On February 18, Prana Biotechnology reported top line results of its Reach2HD Phase 2 clinical trial. This trial investigated the safety and tolerability of PBT2 in patients with Huntington’s disease (HD), a progressive form of neurodegeneration for which there are no effective therapies and in which no drug has yet shown a cognitive benefit. The Melbourne, Australia-based company reports that the trial met primary safety endpoints and gave an inkling that PBT2 may bolster executive function. Several outside scientists were careful to point out that the study was not powered to evaluate the drug’s effectiveness. In this trial, people on PBT2 fared no better than those on placebo on tests of motor function, behavior, functional abilities, or biomarkers. “It is good to see that PBT2 met its safety goals so that it can progress to an efficacy study,” said Lon Schneider, University of Southern California, Los Angeles. However, he cautioned that “the clinical outcomes of this Phase 2 study should not be used to predict outcomes of a Phase 3 study.”

PBT2 is a small molecule that is thought to work by ushering copper and zinc back into cells, reducing their extracellular concentration and diminishing metal-mediated protein aggregation. Previous animal studies reported that PBT2 reduces brain Aβ and restores cognitive function in mouse models of Alzheimer’s disease (see Jul 2008 news article). A Phase 2a study in AD suggested the drug was both safe and tolerable while lowering CSF Aβ and apparently improving executive function (see Aug 2008 news story). A 12-month double-blind Phase 2 clinical trial of PBT2 is underway for people with AD.

Previous studies reported that copper drives aggregation of the mutant huntingtin protein and that PBT2 improved motor performance in mouse models of HD and kept them alive longer (see Fox et al., 2007;  Cherny et al., 2012). To see if the drug would help people with the disease, the Huntington Study Group conducted the double-blinded Reach2HD trial in participants from 20 research sites in the United States and Australia. Researchers randomly assigned 54 men and 55 women with early to mid-stage Huntington’s to receive 250 mg of PBT2, 100 mg, or placebo each day for 26 weeks.  Thirty-six patients took the high dose, 38 the low dose, and 35 placebo.

The study’s primary objective was to determine whether the drug was safe and tolerable. While five people dropped out of the trial, PBT2 met both criteria for the remaining participants, according to Prana's press release. Nine of 10 serious adverse events occurred in the PBT2 groups. Aside from one person who reported a worsening of HD symptoms after the six-month treatment period, Prana claims that all other serious adverse events were unrelated to the drug. Not all researchers contacted for this article were convinced based on the top-line data. “We can’t be sure that the drug met safety and tolerability requirements based on the limited data presented,” said Rachelle Doody, Baylor College of Medicine, Houston, who was uninvolved in the trial. Doody said she would need to see more specifics on how many adverse events and serious adverse events occurred in each group. 

A peer-reviewed paper is forthcoming, said Ray Dorsey, University of Rochester, New York, in a presentation to investors. Dorsey is the principal investigator of the trial. "I was pleased to hear these results would be submitted to peer-reviewed publications,” noted Cristina Sampaio, CHDI, Princeton, New Jersey. "A proper evaluation of this trial must await full access to the data. Until that happens, undue enthusiasm can only harm the patients."

Trial researchers also assessed seven secondary outcomes. Of those, they pre-specified cognition as their main efficacy variable based on the previous Phase 2a results in AD. An executive function composite score, made up of the Category Fluency test and the Trail Making Test Part B, showed a trend toward improvement in people taking 250 mg of PBT2, and statistical significance in people with mild HD, the company reports. The researchers determined this was due to an improvement compared with placebo for the high dose in the Trail Making Test. This test was also the basis for the positive effect seen in the earlier AD trial. “Even though the study was small, the fact that we saw a statistically significant signal on one key measure of executive function, which we know to be impaired [in HD], was surprising and encouraging to us,” said Dorsey. 

Paul Aisen, University of California, San Diego, pointed out that these results cannot be interpreted as suggesting efficacy, however, because the Trail Making Test was the only one of eight cognitive tests administered that showed a positive effect, and also because Prana did not control for false positives on this outcome. “Analyses of anything having to do with cognition or function did not meet the pre-specified objectives,” added Doody. “The tertiary analyses of various subcomponents are inconclusive and uninterpretable.”

