Results tagged “Huntington's disease” from Pathophilia

The defunct Russian antihistamine Dimebon may (may) improve cognition in Huntington disease, according to newly published results of a short-term, but well-controlled, trial in the Archives of Neurology. However, the efficacy outcome—which was just 1 of 3 efficacy measures made in the trial—was not the primary endpoint of this company-sponsored phase 2 study of the drug's tolerability.

Among 91 ambulatory enrollees with HD,* 90-day treatment with Dimebon, 20 mg tid, significantly improved the mean score on the 30-point MMSE by less than 1 point (0.97; P = .03, vs placebo). No significant differences between Dimebon and placebo treatment were noted, however, on the Unified Huntington's Disease Rating Scale (which assesses motor function, as well as cognition) or the 13-item ADAS-cog. Tolerability of Dimebon, the primary outcome measure, was comparable to that of placebo: 87% and 82% of patients, respectively, completed treatment. No significant treatment differences were noted with regard to the most commonly reported adverse events (eg, falls, headache, and dizziness).

The rationale for studying Dimebon in HD and other neurodegenerative disorders, like Alzheimer disease, is based on the drug's ability in the laboratory to stabilize mitochondrial membranes and possibly promote neuronal stability or even regeneration. According to the study authors, "Abnormal mitochondrial depolarization, which can lead to collapse of the mitochondrial membrane and ultimately neuronal apoptosis, has been implicated in the pathophysiologic progression of HD and other neurodegenerative diseases."

A placebo-controlled study of Dimebon in AD revealed significant improvement in cognition, behavior, and general function at 6 and 12 months. Results of this study evidently motivated Pfizer to give Medivation $725 million in 2008 for worldwide marketing rights to the drug. Corporate-funded phase 3 studies of Dimebon are currently recruiting patients with HD (here) or AD (for instance, here or here).

News of the phase 2 results was associated with a bump in Medivation's share price (but not Pfizer's).

N.B.--Dimebon is the trade name for dimebolin HCl or latrepirdine.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; MMSE = Mini-Mental State Examination.

* Study-eligible patients were allowed to take antipsychotic agents (at stable dosages), but they could not take cholinesterase inhibitors (eg, Aricept) or N-methyl-D-aspartate antagonists (eg, Namenda).

Image of Dimebon structure from Wikipedia.

Although the gene responsible for Huntington's disease (HD), a dominantly inherited neurodegenerative disorder, was detected more than 10 years ago, the mechanism of its brain-specific pathology has remained elusive. Now investigators at Johns Hopkins reveal, in an elegant series of cell-line experiments, how the genetic disorder preferentially affects the corpus striatum, despite the fact that the mutant protein is found in cells throughout the body. Their findings are available in the journal Science. 

But first some necessary background...

HD is characterized by the expansion of a 3-nucleotide repeat section in the gene that encodes for the protein huntingtin (Htt). Neurotoxicity in HD is related to the cellular solubility of the mutant form of Htt, or mHtt. Protein aggregates of mHtt appear to be neuroprotective, whereas soluble mHtt is associated with cytotoxicity. It is also important to note that the mutant protein is sumoylated—meaning that it is covalently bound to a small ubiquitin-like modifier (SUMO)—which reduces neuroprotective protein aggregation.

Investigating Rhes protein...

The Hopkins investigators chose to examine the relationship between mHtt and the protein Rhes, because the latter is very selectively expressed in the corpus striatum. By using striatal (mouse) cell lines that overexpressed Rhes or that were Rhes deficient, investigators determined that Rhes binds "robustly" to endogenous Htt—but much more so to mHtt than to wild-type Htt. Moreover, overexpression of Rhes, in particular, profoundly affected the survival of cells that expressed mHtt (but not those expressing wild-type Htt). Specifically they found that the cytotoxic effect of overexpressed Rhes was concentration dependent. And in a final set of experiments, investigators determined that overexpressed Rhes augments the sumoylation of mHtt, thereby causing the disaggregation of mHtt and cell death.

So...it appears that striatal Rhes promotes localized neuronal degeneration in HD by enhancing the sumoylation of mHtt. Drugs that block the interaction between Rhes and mHtt may have therapeutic potential in HD, the authors conclude.

Public-domain photo of American folk legend Woody Guthrie, who died of complications due to HD in 1967.

Despite the discovery in 1993 of the altered gene that causes Huntington's disease (HD), treatment for this dismal illness remains purely symptomatic and supportive. In the United States, medical therapy for HD chorea has been limited to traditional dopamine-receptor-blocking neuroleptics; however, these medications are associated with a high incidence of extrapyramidal side effects (eg, Parkinsonism) and irreversible tardive dyskinesia.

On Friday, the FDA approved tetrabenazine (Xenazine; Prestwick Pharmaceuticals), a well-known dopamine-depleting agent, for the treatment of HD chorea. The drug, which was granted "orphan drug status," is the first medication approved in the United States for the movement disorder; although tetrabenazine has been in use for HD chorea in Canada, Europe, and other parts of the world. The agent, which probably has limited dopamine-receptor-blocking properties at therapeutic dosages, has not been associated with the development of tardive dyskinesia.

Tetrabenazine was approved for HD chorea on the basis of a multicenter, prospective, double-blind, placebo-controlled study of ambulatory patients with HD (N = 84). Randomly assigned tetrabenazine* was associated with a 3.5-unit relative reduction of the chorea score (Unified HD Rating Scale) at 12 weeks. Five tetrabenazine-treated patients withdrew from the study, and 5 serious adverse events—drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer—were reported with treatment. Nevertheless, another controlled study (industry sponsored) and open-label studies support the drug's use in HD.

With the approval of tetrabenazine, the FDA requires a company-supplied Risk Evaluation and Mitigation Strategy (REMS) to manage any serious risks associated with the drug.

* Titrated up to a maximum of dosage of 100 mg/d.

Public-domain photo of American folk legend Woody Guthrie, who died of complications due to HD in 1967.