise

PREVIEW: “Preclinical/Clinical Translational Evidence for a Potential Hearing Restoration Therapeutic, FX-322” [ARO 2021 Podium Presentation]

Here is a sneak preview of an upcoming podium presentation from Will McLean (Frequency Therapeutics) about hearing restoration and FX-322:

FX-322 podium abstract for ARO February 2021

What’s happening:

In less than two weeks from today, the 44th Annual ARO MidWinter Meeting will begin.

It is a virtual conference.

On Monday, February 22, 2021, Will McLean (Frequency Therapeutics) will give a podium presentation at this virtual conference.

Topic? FX-322…

Here is a copy of McLean’s podium abstract:

Preclinical/Clinical Translational Evidence for a Potential Hearing Restoration Therapeutic, FX-322

Background: Cochlear hair cell loss in mammals is permanent because progenitor cells fail to divide and differentiate on their own. Previous work has shown that the two compounds in FX-322 enhance the regenerative potential of mouse and human progenitor cells in vitro. This multi-group collaboration assessed the pharmacodynamic (PD) and restorative potential of FX-322 in a mouse noise-induced hearing loss (NIHL) model, cochlear pharmacokinetics (PK) of intratympanically injected FX-322 in guinea pigs, perilymph concentrations in patients undergoing cochlear implantation, and a safety study of FX-322 in patients with permanent sensorineural hearing loss (SNHL).

Methods: PD effects were first assessed in a NIHL mouse model to assess the therapeutic potential of FX-322. PK studies with FX-322 were performed in guinea pigs to calibrate a well-established computer model predicting drug distribution over the length of the cochlea with time. The animal PK model was extended to humans by analysis of perilymph samples collected from subjects undergoing cochlear implant surgery. A double-blinded, placebo-controlled, safety trial in patients with permanent/stable SNHL was conducted to assess the systemic safety, plasma PK, and effects on otoscopy, audiometry, and word testing (WR, WIN). The trial enrolled 23 patients with medical histories consistent with either NIHL or sudden SNHL. Treatment was a single unilateral intratympanic dose and patients were monitored overnight for safety, PK and PD over a 90-day period.

Results: Animal PD – A single intratympanic injection of FX322 was associated with increased hair cell counts and improved auditory function compared to placebo in mice with NIHL within one month after treatment. Guinea Pig PK – FX-322 concentrations in samples taken from the RW niche were found to decrease with time, with elimination half-times under 1 hour. The highest drug concentration was observed in the basal regions. Human PK – Intraoperative middle ear contents and perilymph were analyzed for FX-322 approximately 1 hour into surgery for cochlear implant subjects (n=7). While some subjects had anatomical features that have been speculated to impair drug entry, such as mucosal folds or bony overhangs, FX-322 was quantified in all samples analyzed. Human Safety and PD – FX-322 was associated with a favorable safety profile. In FX-322-treated subject ears WR and WIN improved over the duration of the study while placebo-treated subject ears did not.

Conclusions: Both preclinical and clinical PK analyses suggest that FX-322 was able to achieve therapeutically active levels in the extended high frequency region of the cochlea. Preclinically, this was associated with an increase in hair cell counts and auditory brainstem response thresholds. The present work provides the first evidence that a novel potential therapeutic, FX-322, is associated with clinically meaningful improvements in speech recognition in subjects with permanent and stable SNHL, and larger clinical studies are underway.

The source of this “podium abstract” is the Association for Research in Otolaryngology (ARO)’s 44th Annual Mid-Winter Meeting event website.

Here is a link to the official PDF copy of the February 22, 2021 FX-322 podium presentation [EDIT #1: the link does not work, removed] (uploaded online by ARO’s event organizers… who have once again done a superb job organizing all of the presentations, speakers, podiums, posters, and more, into a friendly and searchable format *even when some links don’t work!).

What’s “new” here?

For readers who have been closely following FX-322 updates… there is nothing truly “new” in this presentation preview. However, we do not know what other data or information or announcements will be shared alongside this presentation. Perhaps we will also get a press release on Monday, February 22 which gives us more substantial “news” *fingers crossed*…

RE: FX-322 updates…

If you’re interested in news updates RE: the very latest hearing loss treatments and recent progress toward potential cures… remember to sign up for the HearingLossTreatmentReport.com email newsletter. It’s 100% free and the goal is to give you an easy (and fast) way to get updates about FX-322 and other promising hearing restoration therapeutics – earlier… often days (and sometimes weeks) ahead of “mainstream” sources.

