[ TECHNOLOGY OPPORTUNITY 1995 -033 ]

NO-Chimera Drugs & NO-Mimetic Therapeutic Approaches to Neurological Disorders including Alzheimer’s Disease

1. The Opportunity

• NO enhanced nitrate therapeutics are in intensive preclinical and clinical development across a broad range of therapeutic targets supported by big pharma.
• NO-chimera nitrate therapeutics provide exciting, novel approaches to unmet neurological disorders including Alzheimer’s and Parkinson’s.
• A large proprietary library of novel nitrates and NO-chimera drugs have been developed and are extensively protected by patents that cover novel composition and methods of preparation and use including in neurological disorders.
• This technology has attracted significant investment to-date, moving one NO- chimera drug candidate into clinical trials for Alzheimer’s.
• The technology presents a significant opportunity for companies with drug discovery programs in the CNS area and those interested in acquiring a novel drug discovery platform.
• The technology continues to attract awards and grants from agencies including NIH.
• The technology, including an extensive drug discovery portfolio of NO-mimetics and NO-chimeras, has recently become available for licensing.

2. Background

The nitric oxide (NO) mimetic nitrate, nitroglycerin, has been in clinical use for over a century, but it was not until 1998 that the Nobel Prize was awarded recognizing the discovery of NO as an essential molecule for life. Disruption of NO homeostasis is implicated in diseases from hypertension to cancer to neurodegeneration. NO signaling is essential for learning and memory and is disrupted in diseases such as Alzheimer’s (Thatcher et al, 2005).

Nitrates mimic the biological activity of NO, while generating no more than small quantities of cellular NO. NO-mimetics that incorporate at least one additional pharmacophore are NO-chimeras; novel therapeutics engineered to target more than one site of action.

Deriving from earlier academic research, a drug discovery program was initiated at Queen’s University at Kingston in 1996 resulting in the development of an extensive library of NO-chimeras and NO-mimetics. A spin-off company was formed, GB Therapeutics and the entire program has been under exclusive license since 1997. The program benefited from significant investment from the venture capital community in a technology that included 3 lead compounds validated by animal models in different disease areas. Given the compelling animal data of GT 1061, the company moved this NO-chimera into preclinical and early clinical development. The renamed company, Cita Neuro pharmaceuticals, has since been acquired and this unique technology portfolio has become available because of a shift in focus to late stage clinical development.

3. Assets

• An extensive patent portfolio of issued patents and pending patent applications providing per-se coverage of the compounds and multiple method of treating and methods of making claim sets. The portfolio contains two families: Family A contains 6 issued US patents, 5 international patents (Europe, Australia (2), Mexico and Canada) and pending applications in 4 additional jurisdictions; Family B contains 3 issued international patents (Australia, Europe, and Hong Kong), allowed US and pending applications in three additional jurisdictions.

• A complete pre-clinical and clinical data package relating to the development of GT1061 is available on a limited option basis. Appendix 1 lists the table of contents of the package.

4. Compounds

a. Animal Data

• GT 1061 is a novel NO-chimera drug that incorporates an ancillary pharmacophore with demonstrated neuroprotective properties. It is an orally effective cognition enhancing agent in rats in which a cognition deficit has been induced (Bennett et al, 2006); it has anticonvulsant activity, antidepressant activity, and is sedative at higher doses.

The decision to move GT 1061 to the clinic was based upon compelling animal data showing reversal of cognitive deficits in a variety of behavioural paradigms and using agents such as ß-amyloid to induce deficits in learning and memory (Table 1).

Fig. 1 (left). GT1061 and donepezil improve performance in the DMTS task, which measures recognition memory performance. The decreased accuracy in the task after cholinergic depletion was reversed at all doses of GT1061.

