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- Raptor Pharmaceuticals Announces Phase 2/3 Clinical Trial Results with Cysteamine (RP103) in Huntington’s disease
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Prana Planning Phase II trial of their Copper Chelator
Prana Biotechnology's iron chelator is moving through the HD pipeline. Prana will conduct a Phase II trial of PBT2 toward the end of the year.
In 2007, Dr. Steven Hersch and colleagues showed that concentrations of copper are elevated in HD and provided evidence that interactions between copper and the HD protein and highly copper-sensitive lactate dehydogenase (LDH) contribute to HD pathology.
In 2005, Dr. Steven Massa and colleagues first found that clioquinol looked promising in a cell model and then administered it to R6/2 mice. As compared to untreated R6/2 mice, the clioquinol group experienced less atrophy of the striatum, lost less weight, performed better on the rotarod, and lived twenty percent longer.
Clioquinol is an old antibiotic which is currently used as a topical cream for skin infections. Clioquinol was at one time given internally in Japan but was banned in 1970 after it was discovered to cause neurotoxicity, a syndrome called subacute myelo-opticoneuropathy (SMON). The mechanism which caused the neurotoxicity was never determined. Copper deficiency, Vitamin 12 deficiency, and impurities have all been hypothesized to have been the source of the problem.
Prana first began its research with clioquinol but was unable to remove impurities in the manufacturing process. It then developed a second-generation version of the drug which has been in clinical trials for Alzheimer's patients. In a twelve-week phase IIa trial with early AD patients, PBT2 was found to be safe and well-tolerated and to improve cognition.
A newly published study which I will be covering within the next week provides more information on the role of copper in HD pathology. Jonathan Fox, Steven Hersch, and colleagues present data which suggests that the Huntington's disease protein is subject to oxidation which causes the formation of oligomers, very small aggregates. Preventing oligomer formation enhances the clearance of the toxic soluble protein and could be neuroprotective. Previously, they showed that copper oxidizes the HD protein. The current study shows that copper promotes oligomerization of N-terminal huntingtin by binding to a copper site within the protein.
Based on published data, there does not appear to be a mechanism where PBT2 could lead to cognitive improvement although there is certainly evidence pointing to possible neuroprotection. I will report on any additional data that becomes available.
Jonathan Fox, Teal Connor, Megan Stiles, Jibrin Kama, Zhen Lu, Kathryn Dorsey, Gregory Liebermann, Ellen Sapp, Robert Cherny, Mary Banks, Irene Volitakis, Marian DiFiglia, Oksana Berezovska, Ashley Bush, Steven Hersch. "Cystein Oxidation within N-Terminal Mutant Huntingtin Promotes Oligomerization and Delays Clearance of Soluble Protein." 2011 Mar 30. [Epub ahead of print]
Jonathan H. Fox, Jibrin A. Kama, Gregory Lieberman, Raman Chopra, Kate Dorsey, Vanita Chopra, Irene Volitakis, Robert A. Cherny, Ashley I. Bush, Steven Hersch. "Mechanisms of copper ion mediated Huntington's disease progression." PLoS ONE 2(3): e334. doi:10.1371/journal.pone.0000334
Trent Nguyen , Aaron Hamby, and Steven M. Massa. "Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model." Proceedings of the Nat'l Academy of Sciences of the USA. August 16, 2005 , vol. 102, 11840-5.
- Marsha L. Miller, Ph.D., April 20, 2011
Prana accelerates PBT2 commercial development
• Alzheimer's Disease Phase II Imaging Trial planned 3rd Qtr 2011
• Huntington's Disease Phase II Trial planned 4th Qtr 2011
Melbourne - 20 April 2011: Prana Biotechnology (NASDAQ:PRAN; ASX:PBT) today announced its business strategy to accelerate development of its lead asset, PBT2. The strategy, that now includes Huntington's Disease, should enable Prana to target market approval for PBT2 several years sooner than previously planned and at considerably less cost.