Questions? Comments? Feedback? Send an email to michael@urgentresearch.com and say hello.

Frequency Therapeutics appoints Chief Manufacturing Officer as it prepares for larger studies in support of lead FX-322 program

https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-appoints-quentin-mccubbin-phd-chief

Frequency Therapeutics Appoints Quentin McCubbin, Ph.D., as Chief Manufacturing Officer
WOBURN, Mass.–(BUSINESS WIRE)–Jan. 19, 2021– Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage biotechnology company focused on harnessing the body’s innate biology to repair or reverse damage caused by a broad range of degenerative diseases, today announced the appointment of Quentin McCubbin, Ph.D., as chief manufacturing officer. Dr. McCubbin will oversee Company technical operations, leading drug product formulation, chemistry manufacturing and controls (CMC) and supply chain, to support the development of Frequency’s pipeline of product candidates.

Dr. McCubbin joins Frequency from Cerevel Therapeutics, a clinical-stage biotechnology company where he served as head of technical operations. Prior to Cerevel, he spent 19 years at Takeda/Millennium Pharmaceuticals in various roles progressing in responsibility, including six years as vice president of pharmaceutical sciences and global head of process chemistry.

“Quentin’s background and leadership in technical operations will be critical as we prepare for larger studies in support of our lead FX-322 program that aims to treat the most common form of hearing loss, and as we look to diversify and expand our clinical pipeline with a program for remyelination in multiple sclerosis,” sa

Sensorion Provides Update on Development of SENS-401 for Sudden Sensorineural Hearing Loss: Phase 2 topline results delayed, now expected in Q4 2021…

https://www.businesswire.com/news/home/20210104005852/en/Sensorion-Provides-an-Update-on-Plans-and-Progress-in-the-Development-of-SENS-401-for-the-Prevention-of-Hearing-Loss

Sensorion Provides an Update on Plans and Progress in the Development of SENS-401 for the Prevention of Hearing Loss
Clinical trial to treat patients suffering from Cisplatin Induced Ototoxicity (CIO) with SENS-401 expected to start in H2 2021
Natural history study in CIO expected to start in H1 2021 to generate data on disease evolution

Phase 2 topline results from SENS-401 study in SSNHL delayed further due to COVID-19 and now expected in Q4 2021

Frequency Therapeutics to Host Investor Event on the Potential for Restorative Treatments for Acquired Sensorineural Hearing Loss

CATEGORY:
News, Companies, Press Releases

TAGS:
Frequency Therapeutics

TITLE:
Frequency Therapeutics to Host Investor Event on the Potential for Restorative Treatments for Acquired Sensorineural Hearing Loss

DESCRIPTION:
Event to be Held   January 19, 2021 at 8:00 am ET ; Will Feature Prominent Otolaryngology and Audiology Key Opinion Leaders Phase 2a Day-90 Readout for FX-322, Frequency’s Lead Product Candidate, for Acquired Sensorineural Hearing Loss Anticipated in Late Q1 2021; End of Study Readout in Late Q2

SOURCE:
Frequency Therapeutics

GUID:
aa0e5cd3eeeda8adba6fabfea4ff535c

ID:
b96d0a0b599e6d4315f064cd6ff0e099aa0e5cd3eeeda8adba6fabfea4ff535c

DATE – PUBLISHED:

DATE – FOUND:
12/18/20 08:22AM

LINK – PUBLISHER:
https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-host-investor-event-potential-restorative/

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2020-12-18T13:22:17+00:00, https://www.hearinglosstreatmentreport.com.

Otonomy Reports Positive Top-Line Results from Phase 1/2 Clinical Trial of OTO-413 in Patients with Hearing Loss

https://investors.otonomy.com/news-releases/news-release-details/otonomy-reports-positive-top-line-results-phase-12-clinical-0

Otonomy Reports Positive Top-Line Results from Phase 1/2 Clinical Trial of OTO-413 in Patients with Hearing Loss
December 17, 2020 at 7:00 AM EST
OTO-413 demonstrated a higher proportion of responders than placebo based on multiple speech-in-noise hearing tests

Clinical Trial of FX-322 for Age-Related Hearing Loss Is Now ACTIVE

Study is no longer recruiting participants. 30 patients enrolled. Half will get a single dose of FX-322, other half will get a placebo. Estimated primary completion date: March 2021. Estimated study completion date: June 2021. Stay tuned…

Link to official study record (last update posted on December 16, 2020):

https://clinicaltrials.gov/ct2/show/NCT04601909

The other recently-added FX-322 study (for severe sensorineural hearing loss) is expected to start before the end of the year, according to a November 16 press release from Frequency Therapeutics.