Cognitive measures that scored no differently among the treatment and control arms included the Trail Making Test Part A, Map Search, Symbol Digit Modalities, Montreal Cognitive Assessment, and Stroop Word Reading tests. 

Besides cognition, secondary efficacy measures included tests of motor function, behavior, functional abilities, and overall change in health. No differences cropped up between groups in any of these measures, although the company says that patients in the PBT2 groups trended toward a slowing of functional decline. The trial also measured experimental biomarkers for HD. Levels of soluble total huntingtin and of the mutant form in the blood, as well as urine levels of 8 hydroxy 2’deoxyguanosine and creatinine, remained comparable between treatment and placebo groups. Prana reported that its preliminary analysis from an MRI substudy suggested that PBT2 seemed to slow atrophy in the basal ganglia and some cortical regions, the major sites of neurodegeneration in Huntington’s disease. That finding was based on imaging of two people from each treatment group. It suggests that more imaging is warranted, said Rudy Tanzi, Massachusetts General Hospital, Charlestown. Tanzi is a co-founder and chief scientific advisor of Prana. Outside scientists cautioned that this substudy was too small to support conclusions. 

Prana plans to advance PBT2 to a Phase 3 trial for HD. The company’s stock price jumped nearly 40 percent yesterday after it released the Reach2HD results.—Gwyneth Dickey Zakaib


  1. While we will have to wait for the publication of the peer-reviewed paper to properly assess the results of the Reach2HD Huntington disease (HD) trial, for those interested, I have summarized below the key findings that were provided in Prana's press release on the results of the trial. What is most interesting to me is that this is the second time that treatment with PBT2 (250 mg) led to statistically significant improved performance on the Trail Making Test B for executive function, the first time being in Prana's 2008 phase 2A Alzheimer's disease trial. In my opinion, this suggests a possible common mechanism of action in these two trials and warrants further confirmatory trials.

    Key Points:

    1. Primary endpoints of safety and tolerability were met. Ninety-five percent (104 of 109) of participants completed the study on their assigned dose. There were no substantial differences in adverse events across the two PBT2 dose groups and the placebo group. One of the 10 reported serious adverse events was deemed by the clinical site investigator to be related to drug treatment. This occurred during the four-week follow-up period (i.e., not on study drug) after completing the six-month treatment.

    2. Regarding the secondary endpoints on efficacy, the effects of PBT2 were tested on cognition, motor performance, behavior, and functional capacity, of which cognition was pre-specified as the main efficacy outcome. Across all study participants, there was statistically significant improvement in performance only on the Trail Making Test Part B in the PBT2 (250 mg) group compared to placebo at both 12 (p<0.001) and 26 weeks (p=0.042). Trail Making Test Part B is a measure of executive function (e.g., ability to plan activities), which is impaired early in the course of Huntington's disease and is also affected in Alzheimer’s disease.

    3. Given the evidence from an earlier trial (2008), which showed that PBT2 improved executive function in Alzheimer’s disease patients, the Reach2HD trial included a plan to assess the effects of PBT2 on an Executive Function Composite z-score. There was a statistically significant improvement in this z-score (p=0.038), but only in a pre-specified analysis of Reach2HD participants with early stage Huntington disease, as measured by their Total Functioning Capacity score. Across all study participants, who comprised both early and mid-stage HD patients, there was a trend to improvement (p=0.069).

    4. No significant improvements were seen on other secondary efficacy measures in the study.

    5. An exploratory sub-study using magnetic resonance imaging (MRI) was performed in a small subset of patients (n=6) to map anatomical changes in brain structure. In the combined PBT2 groups (n=4) a preliminary observation of reduction in atrophy of brain tissue in regions of the brain known to be affected by Huntington's disease was observed compared to the placebo group.

    Disclosure: I am the scientific co-founder of Prana Biotechnology. I am paid consultant of Prana Biotechnology (Chief Scientific Advisor) and a shareholder.

  2. In this small Phase 2 trial of only 109 patients the sponsor's safety objectives were met, and there appears to be no regulatory barrier to going forward to Phase 3 and assessing PBT2 for efficacy. The trial wasn't intended as an efficacy trial and shouldn't be interpreted as one; indeed, none was found, nor should efficacy have been expected.

