EPIX believes that the company’s proprietary drug discovery technology and approach, based on the structure of the target protein and other off-target proteins, can address many of the challenges that have hindered traditional G-Protein Coupled Receptor (GPCR) and ion channel drug discovery. Using their proprietary algorithms, EPIX models the 3D structure of any GPCR from its primary amino acid sequence. The company utilizes known experimental data about the target and can incorporate known drug structures into the in silico construction of the 3D structure. EPIX's technology enables the company to explore all possible structural geometries of the protein target, taking into account specific interactions between the protein and the membrane, as well as specific interactions within the protein itself.
EPIX uses these structures of the target GPCR or ion channel together with other off-target structures and predictive algorithms to discover and optimize highly selective drugs with anticipated favorable side effect profiles. Using this technology and approach EPIX can:
- incorporate greater selectivity into the company’s drug candidates by examining the interaction of suggested compounds with our structures in silico, and eliminating those that may have affinity for other targets, which the company believes will result in drug candidates with favorable side effect profiles;
- identify some potential safety, pharmacokinetics and toxicology issues through in silico predictions prior to the company’s medicinal chemists synthesizing and testing actual compounds; and
- synthesize 10-30 fold fewer compounds than in traditional GPCR or ion channel lead optimization programs by adopting structure-based lead optimization strategies and evaluating compounds in silico prior to the synthesis of actual compounds.
EPIX believes their ability to achieve success in drug discovery and optimization was first demonstrated in their anxiety and depression program, targeting the GPCR known as 5-HT1A. The company’s initial lead compound identified from in silico screening had good affinity for 5-HT1A but was problematic due to its high affinity for the off-target GPCRs named the alpha-adrenergic receptors type 1 and 2, which are believed to be associated with hypotension and lightheadedness. During the first cycle of lead optimization, EPIX determined the structure of these off-target GPCRs, studied the interaction of their lead compound with these structures, and then modified their compound to reduce its affinity for the off-target GPCRs while maintaining its affinity for the target. EPIX accomplished this within fifteen compounds synthesized and in less than two months.
The next challenge EPIX faced in lead optimization was reducing affinity for a specific potassium ion channel protein named hERG that has been linked to drug-induced cardiac arrhythmia. In EPIX’s second round of lead optimization, starting from their fifteenth molecule, the company created an in silico structure of the hERG ion channel and modified their compound to reduce its affinity for this ion channel. Using their proprietary technology and approach, EPIX was able to maintain a good drug-like profile and solve the hERG issue, and EPIX nominated their twenty-third synthesized compound, PRX-00023, as a drug candidate. PRX-00023 completed a Phase 2 clinical trial in GAD in July 2005. EPIX initiated a Phase 3 clinical trial with PRX-00023 in patients with GAD in August 2005 under Special Protocol Assessment with the FDA. The results from this Phase 3 trial were announced in September 2006.