More updates to follow. Remember to subscribe to the email newsletter, which will begin sending soon. Email michael@urgentresearch.com if you have any comments or feedback.

Sonova Invests €5 Million in Sensorion [SENS-401] as the Companies Plan a Collaboration in Hearing Loss

https://www.businesswire.com/news/home/20201214005892/en/Sonova-Invests-%E2%82%AC5-Million-in-Sensorion-as-the-Companies-Plan-a-Collaboration-in-Hearing-Loss

Sonova Invests €5 Million in Sensorion as the Companies Plan a Collaboration in Hearing Loss
Sonova invests at €1.70 per share, to hold circa 3.7% stake in Sensorion
Companies signed a letter of intent relating to a collaboration to develop new solutions for hearing loss

Upcoming Webinar from the Hearing Medicines Discovery Syndicate: “How and Why” to Commercialise your Hearing Research (Nov 26)

https://go.md.catapult.org.uk/how-why-commercialise-hearing-research/

The Emerging Hearing Medicines Landscape

A monthly webinar series developed by the Hearing Medicines Discovery Syndicate, exploring hearing drug discovery in the context of an emerging area for medicines development and a growing market.

Through this series of webinars, we will explore the emerging hearing medicines landscape by inviting leading clinicians, academics and industry representatives along with people with lived experience of hearing loss, to share their expertise and insight.

Over 4 webinars we will provide a 360-view of the field covering the patient need, the key challenges faced by innovators, how to commercialise your hearing research and why regenerative approaches could be a game-changer for hearing medicines discovery.

Frequency Therapeutics adds YET ANOTHER new FX-322 clinical trial… for SEVERE sensorineural hearing loss

Added today: A Phase 1b, Prospective, Randomized, Double-Blind, Placebo- Controlled, Single-Dose, Multicenter, Safety Study of FX-322 Administered by Intratympanic Injection in Adults With Severe Sensorineural Hearing Loss.

This is a Phase 1b placebo-controlled, double-blind, single-dose safety study of intratympanic FX-322 dosed in subjects with severe sensorineural hearing loss.

Approximately 30 subjects are planned to be enrolled in this study. The subjects will be randomized to receive one dose FX-322 (24) or placebo (6) and will return for safety, otologic, and audiologic assessments at Days 30 and 90 after the study injection.

What makes this new FX-322 trial different (compared to the trial that was added last month)?

This new study is for severe sensorineural hearing loss (previously added study is for age-related hearing loss). The inclusion criteria requires a “pure tone average of “26-70 dB at 500Hz, 1000Hz, 2000Hz, and 4000Hz at screening in the ear to be injected.”

Does it include a Tinnitus Assessment as a secondary outcome measure?

Yes.

Measured by the Tinnitus Functional Index (TFI), with a scale ranging from 0 to 100 that defines severity categories based on 25 self-reported answers.

What else? More fun facts:

Study is Recruiting and will enroll 30 participants. It does involve a placebo group however the ratio is 4:1 which means most (24) of the participants will get FX-322.

If you like those odds, here are the states where clinical trial sites are located:

  • Florida
  • Nebraska
  • New York
  • Texas
  • Virginia

Could more locations be added?

Very possible. We will post an update if/when more sites are added.

Here is the official link to the study:

https://clinicaltrials.gov/ct2/show/NCT04629664

More FX-322 updates:

If you want ALL of the FX-322 updates and exclusive hearing loss treatment-updates sign up for the free email newsletter.

Frequency Therapeutics Announces Expanded FX-322 Clinical Development Program and Upcoming Day-90 Phase 2a Analysis

https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-announces-expanded-fx-322-clinical

Frequency Therapeutics Announces Expanded FX-322 Clinical Development Program and Upcoming Day-90 Phase 2a Analysis
Company Will Report Data from Phase 2a Sensorineural Hearing Loss (SNHL) Study in Late Q1 2021

First Patient Dosed in Phase 1b Study of Age-Related Hearing Loss; Additional Phase 1b Study for Severe SNHL Patients to Start This Quarter

SENS-401 Phase 2 trial results expected in mid-2021, prelinical data expected by end of 2020

https://www.businesswire.com/news/home/20201020006234/en/Sensorion-reports-2020-first-half-results

Preclinical data from these studies are expected by the end of 2020.

