Preclinical Pipeline

SXP2523: Best-In-Class Antibiotic for Drug Resistant Gram-Negative Infections

Resistance among hospital acquired infections represents a global challenge for medicine and the treatment of infectious disease.   Antibiotic resistance has become a major cause of morbidity and mortality in the hospital setting resulting in escalating healthcare costs.  Hospital acquired infections alone, with approximately 2 million cases annually, contribute to over $5 billion in US healthcare costs.

Bacteria continue to become more resistant to nearly all of the currently available antibiotics through a variety of resistant mechanisms.  As a result, many key opinion leaders and experts in the field of infectious diseases have expressed concerns as to where the next generation of drugs to combat such pathogens will come from.  This is an especially urgent concern for gram-negative pathogens because nearly all new antibiotic development over the past decade has focused on agents used to treat gram-positive infections.  Thus, there is a dearth of gram-negative agents and consequent urgent unmet need.

The company’s most advanced program, development candidate SXP2523, is a next generation aminoglycoside antibiotic for serious drug resistant gram-negative infections.

SXP2523 is significantly differentiated from both marketed and development stage gram-negative antibiotics with the following profile and key advantages:

• Superior potency against a broad-spectrum of MDR gram-negative clinical isolates including P. aeruginosa, K. pneumoniae, A. baumannii, E. coli, and Staphylococcus aureus (MIC90s < 4 µg/ml)

• Excellent potency against ESBL, efflux, other major mechanisms of resistance

• Cidal with rapid killing kinetics

• Very low frequency of spontaneous resistance development, excellent stability against major MORs – built to be “resistant to resistance”

• Efficacy demonstrated in a variety of animal infection models

• Excellent margin of safety and predicted therapeutic index

• Synergistic with beta-lactam and glycopeptide antibiotics

Best-In-Class Inhaled Aminoglycoside for Drug Resistant Gram-Negative Infections in Cystic Fibrosis and Other Respiratory Diseases

SelectX is also developing a next generation inhaled aminoglycoside antibiotic for drug resistant gram-negative infections in patients with Cystic Fibrosis (CF) and other respiratory diseases.

Cystic Fibrosis (CF) affects over 70,000 patients worldwide.  Hyperviscous mucus in the lungs of CF patients’ impairs its clearance, leading to the retention of  bacteria and development of a biofilm that is not well penetrated by currently available inhaled antibiotics.  CF patients thus become chronically infected at an early age by various organisms, particularly P. aeruginosa.   In fact, more than 50% of CF patients are chronically infected with P. aeruginosa and, of those, over 25% are infected by multi-drug-resistant strains of the bacteria.  However, none of the currently approved inhaled antibiotics or those in clinical development has activity against multi-drug-resistant P. aeruginosa.   This presents a very attractive opportunity which SelectX is well-positioned to address.

The SelectX inhaled aminoglycoside program is focused on creating highly differentiated aminoglycoside antibiotics with the following key advantages:

• Superior potency against resistant bacteria commonly found in lung infections, including P. aeruginosa, K. pneumoniae, B. cepacia and A. baumannii

• Built-in mucolytic activity to enable deep biofilm penetration and improved effects on lung function

• Cidal with rapid killing kinetics

• Excellent margin of safety and significantly improved therapeutic index compared to currently available antibiotics

SelectX is currently focused on SXP2554, a promising lead that could enter preclinical development in 2011.

First-in-Class Aminoglycoside Therapeutics for a Variety of Applications

SelectX’s market-leading Aminoglycoside platform is broadly applicable. In addition to its antimicrobial programs, SelectX has efforts underway to identify and optimize non-antibiotic aminoglycoside (naAG) leads for discovery programs targeting key pathways including:

• Cell migration inhibition: SelectX naAGs have demonstrated potent and cell-type specific inhibition of cell migration; AGs/glycomimetics block the actions of several key pro-angiogenic factors
  (Target Indications: Inflammation, Cancer, Atherosclerosis, AMD,COPD)

• Calcium channel antagonists: SelectX naAGs have demonstrated inhibition of calcium channels and significant proprietary SAR has been developed
  (Target Indications: Pain, CV)

• Metalloproteinase inhibition: SelectX naAGs strongly inhibit Anthrax Lethal Factor (ALF), a metalloproteinase
  (Target Indications: Cancer, Arthritis, AMD, Anthrax)

• Nonsense Mutation Correction: Gentamicin and other aminoglycosides have demonstrated the ability to phenotypically correct nonsense mutations in models of several genetic disorders and tumor suppressors
  (Target Indications: Genetic Diseases, Cancer)

• Anti-viral: Aminoglycosides bind and can block translation of viral RNA
  (Target Indications: HIV, HCV, RSV, et al)

The SelectX Aminoglycoside Platform: Redefining the Paradigm for Aminoglycoside Therapeutics

SelectX has developed a powerful platform of proprietary tools to enable the discovery of novel aminoglycoside compounds.  The SelectX platform includes:

• State-of-the-art comprehensive aminoglycoside medicinal, synthetic analytical chemistry, molecular modeling and structural biology

• Integrated complementary genetic chemistry provides access to otherwise complex/intractable chemistry and SAR, and biosynthesis of complex intermediates

• Proprietary biochemical and whole-cell functional assays permit early and accurate prediction of aminoglycoside efficacy and safety

• Proprietary structure-activity and structure-toxicity relationships (SAR, STR) and deep understanding of mechanisms of mammalian toxicity permit optimization of safety margin

SelectX Pharmaceuticals, Inc.
One Innovation Drive
Worcester, MA  01605
Phone: (508) 798-0216
Fax: (508) 798-0217