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Rescue Hearing Inc scientific advisor Dr. Zheng-Yi Chen of Massachusetts Eye and Ear Infirmary has published a new study entitled “Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents” in the scientific journal “Nature”.  Dr. Chen is an expert in the use of Crispr Cas-9 technology in the development of gene therapies for hearing loss.  The team at Rescue Hearing Inc wishes to congratulate Dr. Chen on the publication of this pivotal study.

THE NEXT LOGICAL STEP

In January 2015, I read a New York Times article by Andrew Pollack entitled “Ear Ailments are New Focus for Drugs from Vertigo to Tinnitus”.  Since that day in January of 2015, I have personally interviewed over 25 experts in the hearing loss field (Key Opinion Leaders), profiled over 21 companies involved in developing hearing loss therapies, established relationships with hearing loss foundations, attended my first scientific conference ARO (Association for Research in Otolaryngology) and created this blog on Linked-In called “Dispatches from the Hearing Loss Space”.

As a result of my many interviews, meetings, conferences, scientific articles read and the support I have received from the scientific community (especially Dr. Larry Lustig), I move to the next logical step. Create a company dedicated to developing therapies for those with hearing loss.  That company is “Rescue Hearing Inc.”.

THE RESCUE HEARING INC VISION & MISSIONS

The Rescue Hearing Inc (RHI) vision is to “Eliminate Hearing Loss as a Chronic Condition”

RHI has assembled a group of visionary, internationally recognized physicians, scientists and bio engineers who share a common passion for developing therapies for humans suffering from hearing loss.  The team is developing therapeutic and diagnostic platforms that will address the most difficult of hearing loss indications.

To realize its vision the RHI team will focus on 3 specific missions:

• Develop therapies for congenital, non-congenital, syndromic and non-syndromic hearing loss
• Develop and refine diagnostic tools to confirm individual causes of hearing loss
• Develop real time imaging of human hair cells In Vivo

The RHI team will utilize cutting edge scientific tools such as: gene therapy, stem cells, anti-sense oligonucleotides, and small molecules to develop therapies and diagnostics in the laboratory and bring them into human clinical trials.

THE RESCUE HEARING SCIENTIFIC ADVISORY BOARD (SAB)

Lawrence R. Lustig, MD

NewYork-Presbyterian Hospital/Columbia University Medical Center

Howard W. Smith Professor of Otolaryngology—Head & Neck Surgery

Chair, Department of Otolaryngology—Head & Neck Surgery

Expertise:  PI in hearing loss clinical trial (gene therapy), practicing otolaryngologist and surgeon treating adults and children, one of the nation’s leading experts in hearing loss therapy, SBIR / STTR grant funding, writing and review.

Xue Zhong Liu, MD, PhD, FACS

University of Miami (Coral Gables, Fl)

Leonard M. Miller Professor of Otolaryngology, Human Genetics, Pediatrics, and Biochemistry

Otolaryngology Vice Chairman of Research

Director, Center for Communication Sciences and Disorders

Director of Miami Otogenetic Program

Expertise:  Practicing otolaryngologist and surgeon treating adults and children, one of the nation’s leading experts in genetic causes of hearing loss, operates lab dedicated to developing genetic therapies for hearing loss, development of transgenic mouse colonies for hearing loss research, SBIR / STTR grant funding, writing and review.

Zheng-Yi Chen, D.Phil.

Massachusetts Eye and Ear Infirmary- Associate Scientist

Associate Professor of Otolaryngology-Harvard Medical School

Expertise: Operates lab dedicated to developing genetic therapies for hearing loss, CRISPR/Cas9 technology, AAV vector and gene therapy conjugation, combining protein delivery and genome editing as treatment for genetic hearing loss, development of transgenic mouse colonies for hearing loss research, SBIR / STTR grant funding, writing and review.

Robert D. Frisina, PhD

University of South Florida (Tampa)

Director of the Global Center for Hearing & Speech Research

Director Biomedical Engineering

Professor of Chemical & Biomedical Engineering, Communication Sciences and Disorders

Expertise: PI in hearing loss clinical trial (age related hearing loss), SBIR / STTR grant funding, writing and review, operates biomedical engineering lab with focus on the function and disorders of the auditory system, operates acoustic chambers to test hearing in animal research models, cochlear cell line testing, formulation of drug delivery systems to the cochlea.