Sensorion reports 2020 first half results
Financial position strengthened with €31m (US$36.5m) capital raise in September 2020

Gene therapy agreement expands pipeline and preclinical data
SENS-401 Phase II trial progressing with results expected in mid-2021
Cash position of €30.7m as of June 30, 2020, further reinforced by September capital raise
Cash runway now extended to H2 2022

Estimated FX-322 Phase 2a Study Completion Date: May 21, 2021

Very quick update:

The FX-322 Phase 2a clinical trial is now *officially* active and we now have an updated estimated completion date for the study: May 21, 2021.

Details below:

  • The FX-322 study record was updated on October 8, 2020
  • The study status was changed from “Recruiting” to “Active, not recruiting”
  • The study completion date was changed from September 30, 2020 [Anticipated] to May 21, 2021 [Anticipated].

FX-322 trial update October 8, 2020 now active

Source: History of Changes for Study: NCT04120116 (FX-322 in Adults With Stable Sensorineural Hearing Loss)

That’s all for now.

For the latest FX-322 updates and news of other hearing loss treatments, sign up for the free once-weekly email newsletter.

Email michael@urgentresearch.com and say hello. Let me know what type of hearing loss treatment updates you like best. Feedback encouraged.

Also, remember to check out TinnitusTreatmentReport.com if you don’t already know about it.

How much will FX-322 cost? David Lucchino, Frequency Therapeutics CEO, talks pricing and value…

How much will FX-322 cost?

David Lucchino, CEO of Frequency Therapeutics, was recently asked for some “rough ideas around [the] pricing and reimbursement” of FX-322.

Here is a lightly edited* almost-word-for-word transcript of David’s response**:

*EDITED HOW? Disconnected parts of speech and filler words such as umm, well, you know, etc., have been removed for sake of clarity.

**SPOILER ALERT: David, understandably, does NOT give us a specific number. He gives us the answer we all expected, that of a responsible CEO. As he says, “specifics around pricing and regulatory ‘really need to be managed and played out appropriately'” (in other words, NOT eagerly telling us “FX-322 WILL COST EXACTLY THESE MANY DOLLARS” while the drug is still in phase 2a clinical trials).

Alas.

Specifics? Best I can do is this:

HOST: […] walk us through your thinking around the target patient population and maybe some kind of rough ideas around pricing and reimbursement […]

DAVID LUCCHINO: I’m still evolving our understanding of this as we really work in partner with the FDA to understand exactly the true, we think, impact of our therapy. So it’s hard for me to speak in any absolutes. We know that the market is absolutely substantial and the unmet clinical need is very, very high. We think that hearing aids will continue to have a real role and be a good option for patients, though we think having a therapy that can truly start to heal someone’s hearing and create a healthy cochlea, if you will, is going to be a very strong value proposition both with or without hearing aids. I think that specifics around pricing and regulatory, those really need to be managed and played out appropriately. I think that we’re aware of what hearing aids are priced at, and we’re aware of what cochlear implants are priced at, and how hearing aids are handled from a regulatory standpoint and our goal is to deliver a highly effective therapy and do it in a way where we can continue to build out a very successful company that investors will recognize for years and years to come.

HOST: Excellent, super helpful.

SOURCE: Where is this from? These comments were made during a live Q&A at the Oppenheimer Virtual Fall Healthcare Life Sciences & MedTech Summit, which took place on Tuesday, September 22, 2020 at 10:00 am Eastern Time.

As David’s comments suggest, a lot of work goes into determining the price of a treatment such as FX-322. Meanwhile, the drug only recently completed enrollment for its Phase 2a study.

So don’t expect any “Hey it will cost THIS many dollars” answers yet…

For now, this recent commentary is the most recent and up-to-date information regarding FX-322’s price tag. Straight from the CEO’s mouth.

And let’s be honest, it is the reply we all expected… But with some interesting “price anchoring” thrown in with the mention of hearing aid costs (average price: $2372) and cochlear implant costs (average price: between $30,000-$100,000).***

Why would David mention those price points? How do drug companies calculate price? How do comparisons and price anchoring factor into that calculation?

