The IMAGINE Trial – Phase 2 Clinical Trial
The IMAGINE Trial is a randomised, double-blind and placebo-controlled study which is assessing the safety and tolerability of PBT2, and its effect on amyloid deposition in the brains of patients with prodromal or mild Alzheimer’s disease.
The trial has successfully recruited 42 patients via hospital test sites across the state of Victoria, in Australia. Patients have commenced one year (52 weeks) of treatment with either a daily placebo tablet or 250mg of PBT2.
Participants are undergoing brain scans to measure PBT2’s effect on amyloid deposits in the brain and effects on increasing brain activity. Cognition effects are being measured using a scientifically validated test that measures the type of cognitive problems experienced by prodromal and early Alzheimer’s patients.
It is thought PBT2 would benefit Alzheimer’s disease patients by selectively binding to, and redistributing, brain metals (copper, zinc) that have become imbalanced due to disease or the ageing process. This would prevent build-up of a toxic by-product of this imbalance – Abeta – which is implicated in neurodegenerative disease.
In an earlier 12-week, Phase 2a Alzheimer’s Disease trial, PBT2 significantly reduced the level of Abeta protein in the spinal fluid of treated patients and significantly improved their cognitive Executive Function.1,2,3
The trial has received funding from the Alzheimer’s Drug Discovery Foundation (ADDF), the only non-profit organization whose sole mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer’s disease.
There is strong data in support of PBT2 delivering a meaningful clinical benefit to Alzheimer’s disease patients.
IMAGINE EXTENSION TRIAL
In July 2013, Prana announced that the Austin Health Human Research Ethics Committee (HREC) approved a 12-month open label extension study for patients completing the double- blind placebo-controlled IMAGINE trial. There is no placebo group in the Extension trial. All participants receive a once daily dose of 250mg of PBT2. PBT2 is Prana’s drug in Phase 2 development for Alzheimer’s and Huntington’s diseases.
The approval followed a full review by the Austin Health HREC of the potential benefit to patients and safety data collected during the IMAGINE trial.
All patients in the IMAGINE trial were given the opportunity to participate in the Extension trial. Participation in the Extension study required patients to consent to receive PBT2 for 12 months following the end of the IMAGINE trial, as well as undergoing further brain scans, blood tests and cognitive testing.
A total of 33 patients have elected to go into the Extension trial, representing 83% of the 40 patients who completed 12 months of treatment in the IMAGINE trial.
Prana Biotechnology released the top line results of the IMAGINE Trial on March 31, 2014.
Prana’s PBT2 did not meet its primary endpoint of a statistically significant reduction in the levels of beta-amyloid plaques in the brains of prodromal/mild Alzheimer’s disease patients, as measured using PiB-PET Standardized Uptake Value Ratio (SUVR). Whilst there was a reduction in the overall levels of the PiB PET signal in patients treated with PBT2, the results were confounded by an atypical reduction of levels of the PiB PET signal in the placebo group as well.
No improvement was observed on the secondary endpoints of brain metabolic activity, cognition and function; however there was a trend towards preserving hippocampal brain volume in the PBT2 group. Specifically, there was less atrophy in those patients treated with PBT2 relative to placebo, 2.6% and 4.0%, respectively. This is consistent with published measures of atrophy in AD patients versus healthy controls2 of 4.7% and 1.4%, respectively. The company is tracking measures of brain volume and cognition in the current 12 month extension study that will be completed at the end of the year. Further analysis of the results is ongoing.
Importantly, PBT2 was shown to be safe and very well tolerated over the 52 weeks. The adverse event profile was equivalent between placebo and treated groups. Forty of the 42 enrolled participants (95%) completed the 52 week treatment period.
Prana is proceeding with its plans toward a confirmatory study for Huntington disease. Based on Prana’s previous discussion with the US Food and Drug Administration, the data on safety and tolerability of PBT2 in Alzheimer’s disease will support the future clinical development and, ultimately, a New Drug Application in Huntington disease.
Prana has a cash position of AU$25.4 million as at 31 March 2014.
The Phase 2 clinical trial was fully recruited in November of 2012. Results were released in March 2014.
1. Lannfelt et al. “Safety, Efficacy, and biomarker findings of PBT2 in targeting Abeta modifying therapy for Alzheimer’s disease: a controlled Phase 2a, double-blind, randomized, placebo-controlled trial”, Lancet Neurology (2008) vol. 7, pp. 779-86.
2. Lannfelt et al. Errata: Lancet Neurology (2009) vol. 8, pp. 981.
3. Faux et al “PBT2 Rapidly Improves Cognition in Alzheimer's Disease: Additional Phase 2 Analyses”, Journal of Alzheimer’s Disease (2010) vol. 20 pp. 509-516
What is PBT2?
Research has shown that certain normally occurring metals in the brain play a significant role in diseases such as Alzheimer’s disease and more recently, Huntington disease.
Researchers at Prana Biotechnology have created a chemical library of small chemical agents termed ‘MPACs’ (Metal Protein Attenuating Compounds) designed to interrupt interactions between these metals and target proteins in the brain, to prevent deterioration of brain cells. Prana’s lead MPAC for Alzheimer’s disease, PBT2, has been shown to:
Prevent the metal dependent conversion of amyloid beta protein into oligomers that are toxic to synapses; and
Restore normal brain metal distribution that is essential for neuronal health and synaptic function.
Previously in a Phase 2a study, PBT2 significantly decreased beta-amyloid in the cerebrospinal fluid and significantly improved Executive Function in mild Alzheimer’s disease patients within three months of treatment (see above Related Documents).
The ADDF funded Phase 2 study will ask the question, “what is happening to the amyloid burden of these patients using the same dose (250mg) that previously resulted in cognitive improvements, and is this change sustainable?”.