Victoria Sanchez-Williams, AuD, PhD

University of South Florida, Tampa

Clinical / Research Audiologist

Au.D., Ph.D., CCC-A/F-AAA

Expertise: Patient selection for human clinical trials for hearing loss, ongoing monitoring and testing of patients involved in hearing loss clinical trials.

NEXT STEPS

In the coming weeks there will be an RHI website with more details.  As with any CEO / Founder, my primary function is to raise operating capital.  My goal is to raise between $200K and 300K to begin our work in mouse. I’ll be leveraging any and all potential sources of seed capital including: my NYC entrepreneurial ecosystem contacts, universities, foundations, VC / PE investment firms and parents of children with congenital and / or progressive hearing loss, et al.

The longest of journeys begins with the first step.  The first step has been taken.

Profiles in Courage

I’m not sure who coined the phrase “to the pioneers go the arrows” but I’ve found this to be true across most worthy endeavors from civil rights activism to the business of science.  In the business of science, the arrows come in many forms: lack of research funding, peer and investor skepticism and the inevitable dead end(s) when an experiment’s hypothesis fails.  To march on takes courage.

Jennifer Lentz PhD (LSU Health Science Center) and Michelle Hastings PhD (Associate Professor Chicago Medical School) are scientists pursuing a unique approach, Antisense Oligonucleotide therapy (ASO), to help those born with congenital deafness.  The ASO therapy approach is detailed in their 2013 article entitled “Rescue of Hearing and Vestibular Function by Antisense Oligonucleotides in a Mouse Model of Human Deafness” published in Nature Medicine.

What is ASO Therapy and How Does it Work?

Hereditary deafness can be caused by genetic mutations that lead to improper development or degeneration of cochlear hair cells.  In theory, if we could identify the mutant gene and “silence, turn-off, knock down, knock out” its genetic instructions, the mutation would cease to occur.  ASOs are small sequences of DNA that block, silence, turn-off, knock down or knock out disease processes by interfering with the production of a particular protein produced by the (mutant) gene of interest.

The ASO Study in Mouse Using Usher Syndrome Disease Model

In their study published in Nature Medicine, Lentz and Hastings (et al.) “showed that hearing and vestibular function could be rescued in a mouse model of human hereditary deafness.  An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness”.

“Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low frequency hearing in mice.  These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness.”

Current ASO Clinical Trial Activity in the Hearing Loss Space

That’s easy, nothing.  A quick scan of Clinical Trials Dot Gov shows 13 open trials using ASO interventions with indications spanning GBM tumors to dermatitis but “0” trials for hearing loss.

Companies with the Potential to Develop ASO Therapies

I’ll handicap some of the companies playing in the ASO space:

The Major Player:  ISIS pharmaceuticals is a leading manufacturer of ASO drug substance and drug product for commercial and research use.  Its staff has the technical and experiential expertise to support an ASO clinical trial in hearing loss (e.g. Frank Rigo is listed as a co-author in the article mentioned here and was affiliated with ISIS at the time of its publication).  It’s a good bet that any ASO hearing loss trial will be in some way supported by ISIS. The ISIS ASO pipeline is robust but they have no hearing loss projects in the pipeline at the time of this writing.

Up and Coming: Quark Pharmaceuticals Inc. is an RNAi based late stage clinical company with a diverse pipeline of products in the clinic.  Its hearing loss projects are all preclinical including QP-HL3, a project intended to promote hearing regeneration.

Wild Card: Decibel Therapeutics is a preclinical company devoted solely to developing hearing loss therapies.  Founded by KOLs at Harvard, Univ of Michigan and Scripps, investors think highly of Decibel’s chances of developing profitable products for the hearing loss population to the tune of a $53M seed round.  As of this writing, there was no mention of any ASO projects on their website.

The “Build-to-Buy”Framework  

Three parties are used: (a) a science company with a novel technology, (b) a venture capital firm and (c) a big pharma company.