As an example, DMTS tests visual recognition memory loss, a type of memory deficit seen in humans in early stage Alzheimer’s. Many conditions adversely affecting learning, memory, and cognition are associated with reductions of forebrain acetylcholine, most notably aging and Alzheimer’s disease. Selective experimental depletions of forebrain acetylcholine in animals produce a variety of cognitive disorders, including specific learning and memory problems. An important strategy for developing potential new enhancers of cognition in relevant disorders includes an evaluation of their efficacy in reversing memory deficits induced by selective cholinergic depletion. The study was designed to evaluate the cognition enhancing properties of the nitrate ester, GT 1061, administered orally in animals that had received bilateral destruction of forebrain cholinergic nuclei. We tested memory performance in a delayed, visual matching-to-sample task (DMTS), which assesses recognition memory performance (Fig.1). We also evaluated the pharmacokinetic properties and CNS availability of GT1061, and potential signal transduction pathways that may be involved in its action.


• GT 715 is an NO-mimetic that is neuroprotective in animal models of Parkinson’s disease and ischemic stroke at least 4 hours after the ischemic event. In the middle cerebral artery occlusion rat model of focal ischemia, GT715 reduced the cerebral infarct by 60-70% when administered 4 hours after the onset of ischemia.

Figure 2 (left). Effect of GT715, administered 4 h after the onset of ischemia, on the outcome of ischemic brain injury. The volume of the total and cerebral infarct in the brains of GT715-treated animals was significantly decreased compared to vehicle-treated animals (*, P<0.01, Student’s t-test). GT715 in DMSO, or DMSO vehicle was administered by subcutaneous injection: (a) 2 h post-ischemia (in five divided doses of 200µmol/kg body weight at 2, 4, 5, 6, 8, and 10 h after the onset of ischemia), see Table 2; or (b) 4 h post-ischemia (in five divided doses of 200 µmol/kg body weight 4, 5, 6, 8, and 10 h after the onset of ischemia.

• GT 094 is an NO-chimera related to GT 715 that incorporates an NSAID-like pharmacophore; it possesses anti-inflammatory, antinociceptive, and analgesic properties; it is chemopreventive against tumor formation and inflammatory biomarkers in rat models of colon cancer.

GT 094 affected both phases of the pain response in the formalin model, indicating that this novel organic nitrate can influence both peripheral and central processes in pain transmission. These agents may be especially useful in conditions where tissue injury (eg., surgery, cancer) or inflammation (eg., arthritis) plays a key role in the sensitization of sensory afferents that increases pain transmission and perception.

b. Preclinical Data

A preclinical work-up of GT 1061 was completed in the Fall of 2003. An extensive Drug Substance, Drug Product and Preclinical Data Package is available for review; a summary table of contents is listed in Appendix 1.

An IND was filed in December 2003 with the US FDA for the conduct of a Phase 1a trial: A Single-Centre Randomized Double-Blind Phase 1a Study of Escalating Single Dose GT1061 Oral Administration to determine its Safety, Tolerability and Pharmacokinetics in Male and Female Healthy Volunteers between 50 and 70 years of age. The Canadian equivalent was filed with the Therapeutic Products Directorate (TPD) of Health Canada in January 2004.

c. Clinical Data

Between January and April 2004, a Phase 1a study was conducted under GCP in Toronto, Ontario. In the initial Phase 1a study, healthy elderly volunteers were orally administered GT1061 as reconstituted from powder-in-a-bottle with citrate buffer. The 10 mg starting dose and the subsequent 30mg dose did not result in adverse events and plasma levels could not be detected. However, for the100 mg dose, the pharmacokinetic profile exhibited a sharp peak shortly after dosing. In addition, some subjects exhibited clinically symptomatic arterial hypotension which was correlated to the peak blood drug concentrations. These events were resolved without intervention within about 30 minutes. For the next cohort, the 150 mg dose was administered with the volunteers in supine position. Again, similar events occurred rapidly after dosing and disappeared within 20 minutes.

Because of the subjects’ reactions, the trial safety committee decided to suspend the study. Further work was recommended to reformulate the drug from the rapid acting solution into an oral dosage form that would dampen the slope and peak height of pharmacokinetic profile. The decision was made by the company to not undertake this work due to the limited availability of funds.

