Then they won't need a trading halt Sunday evening since the market is already closed. Still leaves Monday as a good day to announce.
GZ: The common pathogenesis of these diseases is protein misfolding. The misfolding is facilitated and enhanced by metals—zinc and copper, in particular. The physiologic mechanisms that remove zinc and copper, which are released and exist very transiently in the synapse during neurotransmission, just don't work as well as we age. In younger people, the metals are immediately bound and transported back to their intracellular storage sites. If they stay longer in the synapse—that space between nerve cells—they can interact with those proteins and aggregate. As disease progresses, these metal-binding proteins, or metalloproteins, form plaques, which cause dysfunction in neurotransmission and ultimately an inflammatory response that kills the affected and surrounding neurons. That's when patients begin to get overt symptoms.
In Alzheimer's and Huntington's diseases, the misfolded proteins are beta-amyloid and mutant huntingtin protein, respectively. PBT2 has a chaperone-type activity that appears to strip zinc and copper from these metalloproteins, then transports them across the neuronal cell membrane and delivers them to intracellular proteins, where the metals are normally stored. In animal models, PBT2 has been shown to reduce the amyloid burden in the brain, meaning that the amount of amyloid plaques is reduced. This is the primary endpoint in the ongoing Alzheimer's disease trial, called IMAGINE, that is expected to read out before the end of March.
Here's where it may get very exciting. If PBT2 reduces the amyloid burden in Alzheimer's disease patients after a year of treatment, and improves cognitive function, then it will be the only drug candidate to have shown this. In our view, the risk-reward ratio for PBT2 is tremendous.
Let me just caution readers that PBT2 may also fail to show a reduction in amyloid burden, in which case we expect Prana's stock to take a big hit. But having reviewed the preclinical and early clinical results to date, we think this tr
A surprising thing was discovered in this phase 2a trial. One of the cognitive measures, specifically the Trail Making Test Part B, demonstrated a statistically significant improvement in performance versus placebo at both 12 and 26 weeks. This test is an assessment of executive function—a patient's capacity to plan and organize things and to multitask, which is weakened early on in both HD and AD. The same cognitive function showed a statistically significant improvement with PBT2 in an earlier, phase 2a AD trial, and it is also a secondary endpoint in an ongoing AD trial that's going to read out before the end of March, according to the company's guidance. If this same secondary endpoint is met in the phase 2b trial, that would be confidence building, to say the least.
TLSR: The results of the high dose of 250 mg versus the low dose of 100 mg are delineated in the phase 2a PBT2 trail. Is the efficacy of the high-dose arm strong compared to the low-dose arm?
GZ: That's right. Also, in that regard, a very small substudy was performed, in which the brains of four patients in both PBT2 trial arms were imaged. Just as in Alzheimer's disease, the brain shrinks in Huntington's disease. There was some evidence that brain atrophy was reduced in the HD patients taking PBT2. Understand that this was a trend toward conservation of brain volume with PBT2, and was not statistically significant because of the small patient population. But it was an exciting result, nevertheless.
TLSR: What is it about PBT2 that makes it potentially efficacious in Alzheimer's and Huntington's diseases?