Disclaimer
The purpose of this post is to document for those interested some aspects of the research undertaken on Prana Biotechnology’s principal product PBT2 for treating Alzheimer’s disease.
Due to the complexity and technical content of the references, my limited knowledge of the research work, and my desire to write an understandable account, there could be errors of fact and or interpretation. I welcome any corrections or alternative viewpoints.
Investors in biotech stocks deserve as much objective information as possible before deciding how much of their capital it is prudent to invest. With an understanding of the clinical problem and the difficulties faced by researchers, investors may be more willing to continue their support for the longer term..
I would hope that this post will be seen as a positive for the company, funding as it is research into one of society’s greatest curses. Too often companies come under fire unjustly when the outcome is not as hoped, or investigations are beset by unforeseen difficulties.
A negative result should not be seen as a failure. Knowledge is still advanced, and at least it is then possible to exclude from further calculations measures that do not work.
The Pfizer Limited Experience Researching a drug for the management of Alzheimer’s
Pfizer is reported to have spent $1.6 billion developing a compound known as Bapineuzumab. It failed to improve cognition in AD
Pfizer Inc. (PFE:US), Johnson & Johnson (JNJ:US) and Elan (ELN) Corp.’s experimental Alzheimer’s treatment failed to improve symptoms of dementia in the first of four pivotal studies testing the drug.
Bapineuzumab, designed to target the brain plaques that serve as a hallmark of Alzheimer’s, didn’t aid cognitive or functional ability in patients who carry a gene, called ApoE4, that makes them more likely to get the disease, Pfizer said yesterday in a statement. Doctors now await results from trials in patients without the higher genetic risk.
http://www.businessweek.com/news/2012-07-23/pfizer-j-and-j-alzheimer-s-drug-fails-to-aid-cognition
Prana Biotechnology
Prana becomes a Top 10 global neuro-degennerative investigator with the work of other US pharmaceuticals resulting in negative results.
Its research at present is considered more likely to succeed.
But it has been a roller-coaster ride for Prana Biotechnology Limited, since listing on the ASX in 2000.
Clioquinol (PBT1
Prana raised $8 million in the float from which it funded research into the suitability of the drug Clioquinol (PBT1) for the treatment of Alzheimer’s disease. The rationale for its use was in-vitro and mouse studies suggesting that it had the ability to to render the beta-amyloid plaques of Alzheimer’s disease more soluble and capable of being cleared. Such compounds were termed “metal protein attenuating compounds (MPACs).
http://www.ncbi.nlm.nih.gov/pubmed/20164561
A trial that was carried out compared Clioquinol with placebo in 36 patients. 32 had enough data for analysis.There was no statistically significant difference between the two groups on the Alzheimer’s Disease Assessment Scale. One patient in the treatment group receiving treatment developed neurological symptoms (impaired visual acuity) which resolved on cessation of treatment.
A further trial is documented in which PBT2 was compared with placebo in 78 patients with mild Alzheimer’s disease. There was no significant difference in thee Neuropsychological Test Battery (NTB) scopres.
PBT2
PBT2 is a second-generation 8-hydroxy quinoline analog[1] developed as a successor to Clioquinol as a potential treatment of Alzheimer’s Disease
It has shown greater potential but is still being evaluated. These are three publications supportive of PBT2:
1) PBT2 shows potential to reverse effects of Alzheimer’s and Huntington’s
Prana Biotechnology’s (ASX: PBT) PBT2, which is in development for the treatment of both Alzheimer’s and Huntington’s Disease, has demonstrated an improvement in synaptic activity in neurons needed for memory.
Both Alzheimer’s and Huntington’s affect a patient’s memory and ability to plan and execute tasks. Pathologically, both diseases are associated with the formation of toxic oligomers of a protein.
Scientists from Merz Pharmaceuticals and the Max Planck Institute presented data showing that PBT2 was able to prevent synapatic toxicity or loss of signal conductivity, caused by the formation of toxic Aβ oligomers.
The data indicates that it may be most beneficial for neuroprotective agents such as PBT2, that can interrupt Aβ self-assembly into aggregates, to be administered to early stage patients to best maintain synaptic plasticity and function as an effective treatment for Alzheimer’s Disease.
Importantly, this independent data helps Prana understand how PBT2 can help the brain create new memories by preventing the formation and toxicity of soluble β-amyloid oligomers.
PBT2 resulted in significant cognitive improvement in a clinical trial with Alzheimer’s Disease patients.
In October, Prana Biotechnology research scientist Dr Paul Adlard was awarded a $762,975 National Health and Medical Research Council project grant to study the benefits of PBT2 and other compounds in age-related cognitive impairment.
From Proactivenvestors Australia Monday, November 14, 2011 by Angela Kean
2) Prana Biotechnology’s (ASX: PBT, NASDAQ: PRAN) development of PBT2 to treat Alzheimer’s disease has been backed by several scientific leaders at the recent Celebration of Science Conference in Washington D.C.
The drug has been dubbed a promising emerging therapy by Professor Jeffrey Cummings, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, and chairman of Prana’s Scientific Advisory Board.
Dr Rudy Tanzi, Joseph P and Rose F Kennedy Professor of Neurology, Harvard Medical School, and Prana’s Chief Scientific Advisor, said it “may prove to be the winning technology”.
PBT2 has a unique therapeutic action that can benefit people suffering neurodegenerative disease because of its specialised ability to prevent the toxic relationship between disease proteins and the metals, zinc and copper, in the brain, according to Tanzi.
In a 12 week trial PBT2 both significantly lowered beta-amyloid levels in spinal fluid and improved the cognition of patients with Alzheimer’s disease.
Accordingly PBT2 can stop and perhaps even reverse the neurodegenerative process of Alzheimer’s disease.
Prana is currently undertaking a 12-month IMAGINE trial in which it aims to establish PBT2 as a safe and effective treatment for Alzheimer’s disease.
The double blind placebo controlled trial is enrolling 40 patients with prodromal or mild Alzheimer’s disease in five sites in Melbourne.
Brain imaging is being used to measure PBT2’s effect on amyloid deposits in the brain and effects on increasing brain activity.
Prana is also conducting a six month trial in 100 patients with early to mid-stage Huntington disease.
The trial is aiming to demonstrate safety, motor and behavioural benefits and the same cognitive benefits for Huntington’s patients that it has already demonstrated in Alzheimer’s patients treated with PBT2.
http://www.proactiveinvestors.com.au/companies/news/33297/prana-biotechnologys-pbt2-shows-significant-promise-in-alzheimers-treatment–33297.html
http://www.ncbi.nlm.nih.gov/pubmed/20164561
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3) PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses.
Alzheimers Dis. 2010;20(2):509-16. doi: 10.3233/JAD-2010-1390
Abstract
PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer’s disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.
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