Our initial product candidate is AV-101, an orally-available, non-sedating, non-hallucinogenic prodrug that is rapidly and enzymatically converted in vivo to its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA), one of the most well-characterized, potent and selective synthetic blockers of N-methyl-D-aspartate (NMDA) receptors at the glycine-coagonist (GlyB) site. AV-101 is a potential treatment for multiple diseases and disorders involving the central nervous system (CNS), including Major Depressive Disorder, refractory epilepsy, chronic neuropathic pain and neurodegenerative diseases such as Parkinson’s disease.
We have successfully completed Phase 1 clinical development of AV-101, demonstrating that AV-101 is well tolerated, without any significant safety issues. As a result, AV-101 is a potential Phase 2 clinical development candidate. We are currently in discussion regarding Phase 2 clinical development AV-101 as a potential treatment for Major Depressive Disorder or “MDD”.
Major Depressive Disorder
The World Health Organization (WHO) estimates that 350 million people worldwide suffer from depression. According to the WHO, “depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease.” According to the U.S. Centers for Disease Control and Prevention, nine percent (9%) of the U.S. population suffers from depression.
Although antidepressant medications are available and useful, many patients are treatment-resistant, and currently used depression drugs take several weeks to become effective. A recent exciting development is the finding that ketamine, which is widely used as an anesthetic in surgical settings, has efficacy as a rapidly acting antidepressant in treatment-resistant depression patients. A single intravenous (IV) administration of a sub-anesthetic dose of ketamine results in prompt improvement in mood in depressed individuals, and the beneficial effect is sustained for approximately one week. Despite these promising results, however, IV ketamine’s potential as a long-term antidepressant medication is severely limited due to its addictive nature, anesthetic properties, capacity to produce dissociative (hallucinogenic) effects, even when administered at low doses, and the invasiveness of its most common route of administration (IV). We believe the mechanism of action (MOA) of IV ketamine (an NMDA receptor antagonist) is similar to the MOA of AV-101, but that AV-101 selectively targets a specific glycine site within the NMDA receptor (the GlyB site) and is far less likely to precipitate the adverse effects of IV ketamine.
To date, the NIH has awarded us over $8.8 million of non-dilutive grant funding for our preclinical and successful Phase 1 clinical development of AV-101. We are currently in discussions with the NIH regarding Phase 2 clinical development of AV-101 as a potential new treatment for Major Depressive Disorder.
Preclinical Support for Additional Phase 2 Development of AV-101
AV-101 has been shown to protect against seizures and neuronal damage in animal models of epilepsy, providing preclinical support for its potential as drug candidate for treatment of epilepsy. Epilepsy is one of the most prevalent neurological disorders, affecting almost 1% of the worldwide population. Approximately 2.5 million Americans have epilepsy. Nearly half of the people suffering from epilepsy are not effectively treated with currently available medications. In addition, the anticonvulsants used today 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 result in significant side effects. The endogenous amino acid glycine modulates glutamatergic neurotransmission by stimulating the GlyB co-agonist site of the NMDA receptor. GlyB antagonists inhibit NMDA receptor function and are therefore anticonvulsant and neuroprotective. Importantly, GlyB antagonists have fewer and less severe side effects than classic NMDA receptor antagonists and other antiepileptic agents, making them a safer alternative to, and one expected to be associated with greater patient compliance than, available anticonvulsant medications.
AV-101 has two additional therapeutically important properties as a drug candidate for treatment of epilepsy:
- It is preferentially converted to 7‑Cl‑KYNA in brain areas that neuronal injury. This is because astrocytes, which are responsible for the enzymatic transamination of 4-Cl-KYN to 7-Cl-KYNA, are focally activated at sites of neuronal injury. Due to AV-101’s highly focused site of conversion, local concentrations of newly formed 7‑Cl‑KYNA are greatest at the site of therapeutic need. In addition to delivering the drug where it is needed, this reduces the chance of systemic and dangerous side effects with long-term use of the drug; and
- A metabolite of AV-101, 4-Cl-3-hydroxyanthranilic acid, inhibits the synthesis of quinolinic acid, an endogenous NMDA receptor agonist that causes convulsions and excitotoxic damage.
AV-101’s ability to target activated astrocytes for focal delivery of an anti-epileptic principle, and its dual action as a NMDA receptor GlyB antagonist and quinolinic acid synthesis inhibitor, make AV-101 a potential Phase 2 development candidate epilepsy.
Chronic Neuropathic Pain
The effect of AV-101 on chronic neuropathic pain due to inflammation and nerve damage was assessed in rats by using the Chung nerve ligation model. AV-101 effects were compared to either saline, MK-801 or gabapentin controls. Similarly to what was observed in the formalin and thermal hyperalgesia test systems, AV-101 had a positive effect on chronic neuropathic pain in the Chung model, with no observed adverse behavioral effects. The efficacy observed for AV-101 in both the acute and chronic neuropathic pain model systems was dose dependent, and the drug response was not associated with any side effects within the range of doses administered.
Acute Tissue Injury Hyperalgesia
The antihyperalgesic effect of AV-101 has been evaluated in two standard tissue injury model systems: inflammatory thermal hyperalgesia and the formalin paw test. AV-101 was compared to two positive controls, the classic NMDA antagonist MK-801 (discontinued in preclinical development by Merck due to neurotoxicity) and the anticonvulsant gabapentin. A significant drug response was defined as a response that was greater than or equal to 2 standard deviations (SD) from the response produced by vehicle. Animal behavior and motor function were observed and evaluated throughout the study.
In the formalin hyperalgesia model, MK-801 caused significant spontaneous locomotor activity that prevented assessment of its analgesic activity. However, AV-101 displayed dose-dependent antihyperpathic effects in the absence of behavioral deficits for both Phase 1 (acute nociceptive pain) and Phase 2 (chronic and neuropathic pain) of hyperalgesia. In contrast, gabapentin did not have a significant antihyperpathic response at any dose during Phase 1, but showed a significant positive response during Phase 2.
For the carrageenan inflammatory thermal hyperalgesia model, neither MK-801, gabapentin, nor AV-101 had an effect on acute thermal nociception, but produced a dose dependent block of the carrageenan-induced hyperalgesia that were greater than 2 SD of the vehicle: There were no behavioral changes observed at any AV-101 dose, but signs of behavioral and motor dysfunction were observed for gabapentin and MK-801 treated animals. The profile of analgesic activity observed for AV-101 in the formalin and inflammatory thermal hyperalgesia model systems supports the conclusion that AV-101 demonstrates antihyperalgesic activity in validated models of facilitated pain processing produced by peripheral tissue inflammation.
AV-101 has been shown to activate ventral tegmental area (VTA) dopaminergic (DA) neurons. Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist, as well as a blocker of the 7-nicotinic acid receptor. Mounting evidence suggests that this compound participates in the pathophysiology of schizophrenia. Preclinical studies have shown that elevated levels of endogenous KYNA are associated with increased firing of midbrain DA neurons. Utilizing extra cellular single unit cell recording techniques, we have shown that AV-101, which is converted to the selective NMDA glycine-site antagonist 7-Cl-KYNA, significantly increases the firing rate and percent burst firing activity of VTA DA neurons. These results have potential therapeutic implications for Parkinson’s disease.
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 NMDA receptors triggers an excessive entry of Ca2+, 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), a chronic neurodegenerative disorder, 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. The ability of AV-101 to reduce the brain levels of neurotoxic kynurenine pathway metabolites and to potentially produce significant local concentrations of 7-Cl-KYNA on chronic administration, presents an exciting opportunity for Phase 2 clinical investigation of AV-101 as a potential chronic treatment of HD.