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A NOVEL APPROACH TO FIGHTING NEURODEGENERATIVE DISEASES

Research and Development

WavoDyne Therapeutics supports both preclinical drug discovery efforts and clinical product development programs focused on neurodegenerative diseases. We have taken on the challenge of attacking neurodegenerative diseases with a fundamentally new approach. It is known that activation of the Mixed Lineage Kinase ( MLK ) class of enzymes can set off an inflammatory cascade involving the release of TNFα and IL-6, the generation of free radicals and other pro-inflammatory molecules in the CNS in response to injury, exposure to neurotoxins, or related cellular stresses; this pathologic process is referred to as neuroinflammation. Working in concert, the inflammatory cytokines and chemokines released in neuroinflammation can become autocatalytic, and overwhelm our intrinsic anti-inflammatory defense mechanisms. The process of neuroinflammation impairs the function of neurons and their synaptodendritic networks, eventually leading to impairment of cognition and memory problems.

NeuroInflamatory Process

Activation of our innate immune system in the brain creates sustained neuroinflammation. This occurs due to infiltrating macrophages and transformation of microglia into a neurotoxic phenotype. MLK-3 enzymes play a dominant role in mediating neuroinflammation; Loss of synapses and cognitive decline results.


Neuroinflammation occurs chronically in a number of different neurodegenerative diseases, the chart below is our estimate from a review of the medical literature of the approximate number of patients who suffer memory and cognitive impairments for the disease categories presented.

Disease Targets POCD HAND

Read more about our science, our current progress, and our upcoming clinical trials.

Neurodegenerative Disease

We’re born with > 100 billion nerve cells in our brains which do not replicate or reproduce themselves over the course of our life. These nerve cells form elaborate neural networks with other nerve cells providing us almost unlimited capacity to store memories, learn new skills, and consolidate input from our senses, etc. The touch points between nerve cells are formed by and interconnected through synapses, which serve as relay switches to transmit a neural impulse through a vast network of nerve cells. A single neuron has hundreds to thousands of synaptic connections with other nerve cells, creating a multiplexing network that allows all neurons to communicate with thousands to tens of thousands other nerve cells through the process of neural transmission. This results in an estimated 0.15 quadrillion functional contacts required in a healthy brain for full functional information transfer.

Breakdowns in neural transmission can have multiple causes, dependent on the disease state, but ultimately the nerve cell loses its capacity to self-repair in the face ongoing progressive disease pathology. Impaired functioning of a nerve cell leads to gradual losses in synaptic function, which in turn leads to ever greater progressive losses of our neural networks. Multiple failures of several synapses in a network will soon lead to loss of that network, and the death of the associated neurons. Neuroplasticity is the concept of the brain adapting or modifying its structure to requirements from the internal and external environments. This process allows us to recover from injury or compensate for neurological disorders. However, the unremitting process of neuroinflammation defeats the possible gains or improvements in cognitive function that neuroplasticity can deliver. Therefore, turning off neuroinflammation is the necessary first step to the challenge of recovering cognitive functions and memories through the compensatory process of neuroplasticity.

Therapeutic Approaches

WavoDyne Neurotherapeutic’s drug prototypes target the inhibition of the Mixed Lineage Kinases ( MLK ), which are a family of enzymes whose activation is known to be a precipitating event for setting in-motion the neuroinflammatory process. MLK3 is a major member of this enzyme class and our lead drug URMC-099 demonstrates very potent activity at inhibiting this enzyme. Extensive testing of our lead drug candidate, URMC-099, in both in vitro and in vivo test systems which model Multiple Sclerosis (MS), HIV-associated Neurocognitive Disorders(HAND), and Parkinson’s Disease (PD), and Postoperative Cognitive Dysfunctions (POCD), holds promise that this drug will exhibit similar neuro-anti-inflammatory activity in man.

URMC099 structure

Structure of URMC-099

Disease Targets

The cognition and memory disorders associated with Multiple Sclerosis (MS), Traumatic Brain Injury (TBI), HIV-associated Neurocognitive Disorders(HAND), and Parkinson’s Disease (PD), and Postoperative Cognitive Dysfunctions (POCD) probably share a common pathophysiology involving neuroinflammation. While there are pharmacotherapies to treat many of the symptoms associated with these diseases, the progressive deterioration of memory and cognitive functions resulting from neurodegeneration remains untreated, ultimately compromising the ability of the patient to practice the routine activities of daily living and to live independently of caregivers or social services.

