Pipeline

Talon Pharmaceuticals is developing several small molecule therapeutic agents to treat rare diseases of the CNS and multidrug-resistant (MDR) bacterial infections. Each of Talon’s development candidates incorporates multiple mechanisms of action without tethering therefore maintaining suitable drug-like properties to support once or twice daily dosing.

TPS-100 and ARSACS

Talon’s lead product is currently in preclinical development as a therapeutic for the treatment of motor coordination and neurodegeneration in ARSACS (Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay). ARSACS is an orphan disorder resulting in a mutation in the SACSIN protein and is the second most prevalent autosomal recessive ataxia after Friedreich’s ataxia. ARSACS is a childhood onset disorder with symptoms appearing as early as 12-24 months of age when a child begins to take their first steps. Children with the disorder frequently fall and appear to have an unsteady (Ataxic) gait. ARSACS was first characterized in the Saguenay-Lac St. Jean area of Quebec but is diagnosed in many countries around the world. Some of the signs and symptoms include: stiffness of the legs, appendicular and trunk ataxia, hollow foot and hand deformities, ataxic dysarthria, distal muscle wasting, horizontal gaze nystagmus, and spasticity. Currently there are no treatments for ARSACS.

Some of the signs and symptoms include: stiffness of the legs, appendicular and trunk ataxia, hollow foot and hand deformities, ataxic dysarthria, distal muscle wasting, horizontal gaze nystagmus, and spasticity. Currently there are no treatments for ARSACS.


Amyotrophic Lateral Sclerosis (ALS)

ALS is a devastating adult neurodegenerative disorder characterized by motor neuron degeneration and death around 3-4 years from onset. Riluzole (RILUTEK) is the only treatment available, although it only offers a slight increase in survival. Although RILUTEK improved early survival, measures of muscle strength and neurological function did not show a benefit. The complex etiology of ALS, with several genes able to trigger the disease, makes its study and treatment difficult. We believe that successful treatment of ALS will likely require targeting multiple mechanisms of action.

Talon is utilizing its Multiphore approach to identify potential therapies for the treatment of ALS with the aim of improving both survival but also motor and neurological function.


MULTIPLE ACTION DRUGS TO ADDRESS GROWING BACTERIAL MULTIDRUG RESISTANCE (MDR)

The continuing threat of multidrug resistant (MDR), particularly among gram-negative bacteria, is increasing due in part to a lack of development of new agents that are better designed to evade resistance mechanisms. Resistance is particularly challenging in the hospital environment due to the number of susceptible patients with underlying co-morbidities and/or who are immunocompromised. The most common nosocomial infections include pneumonia, urinary tract infections, bloodstream and surgical site infections, and risk of antibacterial resistance increases in patients with indwelling devices such as endotracheal and nasogastric tubes, urinary and venous catheters. Antibiotic resistance is increasingly prevalent among the ESKAPE pathogens, namely Escherichia coli, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter spp. Pseudomonas aeruginosa and Enterobacteriaceae. In both hospital- and community-acquired pneumonia, the PEAK pathogens (Figure 1) are responsible for much of the increases in MDR gram-negative infections. Compounds under development by Talon are designed to treat infections caused by multidrug-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae and those organisms harbouring extended-spectrum beta-lactamases. To minimize the development of bacterial resistance, several series of new chemical structures, incorporating pharmacophores acting via multiple mechanisms of action, are being synthesized.



Figure 1. Cases of Pneumonia resulting from PEAK Gram-negative Pathogens

Carbapenem resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, and MDR P. aeruginosa represent the most challenging resistant pathogens according to the CDC.



Table 1. Estimated incidence and mortality of problematic Antibiotic-resistant Gram-Negative Pathogens in the US.

Talon has designed two series of novel antibiotics to treat infections caused by MDR P. aeruginosa, CRE and ESBL pathogens. Talon is minimizing the development of resistance through the incorporation of multiple mechanisms of action and pharmacophores designed to evade resistance mechanisms.