Hmmmm…

Let the speculation begin!

Excellent Super Helpful vague troll face meme

LINK TO VIDEO: If you want to watch the interview, here is a link to the video recording of the Frequency Therapeutics virtual event webcast (the FX-322 pricing-related comments begin at around 39:00):

https://wsw.com/webcast/oppenheimer5/freq/2713518

And…

If you want an easy way to follow FX-322 including any future updates RE: cost of FX-322, join the weekly email update list. It’s a free, once-weekly email [starting soon] that lists all the new links that were added to this site’s front page during the previous 7 days. No spam, no nonsense.

***Reference: https://www.hearingtracker.com/how-much-do-hearing-aids-cost, https://www.hearingtracker.com/cochlear-implants#a-how-much-do-cochlear-implants-cost.

Frequency Therapeutics Presents Results Demonstrating Sustained Improvement in Hearing Loss Patients Treated with FX-322

https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-presents-results-demonstrating-sustained

Frequency Therapeutics Presents Results Demonstrating Sustained Improvement in Hearing Loss Patients Treated with FX-322

Evidence of Durable Hearing Improvements in Follow-Up with Patients from Phase 1/2 Study; Speech Intelligibility and Audibility Sustained for Up to 21 Months After Initial Dosing

Data Highlighted at the 2020 American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) Annual Meeting

Role of protein in development of new hearing hair cells: Finding could lead to future treatments for hearing loss

https://www.sciencedaily.com/releases/2020/09/200911200012.htm

Role of protein in development of new hearing hair cells
Finding could lead to future treatments for hearing loss

Date:
September 11, 2020

Source:
University of Maryland School of Medicine

Summary:
Researchers have conducted a study that has determined the role that a critical protein plays in the development of hair cells. These hair cells are vital for hearing. Some of these cells amplify sounds that come into the ear, and others transform sound waves into electrical signals that travel to the brain.

Frequency Therapeutics Expects to Share FX-322 Phase 2a Study Results in Q2 2021

https://www.businesswire.com/news/home/20200812005136/en/

expects to achieve target enrollment by early in the fourth quarter of 2020. Based on this timeline, the Company expects to report study data in the second quarter of 2021.

Frequency Therapeutics Provides Business Updates and Reports Second Quarter 2020 Financial Results
Expects to Complete Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss by Early Q4 2020; Study Readout Anticipated in Q2 2021

Recently Announced Clinical Data Show FX-322 Delivery to the Cochlea and Preliminary Evidence of a Durable Clinical Benefit; Plans New Studies in Additional Patient Populations

Raised $42.3 Million Private Placement, Providing Company Runway into 2023

August 12, 2020 07:30 AM Eastern Daylight Time
WOBURN, Mass.–(BUSINESS WIRE)–Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage biotechnology company focused on harnessing the body’s innate biology to repair or reverse damage caused by a broad range of degenerative diseases, today announced business updates and financial results for the second quarter ended June 30, 2020.

“We are pleased with the steady progress in our Phase 2a study, despite the challenges of the pandemic, and we anticipate completing enrollment early in the fourth quarter of 2020 and sharing data from the study in the second quarter of 2021,” said Frequency Therapeutics Chief Executive Officer David L. Lucchino. “In the last quarter, we generated compelling cochlear drug delivery data for FX-322, as well as important durability data suggesting that some patients who were given a single injection of FX-322 in our original Phase 1/2 study maintained statistically significant improvements in word recognition between 12 and 21 months following administration. We believe that these clinical advances are important building blocks as we work to further our understanding of FX-322 drug activity and the patient populations we hope to treat.

PIPE-505 Clinical Trial Update: Pipeline adds 4 new study locations across the United States…

As anticipated, Pipeline Therapeutics has added additional clinical trial sites to its phase 1/2a study of PIPE-505 for hearing loss.

The official study record (NCT04462198), updated on August 6, 2020, now includes five study locations across the U.S., four of which are now recruiting participants:

  • Boca Raton, Florida, United States, 33487 – added July 17 – Recruiting
  • Winston-Salem, North Carolina, United States, 27103 – added July 27 – Recruiting
  • New Albany, Indiana, United States, 47150 – added August 1 – Recruiting
  • Louisville, Kentucky, United States, 40220 – added August 1 – Recruiting
  • Kansas City, Kansas, United States, 66160 – added August 4 – Not yet recruiting

This post will be updated to include any further changes to the study record. For email updates (which will be starting soon), join the announcement list while it is still open.

