Prana may go it alone with Alzheimers drug

Melbourne meditech company Prana Biotechnology (ASX:PBT, NASDAQ:PRAN) is prepared to take its lead drug for Alzheimer's disease all the way to the market if a major clinical trial in the UK confirms its efficacy.

Prana announced on January 4 that the UK's Medicines and Healthcare Regulatory Agency (MHRA) has approved the Phase II/III clinical trial, which will involve 435 patients with moderate Alzheimer's disease.

The year-long PLACQUE (Progression Limiting in Alzheimer's: Clioquinol's Efficacy) study seeks to confirm indications from an earlier Phase IIa trial that Prana's lead compound PBT1, or clioquinol, significantly slows the progression of the devastating neurodegenerative disorder.

CEO Jon Alsenas described the trial's approval as a "milestone" for Prana, after the company's resolution last year of its dispute with Greek company P.N. Gerolymatos over the IP rights to clioquinol, a discarded antibiotic, used four decades ago to treat traveller's diarrhoea.

But Prana's second-generation metal-protein attenuating compound (MPAC), a next generation clioquinol variant that shows superior activity to clioquinol in dispersing amyloid plaque in in vitro, might catch or even overtake PBT1 on the road to the market, according to Prana's President and Chief Operating Officer Dr Ross Murdoch.

"At the moment PBT1 is in front, however PBT2 continues to move forward rapidly and we hope it might catch up," Murdoch said. "We'd then be in the enviable position of being able to choose from two compounds."

PBT2 retains clioquinol's core 8-hydroxyquinoline molecular structure, but Prana's chemists have made several strategic changes to the functional groups attached to the rings.

Murdoch said the substitutions have improved several of the molecule's properties including solubility and PBT2 now shows some clear differentiation from PBT1. A known adverse effect of chronic clioquinol use is a visual disorder, subacute myelopathic optic neuropathy (SMON), associated with vitamin B12 deficiency and anaemia - the reason for the drug's withdrawal in the early 1970s.

The PLAQUE phase II/III trial is pivotal to commercial registration - if it confirms the strong efficacy of MPACs in slowing or halting the cognitive decline of Alzheimer's disease, Prana will seek discussions with regulatory agencies to register PBT1 on this study alone. But he strongly suspects a further phase III trial would be necessary.

Murdoch said Prana is considering all of the options, including going it alone - "The feedback we're getting from our investors is that if the results of PLACQUE are positive then the support should be there for us to take it through to the market ourselves. It then comes down to the question of risk - not whether we can raise the funds, but the risk that the drug might not succeed.

Despite the failure of an anti-amyloid vaccine developed by Irish biomedical company Elan Pharmaceuticals, which caused bleeding in the brain, Murdoch said there remains some interest in developing an Alzheimer's vaccine - Prana has its own early-stage vaccine project program, and a proprietary target.

Any vaccine that targeted the native beta-amyloid molecule could be problematic because the protein is so abundant in the brain and body, that a massive inflammatory response could be expected.

Murdoch said much research activity now surrounds secretase inhibitors - gamma and beta secretase enzymes are involved in cleaving the Alzheimer's Precursor Protein (APP), releasing a peptide fragment, -amyloid, that aggregates to form amyloid plaques in the brain.

"If someone could find a specific inhibitor of gamma secretase, it might be a competitor," Murdoch said.

"But no other mechanistic based treatment looks like beating us into the market at present, and if PLACQUE confirm our drug as the world's first inhibitor of an underlying mechanism of Alzheimer's disease, as distinct from something that merely treats the symptoms, it will be a blockbuster.