Signs and Symptoms of Cognitive Disorders possibly resulting from NeuroInflammation

  • Deficits in maintaining complex attention
  • Problems in efficiency of information processing
  • Failing long term memory
  • Unable to follow a conversation which is changing topics
  • Unable to maintain employment
  • Unable to run a household
  • Loss of coping skills
  • Shutdowns at periods of peak mental demands
  • Mood disorders, depression, and other neuropsychological impairments

WavoDyne Therapeutics has chosen HAND and POCD has the initial clinical development programs where the efficacy of URMC-099 to inhibit neuroinflammation will be tested in man. Additional information on these two neurological syndromes follow below:

HAND (HIV-Associated Neurocognitive Disorders)

There are approximately 1.2 mm patients currently in the U.S. who are HIV-positive, and about 50,000 newly diagnosed HIV-positive patients join this pool on a yearly basis. The advent of Anti-Retroviral Therapy ( ART ) 30 years ago insures that HIV-positive patients who are compliant with their drug therapy can live near-normal lives. But even with the significant advances made over this time in the selectivity and potency of ART drugs, the HIV virus is still able to elude eradication through its ability to assume a latent, non-infectious form and remain sequestered in certain barrier compartments of the human body, most notably the CNS. As long as this situation persists, the patients can never expect a “cure” from their ART treatments, and the neurotoxins released by the latent form of the HIV virus cause a chronic neuroinfammatory reaction in the brain.

The longer the period of time a person has been infected by the HIV virus, the higher the probability that this person will have some form of cognition or memory impairment resulting from this neuroinflammation. The year 2015 represents something of a watershed event since over 50% of the HIV-infected population of patients in the U.S. will be > 50 years of age. Current market research indicates 50% of HIV-infected patients suffer from HAND, although most do no self-report their symptoms.

POCD (Postoperative Cognitive Dysfunction)

This well-known syndrome is characterized by memory or thinking impairment occurring after surgical operations that have involved general anesthesia. POCD has been quantified through several meta analyses using neuropsychological testing over the years, but its cause still remains an enigma. POCD is a general phenomenon affecting surgical patients of all ages, but in the patients > 65 years of age, POCD can lead to permanent problems with attention, executive level functions, and memory. For patients > 65 years of age undergoing Coronary Artery Bypass Graft ( CABG ) surgery, particular if such patient has a secondary co-morbidity such as diabetes or COPD, the odds are that 1 in 2 patients emerging from CABG surgery are likely to have some step-down in their cognitive abilities from which they will not recover.

The number of elderly patients in the U.S. undergoing CABG surgery on an annual basis places a significant number of people at risk for experiencing POCD.

POCD in seniors

Product Pipeline

Projected Product Pipeline | 2017
WavoDyne Product Pipeline

Intellectual Property

  • Japanese Patent No. 5,873,544
    MLK Inhibitors and Methods of Use.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann and C. Loweth.
    Issuance date: 01/22/2016

  • US Patent No. 9,181,247
    Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann and C. Loweth.
    Issuance date: 11/10/2015

  • US Patent No. 8,846,909
    Bicyclic heteroaryl kinase inhibitors and methods of use.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann, S.B. Ravula and C. Loweth.
    Issuance date: 09/30/2014

  • US Patent No. 8,877,772
    Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann and C. Loweth.
    Issuance date: 11/04/2014

  • New Zealand Patent No. 603644
    Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann, S.B. Ravula and C. Loweth.
    Issuance Date: 02/03/2015

  • China Patent No. 20090152665.1
    MLK Inhibitors and Methods of Use.
    Inventors: H.A. Gelbard, S. Dewhurst, V.S. Goodfellow, T. Wiemann and C. Loweth.
    Issuance date: 02/11/2015

  • PCT Application: PCT/US2009/065878
    Mixed Lineage Kinase (MLK) Inhibitors and Methods of Use
    Filing Date: 11/25/2009
    Pending in Australia, Europe, Japan and New Zealand

  • PCT Application: PCT/US2011/037758
    Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
    Filing Date: 05/24/2011
    Pending in Australia, China, Europe and Japan

Collaborations

Dr. Harris ('Handy') Gelbard

Dr. Gelbard is the Director of the Center for Neural Development and Disease and Professor of Neurology, Pediatrics and Microbiology & Immunology at the University of Rochester Medical Center. Dr. Gelbard’s lab provides support to WavoDyne Therapeutics in identifying our lead product development candidates through his state-of-the-art drug screening technologies which model various aspects of neuroinflammation.

Dr. Steven Dewhurst

Dr. Dewhurst is Vice Dean for Research and Dean's Professor and Chair of Microbiology & Immunology at the University of Rochester School of Medicine and Dentistry (URSMD). His laboratory specializes in neurotoxicity models of HIV infection, neuroinflammatory mediators, and methods or therapeutic modalities for the treatment of HAND.

Mr. Scott Catlin, Esq.

Mr. Catlin is the Associate Vice President in the UR Ventures Office. This office provides access, direction and staff assistance to WavoDyne Therapeutics as we scale-up our operations in the Rochester area.

Dr. Howard Gendelman

Dr. Howard E. Gendelman is the Margaret R. Larson Professor of Internal Medicine and Infectious Diseases, Chairman of the Department of Pharmacology and Experimental Neuroscience, and Director of the Center for Neurodegenerative Disorders at the University of Nebraska Medical Center. Dr. Gendelman is performing experiments with URMC-099 in a humanized mice model of HIV to assess the potential of this molecule to synergize with other ART modalities when presented in a proprietary nano-formulated technology.