All parties must agree on a pre-set acquisition price for (a).  This is the hardest part. (c) retains an exclusive option to purchase (a) at the pre-set price when a specific milestone is achieved e.g. a first lead compound reaching the filing stage of an investigational new drug (IND) application.  Both (b) and (c) contribute funding, drug development expertise and resources to develop (a’s) novel technology.

The players: A science company– Inception 3  

Inception 3 is an effort to bring together a leading academic in the field of hearing loss with a major pharmaceutical company (Roche).  Stefan Heller, professor at the Stanford University School of Medicine, is a pioneer in the field. His research focuses on finding strategies to restore the inner ear sensory cells that detect sound (called hair cells) that are required for hearing.  Dr. Heller discovered the presence of cells in the inner ear of mammals that can differentiate into hair cells. He and other researchers have also developed the concept that drug compounds could regenerate hair cells in the damaged cochlea, restoring hearing in patients.

The players: A venture capital firm- Versant Ventures   

Versant Ventures created the Inception business model to match world-class academic researchers with pharmaceutical partners and form new drug discovery programs. The Inception program has now formed multiple companies, including Inception 1 (partnered with Shire), Inception 3 (partnered with Roche), Inception 4 (partnered with Bayer) and Inception 5 (partnered with Roche).  Versant invested Series A financing into Inception 3 as part of the build-to-buy deal, with Roche contributing the remaining funding into the program.

The players: A big pharma company- Roche

In 2012, Roche signed 55 new agreements, including three product transactions and 43 research and technology collaborations. Among Roche’s main transactions in 2012 was the exclusive partnership with Versant Ventures and Inception Sciences to create a drug discovery incubator, Inception 3, for the treatment of sensorineural hearing loss.

The Exit

Key monetizing event: sale of company (a) at pre negotiated price to (c).  (a) and (b) are paid by selling their shares of (a) to (c). (c) has complete ownership of (a) includingIP and future revenues.  Benefits from the build-to-buy deal construct: Inception 3 benefits from Roche’s funding and drug development expertise; Roche gains access to Inception 3’s innovative technology platform and novel drug candidates; and Inception 3 and Versant Ventures both gain a risk-mitigated path to liquidity.

Source of info: Roche, Versant Ventures and Inception 3 websites.

First-in-man

Somebody’s got to be the first, the pioneer, the risk taker.  Two publicly traded companies, Genvec (NASDAQ:GNVC) and its big pharma partner, Novartis (NYSE:NVS) have taken on this moniker.  Genvec is a pioneer in the design, testing and manufacture of viral vectors (adenoviral-based products) and Novartis is a big pharma company with the money ($248B market cap) and courage to move a gene therapy product into first-in-man clinical trials.  GenVec’s lead product candidate, CGF166, is licensed to Novartis and is currently in a Phase 1/2 clinical study for the treatment of hearing loss and balance disorders.

The Genvec / Novartis gene therapy approach

Approximately 90% of hearing loss is sensorineural, characterized by loss of sensory hair cells in the inner ear.  These sensory cells are critical to both hearing and balance and can become damaged or destroyed due to aging, infection, trauma from certain medications, or exposure to noise.  The goal of the therapy is to regrow the damaged sensory cells and restore hearing.

A common surgical procedure is used to gain access to the inner ear where the drug product (CGF 166) is directly infused. CGF 166 uses a viral vector to deliver the atonal gene (Atoh1) to the supporting cells of the inner ear.  The introduction of the Atoh1 gene triggers the conversion of supporting cells into sensory hair cells in the inner ear.

The Trial

The trail is a phase I/II study that will evaluate the safety / efficacy of the drug as well as the delivery mechanisms (vector, surgical procedure and infusion process).  Who is eligible to participate? Subjects must have bi-lateral, acquired, severe to profound hearing loss.  This counts out those persons with congenital (hereditary) hearing loss like my son.

The primary endpoint is to measure changes in hearing before treatment and after treatment.  Prior to treatment, patient baseline hearing thresholds are established (frequencies 0.125 KHz to 16 KHz).  After treatment, hearing threshold improvements greater than 10db can be considered clinically significant. The trial began recruiting in 2nd QRT of 2014 (at 3 sites: Kansas, MD and NYC) and the first patients were dosed in 4th QRT of 2014.

