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HDAC Inhibitor Found Safe and Tolerable for Huntington's Disease in Phase 2 Trial Level of Mutant Huntingtin Changed in the Bloodstream


Investigators reported that in a phase 2 trial, selisistat, a histone deacetylase inhibitor, was safe and tolerable in Huntington's disease patients, but it had a surprising effect — it increased, rather than decreased, the mutant huntingtin protein level in their bloodstream.

A phase 2 trial of the histone deacetylase (HDAC) inhibitor selisistat found it safe and tolerable for patients with Huntington's disease (HD), and it accomplished something no other experimental treatment has been shown to do in people with the disease — it changed the level of mutant huntingtin in the bloodstream. Surprisingly though, the treatment increased, rather than decreased, the protein level, leaving researchers to wonder whether the treatment points toward a promising or discouraging therapeutic approach.

HDACs are enzymes that remove acetyl groups from proteins. Their targets include the histones around which DNA is wrapped, and in this context, deacetylation condenses the chromatin to reduce transcription. But HDACs also deacetylate numerous other kinds of proteins, including huntingtin. Deacetylation stabilizes mutant huntingtin, contributing to its toxicity, while acetylation contributes to its degradation. Therefore, inhibiting HDACs and thus increasing the acetylation state of huntingtin may promote clearance of the mutant protein, which may be therapeutic.

Acetylation of huntingtin is carried out at least in part by the HDAC, sirtuin 1 (SirT1). Sirtuins have gotten a lot of press for their potentially longevity-enhancing properties, but in HD, SirT1 is believed to play a deleterious role in retarding degradation of mutant huntingtin, according to Ralf Reilmann, MD, PhD, the founding director of the George Huntington Institute in Muenster, Germany.

Recently, selisistat has been developed as a potent and selective SirT1 inhibitor, and has been tested in both cell and animal models of the disease, where it reduced neurodegeneration. Based on those results, and initial safety studies in healthy human volunteers and HD patients, Dr. Reilmann and colleagues conducted a phase 2 trial of selisistat in 144 HD patients at 19 centers in Germany, Great Britain, and Italy.

“The hypothesis of the trial we did was that acetylation of mutant huntingtin would result in disease modification and reduction of disease burden,” Dr. Reilmann said here in a session at the AAN Annual Meeting in Philadelphia in April.


Enrolled patients were randomized to placebo, selisistat at 50 mg per day, or selisistat at 200 mg per day, for 12 weeks. Patients were in the early to intermediate stages of the disease, with a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of at least 5 and a Total Functional Capacity of at least 5.

The drug was well tolerated, except for cases of treatment-related liver abnormalities in about 20 percent of patients receiving active treatment, including three serious cases, all of which resolved after discontinuation. There were no changes in motor performance, cognition, or function, which would not be expected during such a limited trial, Dr. Reilmann said.

But what made the trial potentially more significant than previous treatment trials was that levels of soluble mutant huntingtin in peripheral blood mononuclear cells were measured, and showed a treatment-related change. The assay for detecting protein in the blood is relatively new, and has been not been widely used, so it is unknown whether other, ultimately unsuccessful, treatments tested in HD have altered the protein levels in the serum. To Dr. Reilmann's knowledge, this is the first trial in which treatment has been shown to have such an effect.


DR. RALF REILMANN said that treatment is “engaging the target, and we need to understand further what it really does. I would claim that even if the drug does something bad, we would still learn something important, because it would give us a target for treating the disease if we could understand how it works, and try to influence that mechanism.”

“What we found was not what we expected, however, or might have hoped for,” Dr. Reilmann said. Protein levels increased steadily over the 12-week trial in both active treatment groups, with borderline statistical significance (p=0.058; p=0.075 for the 50 mg and 200 mg groups, respectively), and then reverted to levels consistent with the placebo group at follow-up.