Pipeline Therapeutics Initiates Phase 1/2a Clinical Trial of PIPE-505 in Sensorineural Hearing Loss – Topline results expected in early 2021…

https://www.pipelinetherapeutics.com/news/pr_07-23-2020.php

Pipeline Therapeutics Initiates Phase 1/2a Clinical Trial of PIPE-505 in Sensorineural Hearing Loss
PIPE-505 is the first small molecule developed specifically for the treatment of sensorineural hearing loss (SNHL) associated with speech-in-noise impairment
Topline results expected in early 2021
SAN DIEGO, July 23, 2020 – Pipeline Therapeutics, a biopharmaceutical company focused on the development and commercialization of first-in-class small molecules for neuroregeneration, today announced the initiation of a Phase 1/2a trial of the company’s lead product candidate, PIPE-505, a small molecule gamma secretase inhibitor (GSI), in sensorineural hearing loss (SNHL) associated with hearing speech in noisy environments.

UPDATE: Pipeline Therapeutics Begins Recruiting Patients for Phase 1/2a Study of PIPE-505 for SNHL

This is a follow-up post to the previous PIPE-505 clinical trial update from July 8 where we explained how “patient recruitment could begin any day now.”

Today, less than two weeks later, that forecast proved accurate: the PIPE-505 trial is now RECRUITING, according to the official study record (NCT04462198), which had its Recruitment Status updated yesterday.

Here is an excerpt from that ClinicalTrials.gov record:

STUDY TITLE: A Phase I/IIa, Randomized, Double-Blind, Placebo-Controlled, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Unilateral Intratympanic PIPE-505 in Subjects With Sensorineural Hearing Loss Associated With Speech-in-Noise Impairment

Recruitment Status: Recruiting
First Posted: July 8, 2020
Last Update Posted: July 20, 2020

DESCRIPTION: This is a randomized-controlled, double-blind study of PIPE-505 or placebo given as an injection one time in subjects with sensorineural hearing loss associated with speech-in-noise difficulty. Visits to the clinic will occur at baseline, dosing, and days 1, 7, 14, 30, 60 and 90 after treatment. Safety will be assessed by periodic measurement of vital signs, ear examination, electrocardiogram (ECG), blood laboratory analyses and occurrence of adverse events (AE). Efficacy will be assessed by periodic audiometry and other audiological tests.

ClinicalTrials.gov Identifier: NCT04462198

Where is the PIPE-505 study located?

As of July 21, 2020, there is only one recruitment location (Florida) for the trial. But it is common for studies like this one to expand and add more locations across the country and sometimes internationally, too. We expect more recruitment sites to be added in the next 4-6 weeks, although we do not have an exact list of those locations… yet…

UPDATE: August 29, 2020 – A second recruitment location (North Carolina) has been added to the list. (More to come?)

More updates to follow for PIPE-505 and other up-and-coming hearing loss treatments. Keep an eye on the front page of this website for updates, or get email updates (it’s an upcoming once-weekly email newsletter – no spam, no third parties, privacy respected).

People on the email list will get first access to new versions of this website that track more research from more sources…

Questions? Comments? Corrections? Collaborations? Send an email to michael@urgentresearch.com and say hello.

Pipeline Therapeutics Initiates Phase 1/2 Clinical Trial of PIPE-505 for Sensorineural Hearing Loss

The study titled, Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss, was added to the official ClinicalTrials.gov databased on July 8, 2020.

The recruitment status of the clinical trial is currently set to “Not yet recruiting.” However, that could change very soon, considering a) the follow-up period for trial participants after the initial drug administration lasts 3 months, and b) the anticipated primary completion date of the study is four months away, in November 2020.

These details suggest that patient recruitment could begin any day now and – assuming there are no changes to the study’s current schedule – probably no later than 4-6 weeks from now.

UPDATE (current as of July 21, 2020): the PIPE-505 study is now recruiting patients… see this follow-up post for details or visit the official study page using the link below:

https://clinicaltrials.gov/ct2/show/NCT04462198

Here is further reading about PIPE-505, a small molecule gamma secretase inhibitor (GSI) that will be delivered to select trial participants as a one-time intratympanic injection:

PIPE-505 is the first small molecule developed specifically for the treatment of sensorineural hearing loss (SNHL) associated with cochlear synaptopathy. The therapeutic focus, regeneration of the cochlear synapse, should augment signal-to-noise processing and manifest as improved speech-in-noise comprehension, a chief auditory complaint and unmet need of patients with SNHL.