The Principal Investigator- Hinrich Staecker

 Dr. Staecker is the public clinical face of the trial.  He’s the Neil Armstrong of therapies to restore hearing.  Like Neil Armstrong, there are countless, nameless people who have dedicated their lives to the research that has moved the science to this point.  He will gain the notoriety if the therapy works and bear most of the criticism if the therapy doesn’t work or if somebody gets hurt. While many in the research community believe that therapies to restore hearing loss are 10 years away, Hinrich Staecker is the person who’s stuck his neck out and choose to move forward today.

Wrap up

 The hearing loss world is eagerly awaiting the data from the CGF 166 trail.  The questions are many:

• Does the treatment improve hearing in humans (vs mouse)
• How long does the treatment last (4mos, 12mos, lifetime)
• Does the viral vector delivery mechanism have long term adverse effects on humans

There is no shortage of heroes in this effort.  Not only the ones mentioned above but consider the patients who volunteered to participate in the trial.  An excerpt from the Novartis website “Hearing loss can be frustrating, isolating, and disabling — suffering that is evident from the reaction Hinrich Staecker received after the trial’s launch. Following coverage of the clinical study in the magazine New Scientist in April 2014, he received more than 600 emails and dozens of daily phone calls from potential patients. “There’s a huge amount of interest in this,” he says.

Profiles in Courage?

It may be presumptuous to borrow the title “Profiles in Courage” from the 1957 Pulitzer Prize winning  book to describe the scientists who are pursuing therapies to restore hearing loss, but I feel it’s appropriate.  The more I research, the more I appreciate the difficulty of creating therapies in the lab and then moving them into the “clinic”.

Most scientists I’ve spoken to, or have read about, say that the therapies to restore hearing loss in humans are at least 10 years away.   Some scientists currently working to develop hearing loss therapies will not live long enough to see those therapies in use. If that does not qualify as courage, what does?

Gene therapy for the congenital hearing loss market

I had the pleasure of speaking with Dr. Larry Lustig by phone in late June of this year.  Dr. Lustig is exploring cochlear gene therapy as a potential approach for treating children, like my son, born with genetic forms of hearing loss (aka congenital hearing loss).   The economic and clinical challenges of implementing a gene therapy approach for this market are many:

Economic

• Smaller market: the size of the “congenital” hearing loss market is significantly smaller than the “acquired” hearing loss market (2 levels of magnitude smaller)
• Targets keep changing: the list of specific genetic mutations responsible for hearing loss changes daily
• Personalized medicine: because of individual genomic differences, each patient, may require a unique therapeutic approach

Clinical

• The gene therapy must last for the life of the patient (the mutation cannot reappear
• The delivery vehicle for the gene therapy, in most cases a viral vector, must be correct and efficient
• Combination therapy is a possibility e.g. administering an anti-sense oligo therapy to silence the mutant gene in combination with a hair cell regeneration therapy

Dr. Lustig’s Background

Dr. Lustig earned his bachelor’s degree in microbiology at the University of California, Berkeley, and his medical degree at UCSF, where he also completed a residency in otolaryngology/head and neck surgery.  Before joining UCSF, Dr. Lustig served on the faculty at Johns Hopkins University, where he was a member of the Johns Hopkins Listening Center and cochlear implant team. He also completed a fellowship in otology, neurotology, and skull base surgery at Hopkins.

Dr. Lustig was appointed chair of the Department of Otolaryngology/Head and Neck Surgery at the Columbia University College of Physicians and Surgeons and otolaryngologist-in-chief at New York-Presbyterian/Columbia University Medical Center on  July 1, 2014.

Dr. Lustig is also President of the Association for Research in Otolaryngology (ARO).  The ARO’s annual meeting is a who’s who of the hearing loss research community. It’s a can’t miss event for those who are interested in learning about the latest science in hearing loss.