“This is the first time in clinical trials that we have seen modulation of the protein, if you want to accept that it is modulation,” Dr. Reilmann said, rather than being a merely statistical anomaly. “But we do think it is a real effect.”

This might be bad news, Dr. Reilmann said, if it reflects an increase in protein synthesis; Why that would be a consequence of SirT1 treatment is unclear, he continued, given what is known about its effects and the results in model systems. Alternatively, it may be good news, if it indicates that aggregated huntingtin is being mobilized, the first step in clearance by the cellular recycling system. “We don't really know if we are going the wrong way or the right way,” said Dr. Reilmann.

It is also unknown whether the increase seen peripherally only indicates peripheral activity of the drug, or reflects a change in central huntingtin, given that selisistat crosses the blood-brain barrier. If it does affect central huntingtin, is the increase in the periphery because central huntingtin is being shunted there as part of a clearance mechanism? This too is unclear, and will require further investigation.

“One of the big gaps in our knowledge is what will happen after long exposure to the drug,” Dr. Reilmann said. It is possible, but remains untested, that clearance is occurring, and would eventually lead to a drop in peripheral protein levels.

Whatever is going on, he said, treatment is “engaging the target, and we need to understand further what it really does. I would claim that even if the drug does something bad, we would still learn something important, because it would give us a target for treating the disease if we could understand how it works, and try to influence that mechanism.”


Commenting on the study, Steven Hersch, MD, PhD, a professor of neurology at Harvard Medical School, told Neurology Today: “HDAC inhibition has been a promising avenue for treatment of Huntington's disease for some time, based on results with nonselective inhibitors in animal models. It is great to see this moving to the clinic.”

He cautioned that the relationship between huntingtin levels in the blood and in the brain is entirely unknown. But, he said, regarding the elevation seen in the trial, “I am not sure I would interpret that as a bad direction,” based in part on his own recent natural history study showing that over time, peripheral huntingtin declines. “So achieving an increase with a therapy could be interpreted as the right direction,” he said.

He also noted that while the development of the serum assay is a major step in the search for HD biomarkers, it has not yet been validated against clinical measures in a large phase 3 trial, further hindering its interpretation.

Christopher Ross, MD, PhD, a professor of psychiatry, neurology, pharmacology and neuroscience at Johns Hopkins University School of Medicine in Baltimore, was also cautious about over-interpreting the change in huntingtin, for similar reasons. “The problem is that we don't know what the levels of mutant huntingtin in the blood mean,” he said.

Dr. Ross did praise the design of the trial, which enrolled gene-positive individuals — many of whom were at the very earliest stages of their disease — long before their symptoms became debilitating. In this respect, it was akin to a prevention trial, “and that is the direction the field needs to move in,” he said. “I think that is a highlight of this trial.”


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VIDEOS ON DEMAND: Is selisistat a promising new approach to Huntington's disease? Investigators reported the results of a double-blind, placebo-controlled, international multi-center study of selisistat in individuals with Huntington's disease (HD). They found that, apart from increases in liver function tests in a subset of patients, selisistat was safe and well tolerated, but it increased the mutant huntingtin in the bloodstream. In this video, Neurology Today Editor-in-chief Steven P. Ringel, MD, FAAN, and Associate Editor Robert G. Holloway Jr., MD, MPH, FAAN, discuss the meaning of these results with David Holtzman, MD, FAAN, who has done previous research on the effect of Sirtuin1 on neurodegeneration in animal and cell models of the disease: Dr. Holtzman is professor and chair of neurology at Washington University in St. Louis. See the full meeting abstract here:


•. AAN Annual Meeting Abstract — Safety and tolerability of selisistat for the treatment of Huntington's disease: Results from a randomized, double-blind, placebo-controlled phase II trial:
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      •. Duan W. Targeting sirtuin-1 in Huntington's disease: Rationale and current status. CNS Drugs 2013;27(5):345–352.
        •. Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med 2011; 18(1):153–158.