5. Patent Portfolio

The patent portfolio is organized into two families: one relating to compounds and methods for treating neurological conditions (Family A); and the other relating to methods for providing sedation and anaesthesia, and treating pain and anxiety (Family B).

Family A includes pharmaceutical composition coverage for GT1061, per se coverage for GT 715 and several other compounds in the proprietary library. The portfolio includes six issued US patents and a complimentary array of other jurisdictions. Patent term runs until 2016 or 2017 however patent term extension of 3 to 5 years may be available in certain jurisdictions.

A summary of the patent portfolio is available here.

6. Selected References

Bennett, B.M, Reynolds, J.N,, Prusky, G.T., Douglas, R.M., Sutherland, R.J., and Thatcher, G.R. (2006) Cognitive Deficits in Rats after Forebrain Cholinergic Depletion are Reversed by a Novel NO Mimetic Nitrate Ester. Neuropsychopharmacology. Mar 8.

Lei, S., Orser, B.A., Thatcher, G.R., Reynolds, J.N., and MacDonald, J.F. (2001)
Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons. J Neurophysiol. 85, 2030-2038.

Nicolescu, A.C., Zavorin, S.I., Turro, N.J., Reynolds, J.N. and Thatcher, G.R. (2002). Inhibition of lipid peroxidation in synaptosomes and liposomes by nitrates and nitrites. Chem. Res Toxicol, 15, 985-98.

Reynolds, J.N., Bennett, B.M., Boegman, R.J., Jhamandas, K., Ratz, J.D., Zavorin, S.I., Scutaru, D. and Thatcher, G.R.J. (2002) Neuroprotection against ischemic brain injury conferred by a novel nitrate ester. Bioorg. Med. Chem. Lett. 12, 2863-2866,

Smith, S., Dringenberg, H.C., Bennett, B.M., Thatcher, G.R., and Reynolds, J.N. (2000) A novel nitrate ester reverses the cognitive impairment caused by scopolamine in the Morris water maze. Neuroreport. Nov 27;11 (17):3883-6.

Thatcher, G.R. (2005) An introduction to NO-related therapeutic agents. Curr Top Med Chem. 5, 597-601.

Thatcher, G.R., Bennett, B.M., and Reynolds, J.N. (2005) Nitric oxide mimetic molecules as therapeutic agents in Alzheimer's disease. Curr Alzheimer Res. 2, 171-82.

Thatcher, G.R, Bennett, B.M., Dringenberg, H.C., and Reynolds, J.N. (2004) Novel nitrates as NO mimetics directed at Alzheimer's disease. J Alzheimers Dis., 6, S75-84.

Thatcher, G.R., Nicolescu, A.C., Bennett, B.M., and Toader, V. (2004) Nitrates and NO release: contemporary aspects in biological and medicinal chemistry.
Free Radical Biology & Medicine, 37, 1122-43.

Toong, S., Xiong, Z.G., Zavorin, S.I., Bai, D., Orser, B.A., Thatcher, G.R., Reynolds, J.N. and MacDonald, J.F., (2001) Modulation of AMPA receptors by a novel organic nitrate. Can J Physiol Pharmacol. 79, 422-429.

Yang, K., Lock, J., Sanchez, C., Artz, J.D., Bennett, B.M., Fraser, A.B. and Thatcher, G.R.J., (1996), Synthesis of novel organic nitrate esters: Guanylyl cyclase activation and tissue relaxation. J. Chem. Soc. Perkin. Trans. 1, 1073

Zavorin, S.I., Artz, J.D., Dumitrascu, A., Nicolescu, A., Scutaru, D., Smith, S.V. and Thatcher, G.R. (2001) Nitrate esters as nitric oxide donors: SS-nitrates. Org. Lett, 3, 1113-6.

Appendix A: PreClincial & Clinical Data Package - GT 1061

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