Business vs Science

One of Dr. Lustig ‘s many attributes is his appreciation of entrepreneurship in science.  Maybe it’s his West Coast DNA that allows him to appreciate and welcome entrepreneurship. While some scientists and foundations may shun entrepreneurs and business people, Dr. Lustig seems to understand  that neither entity can exist without the other. In a time where the “zero sum” approach to business is grabbing headlines, the business of science stands in defiance to this approach.

My interest in the hearing loss space was sparked after reading a January 2015 New York Times article by Andrew Pollack entitled “Ear Ailments are New Focus for Drugs from Vertigo to Tinnitus”

After reading the article, I had my “eureka” moment.  The hearing loss space provided me with a personal connection to the science.  My 10 year old son was born with congenital hearing loss and finding a cure for him is what drives me.

Initial Research

In my initial research into the hearing loss market, I found a company called Inception Sciences 3 (IS3).  IS3 is a unique product of the “build-to-buy” deal construct involving Roche, Versant Ventures and IS3.  They are attempting to grow human sensory hearing cells (hair cells) from stem cells.  IS3 is in the cell culture stage.

A Meeting with Scientists from Roche

Based on my interest in the space and IS3, I met with Judith Dunn (VP, Global Head Clinical Development at Roche) and Anirvan Ghosh (Vice President, Global Head, Neuroscience Discovery & Biomarkers at Roche) at the Roche Innovation Center in New York City.

After discussing my research, Judith and Anirvan suggested that I: (1) categorize therapies according to scientific approach and (2) research hearing loss foundations to obtain knowledge on emerging therapies and KOLs (Key Opinion Leaders).

Developing a Framework to Understand the Space

I have established 4 categories (or buckets) of therapeutic approaches: Gene Therapy, Small Molecule, Anti-Sense Oligos and Stem Cell.  I now have a framework to organize, analyze and communicate my understanding of the hearing loss space to others.

Rescue Hearing Inc (RHI) CEO / Founder, Jim Ayala will be presenting at the sold out NY Venture Summit on Wednesday (7/19) at 11 am.   

Rescue Hearing Inc (RHI) is a seed stage, hearing loss Portfolio Company developing products for the hearing loss market (360M persons worldwide).  RHI’s initial gene therapy product will target a genetic mutation known to cause deafness. RHI’s world renowned scientific team is passionate about creating therapies for hearing loss.  The team includes Dr. Hinrich Staecker, the inventor and principal investigator of the first gene therapy to restore hearing (currently in phase II clinical trials at 3 sites in the USA).

Please visit our website to learn more about Rescue Hearing Inc.

AUGUST 2018: Rescue Hearing Inc (RHI) has signed a Sponsored Research Agreement with the University of Kansas Medical Center Research Institute.  RHI will be conducting research to develop gene therapies for hearing loss in the lab of Dr. Hinrich Staecker. Dr. Staecker is a scientific advisor to RHI and he is known for multiple clinical trials, including those focusing on inner-ear drug delivery.

Dr. Staecker is currently evaluating the effect of different vector constructs on cochlear and vestibular function, as well as evaluating the efficacy of atoh1 gene transfer for the regeneration of vestibular function.  A practicing physician / surgeon, Dr. Staecker’s clinical practice focuses on otology and neurotology, specifically cochlear implantation, auditory brain stem implants and acoustic neuroma surgery.Rescue Hearing Inc is developing a gene therapy platform to treat persons with debilitating hearing loss (360M people worldwide).  There are currently no approved therapies for hearing loss. For more information on RHI please visit our website at www.rescuehearing.com or contact CEO / Founder Jim Ayala at jayala@rescuehearing.com.

July 18, 2018:  Rescue Hearing Inc (RHI) has signed a Sponsored Research Agreement with Massachusetts Eye and Ear.  RHI will be conducting research to develop gene therapies for hearing loss in the lab of Dr. Zheng-Yi Chen.  Dr. Chen is a scientific advisor to RHI and an Associate Professor of Otolaryngology at Harvard Medical School.  Dr. Chen’s research interests include functional genomics of hearing, inner ear hair cell regeneration, mechanisms and treatment for age-related and noise-induced hearing loss and gene therapy for hereditary deafness.  For more information on RHI please visit our website at www.rescuehearing.com or contact CEO / Founder Jim Ayala at “jayala@rescuehearing.com“.