DRUG DISCOVERY AND DEVELOPMENT

Objectives

• To expand Prana’s MPAC platform to build new pipeline assets.
• Identification of new MPACs for the treatment of AD.
• Identification of new MPACs for the treatment of other neurodegenerative diseases such as Parkinson’s Disease (PD), Huntington’s Disease (HD), Age-related macular disorder.
• Identification of MPACs for the treatment of selected cancers, including Brain Cancer.
• Identification of non-MPACs for the treatment of AD.

Since the initiation of Prana chemistry in 2001, over 400 hundred compounds now exist in the company's chemical library. Those compounds are tested in a panoply of disease-specific screens, providing structure-activity relationship (SAR) information. The information from these data sets is then critically analysed to rationally design the next set of compounds.

Outcomes of Discovery:

• Up to 2002: Screening of hundreds of potential leads through AD screens to identify the 8-hydroxyquinolines as an active scaffold.
• 2002-2003: Approximately 200 8-hydroxyquinolines were synthesized, resulting in the discovery of PBT2 (nomination as a candidate in 2003)
• 2003-present: Over 200 non-8-hydroxyquinoline Follow-Up compounds were synthesized. From this, a number of candidates for AD (PBT3 series) and other indications (PBT4 series) are being pursued.
• 2002-present: Non-MPACs projects are being pursued as therapeutic and imaging agents.

PBT2 Development so far:

• Pre-clinical efficacy: PBT2 has exhibited superior performance in a variety of in vitro and in vivo efficacy screening assays designed to assess the ability of a compound to interfere with the toxic mechanisms of AD. Particularly, in mouse models, PBT2:
  • Improved mouse memory performance with five (5) days of oral dosing
  • Rapidly reduced the levels of soluble beta-amyloid ("Abeta") in the mouse brain, and
  • Restored normal function of Abeta-impaired synapses
• Non-clinical toxicology: full ICH-compliant pre-Phase I package, plus chronic toxicity studies in 2 species
• Manufacturing: GMP manufacture of PBT2 API and capsules has been done on large scale
• Clinical development of PBT2 is ongoing. See Clinical Program

PBT3 and PBT4 series Development so far:

• Pre-clinical efficacy: testing in models of AD and other indications
• Prana is validating the preclinical efficacy results for a shortlist of Follow-Up compounds. It is anticipated one or more development candidates will be selected for progression to non-clinical toxicity testing during 2008