Source: https://www.pipelinetherapeutics.com/science/synaptogenesis.html

A simpler way to make sensory hearing cells

https://www.sciencedaily.com/releases/2020/07/200701134242.htm

A simpler way to make sensory hearing cells
Date:
July 1, 2020
Source:
Keck School of Medicine of USC
Summary:
Scientists are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as ‘hair cells,’ due to their hair-like protrusions that sense sound waves.

Otonomy Provides Update on OTO-413 Clinical Trial: Results from Phase 1/2 study of OTO-413 for hearing loss expected in fourth quarter of 2020

https://www.globenewswire.com/news-release/2020/06/15/2048357/0/en/Otonomy-Provides-Update-on-Clinical-Trials-and-Development-Programs.html

Otonomy Provides Update on Clinical Trials and Development Programs

June 15, 2020 16:05 ET | Source: Otonomy, Inc.

  • Results from Phase 3 trial of OTIVIDEX® in Ménière’s disease expected in first quarter of 2021
  • Results from Phase 1/2 trial of OTO-313 in tinnitus expected in July 2020
  • Results from Phase 1/2 trial of OTO-413 in hearing loss expected in fourth quarter of 2020

SAN DIEGO, June 15, 2020 (GLOBE NEWSWIRE) — Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today provided an update on its product pipeline and the timeline to results for the company’s three ongoing clinical trials, including the Phase 3 trial of OTIVIDEX in Ménière’s disease. The company will host a conference call and webcast today at 4:30 p.m. ET to review these updates.

NO COVID-19 SLOWDOWN: Frequency Therapeutics Adds Another Recruitment Site for FX-322 Phase 2a Study

Frequency Therapeutics has once again updated the official Study Record of its Phase 2a clinical trial of FX-322 in Adults With Stable Sensorineural Hearing Loss.

The update – which includes a new clinical trial site in Austin, Texas – was posted to ClinicalTrials.gov on April 10, 2020.

No Slowdown Due to COVID-19?

It looks like the FX-322 trial is still moving forward as expected, running on schedule.

Usually, a small change to a study record would not seem like such big news.

However, in the context of COVID-19, it is noteworthy. And uplifting! Why?

Consider this: while many clinical trials across the world are experiencing massive slowdowns and stoppages due to COVID-19, the FX-322 Phase 2a trial is expanding its presence to yet another location in the United States. Expanding!

That is not to say the trial has not been affected by COVID-19. For example, patient recruitment efforts and other logistics have probably become more challenging.

However, despite all that is happening, what we see with this update is more activity and signs of life. Things are happening. Plus, we have proof that the study is not paused or stopped. In fact, there is no sign of any delay at all…

FULL SPEED AHEAD!

The estimated study completion date (September 30, 2020) remains unchanged. Repeat: the estimated completion date of the FX-322 trial has NOT been pushed back despite the impact of COVID-19, according to the latest study record.

Small update, big news.

Link to official study page:

https://clinicaltrials.gov/ct2/show/NCT04120116

Get email updates (while you still can)

The Hearing Loss Treatment Report newsletter will be starting soon. It is a once-weekly email update that will be sent out every Saturday. It is free, your email address will remain private and not be shared with anyone, and you can unsubscribe at any time with a single click.

Click here to subscribe to email updates

(Note: If you have already submitted your email and added your name to the updates list, you are all set. You do not need to sign up again! You’re on the list and will receive updates as soon as they begin.)

Strekin AG Completes Phase 3 Clinical Study of STR001 to Restore Hearing in Patients with SSNHL

Strekin AG, a Swiss-based biopharmaceutical company focused on developing new treatments to reverse hearing loss, has completed its Phase 3 clinical trial of the investigational drug STR001 in patients with Sudden Sensorineural Hearing Loss (SSNHL).

According to the official study record (Source: ClinicalTrials.gov), the Status of Study NCT03331627, Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL, was changed from “Recruiting” to “Completed” on March 25, 2020. The actual completion date of the study was updated to February 6, 2020.

The purpose of this international, randomized, placebo-controlled, Phase 3 study, officially titled Phase III Multicenter, Double-blind, Placebo-controlled, Study Evaluating the Safety, and Efficacy of STR001 Treatment in Adults With Sudden Sensorineural Hearing Loss, was to evaluate the ability of STR001 to restore hearing in patients following a SSNHL event.

