GB Therapeutics: Saying NO to CNS Disorders

Overview
GB Therapeutics Ltd. (GBt) is a private company at the forefront of nitric oxide (NO) therapeutics research and application, having created novel nitrate drugs for the treatment of CNS and cardiovascular disorders. The company's contribution to (and competitive advantage in) drug discovery and development is the engineering of nitrates to become smart nitrates that act as NO-mimetics, which represent a new drug class, based on a novel and fundamental approach to NO therapeutics. GBt's smart nitrates are engineered to act at specific tissues and interfere with pathophysiologic processes, without the limiting cardiovascular side effects associated with nitrate compounds. NO-mimetics are the first compounds whose primary structure is designed for NO activity (unlike NO-donors, which are based on a secondary, add-on NO structure). The company's drug discovery team has generated a library of more than 200 proprietary compounds; five patents have issued and ten are pending, worldwide. Although the principal therapeutic action of NO-mimetics is neuroprotection, cognition enhancement and anticonvulsant properties have been observed; and others, including cardioprotection and applications in pain signaling, are under study. Clinical applications include Alzheimer's disease (AD) and other dementias (e.g., vascular), mild cognitive impairment (MCI), epilepsy and others. GBt's lead drug candidate is GT 1061 for the treatment of AD.

GB Therapeutics Ltd. arose from a highly productive collaboration between scientists in the Chemistry and of Pharmacology & Toxicology departments at Queen's University at Kingston. Initial funding was provided by PARTEQ Innovations in kind, The Queen's University Breakthrough Fund (a joint venture of The Canadian Medical Discoveries Fund and Working Ventures). In December the company signed agreements for CAN $4.5 million convertible Debenture and a further CAN $4.0 million lead commitment towards a CAN $15 to 20 Series A round scheduled to close in April 2003.

From Nitroglycerin to NO-Donors to Engineered NO-Mimetics
Although nitrates have been used for the treatment of angina and coronary artery disease for more than 130 years, the role of NO as a biologic mediator was not discovered until 1980. This mediator was first known as endothelial-derived relaxing factor (EDRF), until NO was identified as the active compound in 1986. Basic science research then escalated dramatically, and various roles of NO as an important signaling molecule were discovered. NO was named "molecule of the year" by Science magazine in 1992, and the Nobel Prize in medicine and physiology was awarded for NO discoveries in 1998. [Interestingly, nitroglycerin was first manufactured by the Swedish industrialist and benefactor, Alfred Nobel.] Pharmaceutical R&D of NO-related therapeutics has remained in high gear for about the last decade; and many discovery programs have been based on the search for NO-donors. The NO-donor approach relies on attaching a secondary, NO-donor function to a parent compound already known to be therapeutic, in order to increase its efficacy.

GBt is taking the quest for NO therapeutics beyond NO-donors to focus on development of engineered nitrates as Smart nitrates. GBt is the first group to discover and develop novel primary nitrate structures that are pharmacologically active under pathophysiologic conditions and exhibit tissue selectivity. Anthony Giovinazzo, CEO, likes the therapeutic opportunities offered by a novel class of small molecule drugs, with mechanisms of action that work at a fundamental signaling level. "Our approach to therapeutics — the engineering of nitrates as NO-mimetics — is advanced in its simplicity. We're taking NO therapeutics to the most fundamental physiologic and pathophysiologic levels. NO-mimetics are pharmacologically active in their own right under disease conditions, unlike NO-donors, which rely on secondary structure for activity. Our Smart nitrates are an entirely new class of therapeutic compound! They act as a major player at a primary signaling level and are neuroprotective. They are novel nitrate structures that are devoid of cardiovascular side effects. They are target tissue-selective and therapeutic in disease states."

GBt scientists have been able to engineer out the cardiovascular side effects, while engineering in tissue selectivity. Classical nitrates such as nitroglycerin require metabolic activation to elicit a biologic response. And it is that activation process, which occurs with high efficiency in vascular smooth muscle, which accounts for the ability of nitrates to lower blood pressure. GBt's nitrate structures do not require metabolic activation to act as NO-mimetics on other tissues, most notably in the CNS. Company scientists have the ability to modulate efficiency and potency and regulate tissue selectivity of their nitrate compounds. Controlling and maximizing tissue selectivity is critically important because of the large number of potential therapeutic applications (and, therefore, different target tissues) of NO-mimetics.