The company has designed a Phase II placebo controlled double blind study in 100 mild Huntington's Disease (HD) patients, in Australia and the US, treated over 6 months. This trial will be conducted in parallel, to the previously announced 12 month Phase II brain imaging study in 40 mild Alzheimer's Disease (AD) patients, in Australia, supported by the US based
Alzheimer's Drug Discovery Foundation. Recruitment for both trials is planned to commence in the second half of the year.
"We are excited by this strategy because from a commercial perspective these diseases are very complimentary. From our earlier Alzheimer's trial we showed that PBT2 significantly improves cognitive executive function. This is very relevant to Huntington's Disease given that these patients also suffer cognitive decline, for which there is no marketed treatment available. Success in the trial that we have announced today will position PBT2 as a frontrunner in the treatment of Huntington's Disease. We believe that PBT2 can bring the same cognitive benefits to Huntington's Disease patients that it did to Alzheimer's Disease patients" commented Mr Geoffrey Kempler, Prana's Executive Chairman.
"Because Huntington's Disease is a relatively uncommon disease, it is classed as an ‘orphan indication' by regulators, a status that typically confers accelerated regulatory review by authorities and faster approval to market. That also means the cost will be considerably less" added Mr Kempler.
The Huntington's Disease Market
HD is a genetically inherited neurodegenerative disease resulting in severe motor dysfunction and cognitive decline. It affects 30,000 people in the US and about 70,000 worldwide. The only treatment currently approved for the disease only targets some of the motor loss symptoms and sells approx. $250 million pa. There are no drugs in development that have established clinical evidence for treating cognitive decline. Prana aims, in this trial, to demonstrate the same cognitive benefits for HD patients that it has already demonstrated in AD patients treated with PBT2. A treatment for HD that addresses the underlying progression of the disease could generate sales of 750 million to $1 billion pa.
What benefits has PBT2 already shown
In a Phase IIa trial of PBT2 in mild Alzheimer's Disease*, cognitive executive function was significantly improved in patients. Recently the company published that PBT2 was able to directly restore neurons critical to cognition in mouse models. In particular it was demonstrated that PBT2 increased the number of spines on the branches (or dendrites) of neurons, an important means of permitting many more neurons to interconnect with any particular neuron thereby increasing the brain's capacity to carry out learning and memory functions.
These findings pointing to the ability of PBT2 to restore cognition in degenerative conditions, together with positive data achieved with PBT2 in mouse models of Huntington's Disease** provide confidence that PBT2 will be able to confer cognitive benefit to patients with HD and
What Alzheimer's and Huntington's diseases have in common
Mechanistically, both AD and HD appear to involve a protein that combines with brain metals to become toxic. In Alzheimer's, Prana scientists believe that the formation of toxic A-beta protein oligomers leading to impaired synaptic function, is a metal dependent event. In Huntington's recent publications*** indicate that copper is critical in the formation of toxic oligomers of the Huntington's Disease protein, huntingtin, that causes the brain degeneration in HD patients.
"The demonstration that PBT2, a Metal Protein Attenuating Compound (MPAC) can redress metal imbalances in the brain and intercede in toxic oligomer formation offers a very promising therapeutic strategy to tackle Huntington's Disease" commented Dr Robert Cherny, Prana's Head of Research.
* Lannfelt et al. Lancet Neurology (2008) vol. 7, pp. 779-86; Lannfelt et al. Lancet Neurology (2009) vol. 8, pp. 981.
*Faux et al. J. Alzheimer's Disease 20 (2010) pp. 509-516.
**Presented at the International Conference on Alzheimer's Disease, Honolulu Hawaii, 2010.
*** Fox et al. J. Bio. Chem. published as manuscript M110.199448
About Prana Biotechnology Limited
Prana Biotechnology was established to commercialize research into age-related neurodegenerative disorders. The Company was incorporated in 1997 and listed on the Australian Securities Exchange in March 2000 and listed on NASDAQ in September 2002. Researchers at prominent international institutions including The University of Melbourne, The Mental Health Research Institute (Melbourne) and Massachusetts General Hospital, a teaching hospital of Harvard Medical School, contributed to the discovery of Prana's technology.
For further information please visit the Company's web site at www.pranabio.com.