Late in December 2012, Prana's Phase 2a double-blind, placebo-controlled study in early- to mid-stage Huntington's Disease (HD) completed enrolment. One hundred and nine patients were randomized to receive 250 mg, 100 mg, or placebo once daily for six months. The study was designed to assess safety and tolerability of PBT2, along with cognitive, motor, behavioral and functional changes in HD patients. A small sub-study within Reach2HD was investigated for the effects of PBT2 on brain metal iron mapping using Magnetic Resonance Imaging (MRI). In addition, possible biomarkers of HD are to be assessed from plasma and urine samples. This study is the first clinical trial with PBT2 in this patient population.
On July 23, 2013, the company announced the successful completion of Reach2HD. Although the initial plan was to recruit 100 patients, 109 were enrolled, reflecting strong support for the trial within the HD clinical research community. Of the total enrolled, 104 patients completed the trial, translating into an impressive retention rate of 95.4%. Reach2HD was conducted across 20 sites in the United States and Australia in collaboration with the U.S. based Huntington Study Group located at the University of Rochester, New York. A Data Safety Monitoring Board met on five occasions throughout the trial and on each occasion recommended that no changes or modifications to the study protocol be made based on their review of the safety data. The trial was completed on time. The results were expected to be reported last October, but are now projected to be released in early 2014.
The primary outcome of the trial is safety and tolerability. The trial also includes a number of secondary outcome measures from the cognitive, motor and behavioral domains affected in Huntington disease. A positive result of Reach2HD will identify signals of therapeutic benefit in one or more of the domains measured, which will inform the design of the crucial Phase 3 clinical trial. Similar to Alzheimer's Disease, HD is characterized by the buildup of toxic protein aggregates, loss of normal neuronal metal homeostasis, and metal induced oxidative stress. As such, biomarkers of oxidative stress and mutant huntington protein aggregation are also to be assessed.
Huntington's disease is a complex and severely debilitating genetic, neurodegenerative disease, for which there is no cure. The disease often affects young adults and, whilst associated with severe physical movement symptoms, progressively impacts the mind and emotions as well. HD causes incapacitation and death about 15 to 25 years after onset. It affects over 30,000 people in the U.S. and 70,000 worldwide. There is a paucity of treatments available, with just one drug approved for treating HD, Tetrabenazine, and it only works on the motor symptoms; there are no treatments approved for the cognitive or behavioral symptoms of the disease.
Assessing the Upcoming Potentially High-Impact Events
PRAN shares spiked 11.3% after the company announced the completion of the Reach2HD study and another 16.5% after the IMAGINE trial concluded, the gains were accompanied by a sharp increase in trading volume. All told, the shares have appreciated some 244% in the six months since the Reach2HD trial-related news. As noted in previous reports, though, triple-digit percentage gains for small-cap biotechnology issues is nothing usual and certainly not preclusive of further outperformance.
Looking to the forthcoming trial results, success in the Reach2HD would be the best outcome as it would undoubtedly shorten the time for PBT2 to come to market, as there are no disease modifying drugs presently available for Huntington's disease. The trial will probably achieve its safety outcomes considering more than 95% of participants stayed in the trial and previous experience with the drug. Efficacy outcomes are certainly far less clear, though. While never assured, we think the IMAGINE trial has a high probability of success, in terms of both efficacy and safety, in view of the results attained in the Phase 2a trial plus the fact that 95% of the participants completed testing and 83% opted to move on to the Extension trial. Patients suffering from Alzheimer's disease have few good options for treatment so PBT2 could rapidly achieve blockbuster status if results are respectable.
Sentiment: Strong Buy
All they have to do is show that the drug is safe and tolerable for the HD patients. With the amount of patients that stayed in the trial this is a given no one should worry this will be tremendous
Sentiment: Strong Buy
Given that the primary endpoint will be met, what else should be expect? Improvement in neurological symptoms, particularly any measure of chorea relaxation across perhaps 10-20% (or less) of the PBT2 arm would be astonishing at 12 weeks. IMO if the PR indicates ANY statistically supportable efficacy, the pps should respond favorably. MORE TO THE POINT - any indication of positive activity at 12 weeks, even subtle, bodes well for the 12 month IMAGINE results, which is what will ultimately determine where the pps goes. As eager as we are for this impending news, it is but a prelude to the much larger drama that awaits us.
Then again, if the secondary endpoints here are super - the IMAGINE results would be like firing the second stage booster.
Sentiment: Strong Buy
I think the key point clovus is trying to make is that it was not POWERED to show statistically significant differences. In other words, they will use the data and the trends to determine the properly powered trial size for p3. What we are looking far are trends in benefit. Anything more would be unexpected. I'm curious what happens to stock price if a trend is shown but no statistical significance. How will the street react-do they understand basic trial stats and powering?
I suspect that the current share price already has some expectation baked into it beyond safety and tolerability of PBT2. The drug has already gone through a Phase I trial and a 3-month Phase IIa trial with excellent safety and tolerability, and the low dropout rate of the year-long AD trial adds further already-existing evidence of safety and tolerability.
So I think people are expecting some level of symptomatic efficacy against Huntington's to be demonstrated. If no efficacy is shown, this would be a blow against Prana's MPAC hypothesis. Certainly not a fatal blow, as we still have the AD trial results pending and AD is not HD. But a blow nonetheless.
I think Goutah pretty much covered it here. Safety at this point would not be very significant news. Efficacy, or lack thereof, in symptoms and biomarkers is the news. Any evidence that MPAC can have demonstrable positive impact on the brain AND be safe; that is news. Drugs that are safe but have no detectable impact on the body are not very interesting except as candidates to replace sugar pills as the placebo in trials...
understood, but the bears will feed if no efficacy....that's just the way it is...Phase I's for safety and tolerability ....Phase II for some efficacy to justify Phase III....that's how I would see it