If the results are promising, STR001 could become the first approved treatment for SSNHL patients.

The previous update related to this clinical trial of STR001 was from over six months ago, on September 12, 2019. That is when Strekin AG announced in a press release the completion of patient recruitment for the study (which involved 165 patients).

Prior to that, the last change to the study record was almost a year ago, on April 10, 2019. That is when the study began recruiting patients, according to the official study page.

Source:

https://clinicaltrials.gov/ct2/show/NCT03331627?type=Intr

To get more exclusive (and early, early, early) hearing loss treatment-related news and updates, remember to join the mailing list for HearingLossTreatmentReport.com Email Updates. It’s free and you can unsubscribe at any time. One email per week – a simple list of links that were posted on the site during the previous 7 days. No spam or nonsense, completely private.

INVITATION TO RESEARCHERS, INDUSTRY PROFESSIONALS, and RESEARCH-SEEKING PATIENTS: For more information about how this site works, and how it automatically gathers all the latest and most relevant hearing loss treatment-related updates non-stop, 24/7… send an email to michael@urgentresearch.com and say hello.
– Michael S.

P.S. Here are three other hearing-related “treatment report” sites that might interest you:

COMPLETED: Novartis Phase 1/2 Trial of CGF166, an Inner Ear Gene Therapy for Hearing Loss

The status of study NCT02132130 (Safety, Tolerability and Efficacy for CGF166 in Patients With Unilateral or Bilateral Severe-to-profound Hearing Loss), was changed from “Active, not recruiting” to “Completed” on March 19, 2020.

According to the official study record, the actual completion date of the trial was December 9, 2019.

The previous update to this clinical trial of CGF166 was posted just over four months ago, on November 15, 2019. That is when the study status was changed from “Recruiting” to “Active, not recruiting.”

Source:
https://clinicaltrials.gov/ct2/show/NCT02132130

Discovery of a pharmacological treatment that could “wake up” the human body’s ability to naturally regenerate lost hair cells and reverse hearing loss

Many fish, frogs, and birds possess special regeneration capacities that allow them to fully recover from hearing impairments and balance dysfunctions caused by lost hair cells.

Humans and other mammals, however, do NOT have this ability.

Sadly, our mammalian ears are vulnerable to permanent hearing loss and balance deficits.

But that could soon change…

Because new research from Jeff T. Corwin at the University of Virginia appears to have uncovered the reason for the permanent nature of hair cell loss in humans. The findings identify why certain creatures can recover from hearing damage and why humans cannot.

The most exciting part?

The team behind the research, part of Corwin’s Laboratory of Inner Ear Sensory Hair Cell Regeneration, has discovered a pharmacological treatment that could “wake up” the special supporting cells that can allow lost hair cells to regenerate in humans.

To learn more about how it works, here is a link to the study itself — which was published on February 20, 2020 in the Journal of Neuroscience.

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear.

Here is the abstract:

J Neurosci. 2020 Feb 19;:
Authors: Kozlowski MM, Rudolf MA, Corwin JT

Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many non-mammalian vertebrates can fully recover from hearing impairments and balance dysfunctions, because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis, and soon after birth vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions.

Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear’s vulnerability to permanent balance and hearing deficits.

SIGNIFICANCE STATEMENT

Millions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but non-mammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.

PMID: 32079647 [PubMed – as supplied by publisher]

Additional research shows that there is a U.S. Provisional Patent Application related to the research posted here is currently pending. The application number is 62/951,996 and it was filed on December 20, 2019. The patent applicant is Jeffrey T. Corwin, and the other inventors listed include Mark Rudolf and Mikolaj Kozlowski.

Hearing Loss Treatment Report will continue to keep an eye on this promising new (potential) hearing loss treatment, which involves treatment with an EGF and a GSK3 inhibitor, and is currently being tested in mice. But considering the patent filing and strong evidence, human trials will surely follow.

Want updates? Remember to sign up for free weekly email updates, here. Especially if you want to know about new hearing loss drugs and experimental treatments as soon as possible.

Questions? Comments? Corrections? Feedback?

Send an email to michael@urgentresearch.com and say hello. This site is almost completely automated (except for occasional “exclusive” articles like this one), but there is a human behind the scenes.