GBt is also working on a novel NO-donor approach. The tagging of non-steroidal anti-inflammatory drugs (NSAIDs) with NO-donor function has been exploited successfully to generate more effective anti-inflammatory agents (i.e., augment NSAID activity). However, this approach depends heavily on the parent molecule for some or all of the pharmacological effect. GBt is now working with known drugs to create NCEs with dual — that is, two very different — pharmacologic activities. Company scientists have developed novel nitrates that exhibit activities that are very different from those of the parent compound.

Lead Drug Candidate - GT 1061
Among the factors supporting the selection of GT 1061 as GBt's lead clinical development candidate are its effectiveness in animal models, oral availability and discoveries within the GT 1061 family of back-up compounds and new generations of anti-neurodegenerative and anticonvulsant compounds. Although the company's engineered nitrates act by novel mechanisms, their chemistries are closely related to particular nitrates and thiazoles. As a result, low toxicities and a high level of human safety are anticipated. [Chlormethiazole is closely related to GT 1061 and has been used in elderly and demented patients with few serious adverse effects.] GBt has begun API production in a GMP-certified facility. Preclinical toxicology studies are underway; and the company expects to file an IND by Q-1, 2004. Plans call for completion of a Phase IIa bridging study by Q-2, 2005.

Alzheimer's disease. The company's current primary objective is to achieve successful development of its Smart nitrate GT 1061 in the treatment of Alzheimer's dementia. Strong experimental and clinical evidence support the use of novel nitrates that affect the brain and behavior in patients with AD; and two demonstrated mechanisms of action suggest that GT 1061 may be effective in patients with Alzheimer's dementia. GT 1061 reversed cognitive impairment in an experimental model of Alzheimer's dementia, suggesting the opportunity to develop a new class of therapeutic agents for the symptomatic treatment of dementia that act by a mechanism other than acetylcholinesterase inhibition. GT 1061 also significantly improved learning and memory in experimental animals in which the cholinergic systems of the basal forebrain had been lesioned (by intracerebroventricular injection of a toxin targeted to cholinergic neurons). GT 1061 performed at a level that was at least equivalent to that of Aricept (donezepil HCl), the current market leader among cholinesterase inhibitors.

In parallel studies by the National Institutes of Health (NIH) Anticonvulsant Screening Program, GT 1061 was found to be an effective, broad-spectrum anticonvulsant. The dual pharmacologic activity offers competitive advantages to GT 106 in AD, compared to available drugs. Anticonvulsant drug (or antiepileptic drugs, AEDs) demonstrate neuroprotective properties and, as a class, have been employed in the management of the Alzheimer's patient. The presence of two pharmacologic activities of GT 1061 — cognition enhancement and neuroprotection — may produce a synergistic therapeutic effect in people afflicted with AD.

Epilepsy is also an important potential indication for GT 1061, supported by in-house data and a strong performance in the NIH Anticonvulsant Screening Program. GBt programs will support drug development for this indication; and the company will use the NIH program to assess anticonvulsant activities of other nitrate compounds in its pipeline.

Other Drug Candidates
Other NO-mimetic agents (and families) are in earlier-stage development at GBt. GT 105 has potential cardiovascular applications, providing both cardioprotection and neuroprotection, which suggests novel application in cardiovascular ischemic conditions in which brain oxygenation may also be compromised (e.g., myocardial infarction, coronary artery bypass grafting, angioplasty). Several compounds have undergone preliminary in vitro and animal model studies.

Business Strategy
Commercially, GBt is seeking to maximize its:

• product portfolio — drugs (and drug families) in development;
• overall proprietary position of nitrate esters as NO-mimetics with neuroprotection and cognition enhancement properties;
• focused, expanding chemical library; and
• drug discovery capabilities.

©Drug and Market Development 2003

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