    Of eight neuropsychological tests, only Trails B was reported as significant. Of three composites of some of these eight tests, only the executive-function composite, which included category fluency and Trails B, was statistically significant.  There was no effect on motor function, behavior, two functional-ability scales, two global assessments, biomarkers, or imaging that favored PBT2—again, as would be expected.

    So only the time for the Trails B test of about 20 possible outcomes and biomarkers was significant.  The effect here was that for people on the 250 mg dose, time to complete the test didn't change, while for those on the lower dose and placebo, the time worsened by 15 seconds. That’s quite a big mean change.  It would be most interesting to see the mean baseline times and standard deviations for the Trails B for each treatment group and the distribution of the change scores, as these data would help with interpreting any meaning to the p value reported. 

    In sum, it's good to see that PBT2 appears to have met its safety goals so that it can progress to an efficacy study.  The clinical outcomes of this Phase 2 study, however, should not be used to predict outcomes of a Phase 3 study.

  3. In response to Dr. Schneider, who stated in his comment on the Reach2HD trial, "The trial wasn't intended as an efficacy trial and shouldn't be interpreted as one; indeed, none was found, nor should efficacy have been expected,” and Dr. Doody, who stated, "“Analyses of anything having to do with cognition or function did not meet the pre-specified objectives,” I would like to point out that the top line results released by Prana actually do report statistical significance for a pre-specified cognitive endpoint.

    In the Prana release, it is stated regarding secondary outcomes, "The effects of PBT2 were tested on cognition, motor performance, behaviour and functional capacity, of which cognition was pre-specified as the main efficacy outcome.” The release goes on to report, "There was a statistically significant improvement in [the Executive Function Composite z-score] (p=0.038) in a pre-specified analysis of Reach2HD participants with early stage Huntington disease, as measured by their Total Functioning Capacity score." Meanwhile, across all participants, there was a trend to improvement based on the Executive Function Composite z-score (p=0.069) after 26 weeks of treatment. Especially given that the trial was powered for the primary outcome of safety and tolerability, and not efficacy, in my opinion, these would appear to be promising results.

    In addition, as I pointed out in my earlier comment, it is particularly interesting that there was a statistically significant improvement across all participants in Reach2HD in performance on the executive-function test known as Trail Making Test Part B, in the PBT2 250-mg group compared to placebo at both 12 (p<0.001) and 26 weeks (p=0.042). This is now the second time that PBT2 significantly improved performance on this test, the first time being in Prana’s 2008 phase 2A trial in AD. 

    In my opinion, the findings in the Reach2HD trials, together with those of the earlier findings in the 2008 AD trial, suggest a common mechanism of action for the effects of PBT2 on cognition, perhaps involving the attenuation of the interaction of metals like copper with huntingtin and beta-amyloid aggregates, or other mechanisms, e.g. neurogenesis, based on previously published pre-clinical data for PBT2.  Of course, a proper assessment of the Reach2HD clinical trial results awaits publication of the peer-reviewed manuscript. In closing, I would agree with the opinion that Phase 3 trials of PBT2 are warranted. Meanwhile, Prana also awaits the results of its second Phase 2 AD clinical trial, “Imagine.”

    Disclosure: I am the scientific co-founder of, a paid consultant (Chief Scientific Advisor) for, and a shareholder in Prana Biotechnology.

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Therapeutics Citations

  1. PBT2

News Citations

  1. Improving Cognition in Mice: Copper Ionophore Shows Some Mettle
  2. Chicago: More Phase 2 News—PBT2 and IVIg

Paper Citations

  1. . Mechanisms of copper ion mediated Huntington's disease progression. PLoS One. 2007;2(3):e334. PubMed.
  2. . PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease. J Huntingtons Dis. 2012 Jan;1(2):211-9. PubMed.

External Citations

  1. top line
  2. Reach2HD
  3. Phase 2
  4. jumped nearly 40 percent

Further Reading


  1. . The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem. 2011 Oct;119(1):220-30. PubMed.
  2. . Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. PubMed.
  3. . Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem. 1994 Apr 22;269(16):12152-8. PubMed.