Prana Alzheimer’s disease Development Plan Update
Professor Colin Masters, the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, will today include data from Prana’s Phase 2 IMAGINE and EURO trials in his presentation at the Alzheimer’s Association International Conference in Copenhagen, Denmark.
The presentation is entitled: “How to change and monitor the rates of Aβ amyloid accumulation and cognitive decline in Alzheimer’s disease”. The presentation can be viewed here.AAIC Panel Presentation_Colin Masters
The IMAGINE trial top-line draft results were released on 31 March 2014. Further sub-analyses of the top line imaging data have been performed, including PiB-PET, MRI and FDG analysis of the effects of a once daily, 250 mg dose of PBT2 over 12 months. IMAGINE enrolled 42 patients, 27 in the PBT2 group and 15 in placebo.
The primary objective of the IMAGINE trial was to explore whether amyloid burden, as measured by PiB-PET would decrease in participants treated with PBT2 relative to placebo. However, in contrast to published literature, the average amyloid burden in the placebo group fell during the trial.
Prana conducted a sub-analysis to better understand the behaviour of the placebo group and what can be learned in the trial about the utility of such exploratory biomarkers for future trials.
In Professor Masters’ presentation, he noted that the starting amyloid burden level (baseline) in the PBT2 treated participant group had an important bearing on the decrease of amyloid over time in that participant (p=0.035), whereas there was no such correlation in the placebo group.
Prof Masters further investigated the response of participants with baseline amyloid burden levels above and below the mean for the IMAGINE cohort (SUVR of 2.5). He showed that in the subgroup of PBT2 treated participants with a baseline of SUVR above 2.5, there was a significant decrease in amyloid burden that was not observed in participants on placebo nor PBT2 participants with a SUVR less than 2.5. In summary, whilst the utility of PiB in small trials may be questioned, it was interesting to note the impact of baseline SUVR amyloid burden level on the response of a cohort, for future trial design.
Separately, Prana has confirmed the top line finding that there is a very promising trend towards the preservation of brain volume (as measured by MRI) in PBT2 treated patients compared to placebo patients.
Mechanism of action of PBT2 in AD
PBT2 prevents formation and toxicity of pathological Aβ species (primarily soluble oligomers) and promotes their clearance. In Professor Masters' presentation he proposes the observed effect upon amyloid burden is due to increased clearance by PBT2 of pools of PIB-detectable non-fibrillar soluble and membrane bound Aβ.
Through its metal chaperone activity, PBT2 activates intracellular signalling pathways which promote neuronal health and plasticity and suppress pathobiological processes including the abnormal phosphorylation of tau. The trend towards reduced hippocampal atrophy seen in the PBT2 treatment group mirrors the Company’s preclinical observations and reinforces a similar trend observed in the Reach2HD Huntington's disease study.
“Understanding the limitations of a small trial, the atypical placebo group response, previous clinical findings (the EURO trial), the strong body of peer reviewed science, along with the sub-analyses of IMAGINE, the company remains enthusiastic about the prospects of a large trial statistically powered to demonstrate cognitive benefit,” Prof. Masters said.
IMAGINE EXTENSION TRIAL UPDATE
Patients who completed the full 12-month term of the IMAGINE trial were eligible for participation in an open-label Extension study. All participants in the Extension study receive a 250mg once daily oral dose of PBT2 for an additional 12 months during which PiB-PET and MRI imaging will continue.
Thirty three patients elected to join the Extension trial and of these, 30 remain on the trial. Of those participants, 21 have now been identified as being randomized to the PBT2 treatment arm in the IMAGINE study. Of these, all 21 patients have completed 14 months of PBT2 administration, 20 have completed 18 months of PBT2 administration and nine have completed 21 months of PBT2 administration.
We are very pleased with the continuing safety profile of the drug. The data safety monitoring board has met a further two times and has not expressed any concerns in relation to adverse events.