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
- Improving Cognition in Mice: Copper Ionophore Shows Some Mettle
- Chicago: More Phase 2 News—PBT2 and IVIg
- Fox JH, Kama JA, Lieberman G, Chopra R, Dorsey K, Chopra V, Volitakis I, Cherny RA, Bush AI, Hersch S. Mechanisms of copper ion mediated Huntington's disease progression. PLoS One. 2007;2(3):e334. PubMed.
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