Potential Future Indications

Neuropathic pain is a complex, chronic pain state that results from problems with signals from nerves. There are various causes of neuropathic pain, including tissue injury, nerve damage or disease, diabetes, infection, toxins, certain types of drugs, such as antivirals and chemotherapeutic agents, certain cancers, and even chronic alcohol intake. With neuropathic pain, damaged, dysfunctional or injured nerve fibers send incorrect signals to other pain centers and impact nerve function both at the site of injury and areas around the injury. Many neuropathic pain treatments on the market today, including gabapentin, have side effects such as anxiety, depression, mild cognitive impairment and/or sedation.

The effects of AV-101 were assessed in published peer-reviewed studies involving four well-established non-clinical models of pain, both hyperalgesia and allodynia, to examine its analgesic and behavioral profile. The publication, titled: "Characterization of the effects of L-4-chlorokynurenine on nociception in rodents," by lead author, Tony L. Yaksh, Ph.D., Professor in Anesthesiology at the University of California, San Diego, was published in The Journal of Pain in April 2017 (DOI: 10.1016/j.jpain.2017.03.014). In these studies, systemic delivery of AV-101 yielded brain concentrations of AV-101's active metabolite, 7-Cl-KYNA. The high CNS levels of 7-Cl-KYNA were calculated to exceed its IC50 at the NMDA receptor GlyB site and resulted in robust, dose-dependent anti-nociceptive effects, similar to gabapentin, but with no discernable negative side effects.

Gabapentin, a commonly used drug for neuropathic pain, causes sedation and mild cognitive impairment. Therefore, an orally-available drug that is equally effective on pain, but is better tolerated than gabapentin, could be quite important for the millions of patients battling chronic neuropathic pain. Taken together with our successful AV-101 Phase 1a and 1b clinical safety studies, we believe the published results of these non-clinical studies support further Phase 2 clinical development of AV-101 to evaluate its potential as a new orally-available, non-sedating, non-opioid alternative to treat debilitating neuropathic pain.

AV-101 has been shown to protect against seizures and neuronal damage in animal models of epilepsy, providing preclinical support for its potential as a novel treatment alternative for epilepsy. Epilepsy is one of the most prevalent neurological disorders, affecting almost 1% of the worldwide population. According to the Epilepsy Foundation, as many as three million Americans have epilepsy, and one-third of those suffering from epilepsy are not effectively treated with currently available medications. In addition, standard anticonvulsants can cause significant side effects, which frequently interfere with compliance.

Glutamate is a neurotransmitter that is critically involved in the pathophysiology of epilepsy. Through its stimulation of the NMDA receptor subtype, glutamate has been implicated in the neuropathology and clinical symptoms of the disease. In support of this, NMDA receptor antagonists are potent anticonvulsants. However, classic NMDA receptor antagonists are limited by adverse effects, such as neurotoxicity, declining mental status, and the onset of psychotic symptoms following administration of the drug. The endogenous amino acid glycine modulates glutamatergic neurotransmission by stimulating the GlyB co-agonist site of the NMDA receptor. GlyB site antagonists inhibit NMDA receptor function and are therefore anticonvulsant and neuroprotective. Importantly, GlyB site antagonists have fewer and less severe side effects than classic channel-blocking NMDA receptor antagonists and other antiepileptic agents, making them a safer potential alternative to, and one expected to be associated with greater patient compliance than, available anticonvulsant medications.

Parkinson's disease (PD) is a chronic and progressive movement disorder, meaning that symptoms continue and worsen over time. According to the Parkinson's Disease Foundation, as many as one million Americans live with PD and more than 10 million people worldwide are living with PD. The cause of PD is unknown, and there is presently no cure.

PD involves the malfunction and death of certain nerve cells in the brain that produce dopamine, a key chemical that sends messages to the part of the brain that controls movement and coordination. As PD progresses, the amount of dopamine produced in the brain decreases, leaving a person unable to control movement normally.

Levodopa (L-DOPA) therapy increases brain levels of dopamine and is the gold standard for treating symptoms of PD in nearly all phases of the disease. Currently, it is considered the most effective drug for controlling the symptoms of PD. However, L-DOPA-induced dyskinesia (LID) is a common, and generally disabling, complication of long-term L-DOPA treatment in PD patients. Studies published in the New England Journal of Medicine and Movement Disorders have shown that LID develops in approximately 45% of L-DOPA-treated PD patients after five years and 80% after 10 years of L-DOPA treatment. This dyskinesia, or uncontrollable muscle movement, induced by L-DOPA therapy, is not part of PD, but instead a complication of L-DOPA therapy. LID interferes not only with L-DOPA treatment of PD, but also negatively impacts the quality of life of PD patients and is a major contributor to disability later in the ordinary course of the disease. While amantadine, a low-affinity NMDA receptor antagonist, has been shown to offer some relief for certain PD patients suffering from LID, more effective and better tolerated pharmacologic management of LID remains a significant unmet medical need.

In a monkey model of PD, AV-101 (250 mg/kg and 450 mg/kg) reduced by 30% the mean dyskinesia score associated with L-DOPA treatment of PD. Maximum dyskinesia scores were also reduced by 17%. Importantly, AV-101 did not reduce the anti-parkinsonian therapeutic benefit of L-DOPA. Moreover, the duration of L-DOPA response and delay to L-DOPA effect were not affected by treatment with AV-101. We believe these preclinical monkey data warrant Phase 2 clinical development of AV-101 in L-DOPA-treated PD patients suffering from LID.

Working together with metabotropic glutamate receptors, the NMDA receptor ensures the establishment of long-term potentiation (LTP), a process believed to be responsible for the acquisition of information. These functions are mediated by calcium entry through the NMDA receptor-associated channel, which in turn influences a wide variety of cellular components, like cytoskeletal proteins or second-messenger synthases. However, over activation at the NMDA receptor triggers an excessive entry of calcium ions, initiating a series of cytoplasmic and nuclear processes that promote neuronal cell death through necrosis as well as apoptosis, and these mechanisms have been implicated in several neurodegenerative diseases.

Huntington's disease (HD) is an inherited disorder that causes degeneration of brain cells, called neurons, in motor control regions of the brain, as well as other areas. Symptoms of the disease, which gets progressively worse, include uncontrolled movements (called chorea), abnormal body postures, and changes in behavior, emotion, judgment, and cognition. HD is caused by an expansion in the number of glutamine repeats beyond 35 at the amino terminal end of a protein termed "huntingtin." Such a mutation in huntingtin leads to a sequence of progressive cellular changes in the brain that result in neuronal loss and other characteristic neuropathological features of HD. These are most prominent in the neostriatum and in the cerebral cortex, but also observed in other brain areas.

The tissue levels of two neurotoxic metabolites of the kynurenine pathway of tryptophan degradation, quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK) are increased in the striatum and neocortex, but not in the cerebellum, in early stage HD. QUIN and 3-HK and especially the joint action of these two metabolites, have long been associated with the neurodegenerative and other features of the pathophysiology of HD. The neuronal death caused by QUIN and 3-HK is due to both free radical formation and NMDA receptor overstimulation (excitotoxicity).

Based on the hypothesis that 3-HK and QUIN are involved in the progression of HD, early intervention aimed at affecting the kynurenine pathway in the brain may present a promising treatment strategy. We believe the ability of AV-101 to reduce the brain levels of neurotoxic QUIN and to potentially produce significant local concentrations of 7-Cl-KYNA on chronic administration, presents an exciting opportunity for further investigation of AV-101 as a potential chronic treatment alternative for certain symptoms of HD.