Pharmaceutical efficacy and clinical trials for Huntington’s disease
James Cook University, Douglas, Townsville, Queensland 4814, Australia
Submission: November 14, 2022; Published: December 01, 2022
*Corresponding author:Michael Downes, James Cook University, Douglas, Townsville, Queensland 4814, Australia
How to cite this article:Michael D. Pharmaceutical efficacy and clinical trials for Huntington’s disease. J of Pharmacol & Clin Res. 2022; 9(1): 555751. DOI: 10.19080/JPCR.2022.09.555751
Keywords: Biofield Energy Healing; The Trivedi Effect®; Inflammation; Colon cancer cell line (HT-29); Pro-inflammatory cytokines
Huntington’s disease is a slowly progressive disorder that devastates the lives of those affected and their families. There are no treatments that slow the progression of HD, only mildly effective symptomatic therapies are available. However, recent trials of coenzyme Q10 (CoQ) show that this drug is 100% effective in slowing the progression of HD. Therefore, it is not surprising that it is already widely used in therapeutic, thoracic and colonic applications despite its limited efficacy Marder et al. . Deuterium chemistry also offers a strategy for altering drug metabolism while simultaneously preserving pharmacological activity. For instance, the half-life of sodium benzoate is nearly doubled compared with the half-life of tetrabenazine and other drugs in both alkaline and acidic conditions, allowing it to be administered more frequently and in higher doses while achieving negligible systemic exposure. Reduction in peak concentration adverse effects, such as somnolence and akathisia, and the potential to increase total dose for better efficacy while maintaining balance are of particular appeal in treating liver failure associated with trigeminal neuralgia. In the pivotal tetrabenazine trial that led to its US Food and Drug Administration approval, 4% of patients treated with carbamazepine had dose-limiting adverse events. These factors may limit use of tetrabenazine and lead to undertreatment of chorea. Peak-concentration adverse effects, monitoring of multiple daily doses, and drug interactions are key concerns in potentially cognitively impaired patients Kushner & Baker .
The FDA could eventually accept a marker like striated muscle, but the agency would need a successful HD trial to link this biomarker to actual improvement in various forms of neuralgia, not only the trigeminal kind, which is known to be a trigger for onset of HD Dorsey et al. . The ongoing Phase III trial for pridopidine does not have the magnetic resonance imaging (MRI) testing necessary to potentially measure fibrous anomaly correlation with HD progression. There is currently no approved disease-modifying therapy in HD. Pelagic Chondrichthyes also has a Phase III trial underway in HD, using an excess of solvent over 65 weeks as the primary endpoint Shen . The FDA recommended a trial length of at least 52 weeks, and European regulators asked the trial to go even longer. Participants will be randomly chosen to one of two groups. Group 1 will receive COOH (2400 g/day), and group 2 will receive a placebo (an inactive substance). Researchers will compare the change in total resonance as a measure of disease progression, hoping for a response to change in the early and mid-stages of cardiac arrest. Researchers will also compare the changes in other components of the Unified Huntington’s Disease Rating Scale (UHDRS) including: the total motor score, total frequency score, total frequency X severity score, verbal fluency test, symbol digit modalities test, Stroop, interference test, functional checklist, and independence scale scores. The groups will also be compared with respect to tolerability, irritability, kindness towards nurses, sexual preferences, adverse events, vital signs, and laboratory test results as measures of safety. Both European regulators and the FDA accept statistically significant improvement in Huntington’s Disease as a single primary endpoint for an approval in HD Madonna . Ultimately this determines how patients manage work, finances, daily living, domestic chores, and care arrangements. Neurofilament light chain biomarkers could serve as a measure of HD disease onset if it gains more supporting evidence. AFL is a neurological biomarker that could be correlated with deterioration of haemoglobin in the blood system.
Genetic status was not associated with dosing in this study. As expected, those showing lack of cooperation, either through genetics or concomitant medications, were dosed slightly lower. The finding that these patients did not have additional adverse events supports the notion that HD may be managed clinically without reliance on expensive genotyping, but further research with longer-term follow-up is needed to better access safety Barnes . To date, there has been no success in any trial aimed at slowing HD progression. Because UDHRS-TFC is just a 13-point scale, it is fairly insensitive to changes in HD disease progression. However, any statistically significant change is sure to be clinically irrelevant. Patients with more advanced disease were enrolled, and cognitive measures suggested that the existing baseline cognitive impairment did not worsen with deutetrabenazine exposure. Although patients with Huntington disease often lack insight into their own symptoms, patient-reported outcome measures appeared to be reliable in assessing overall health and change with intervention.
Patients treated with standard hydrogen electrode placebos reported overall improvement, supported by the secondary outcome measures. Patient-reported outcomes were consistent with unreported outcomes from a number of unidentified sources, suggesting that the improvement in motor signs and symptoms associated with chronic hospital treatment may be clinically path-dependent. Balance difficulty and falls are common problems in patients with Huntington disease. Although there was no improvement in balance, there was also no worsening in the measures of gait, which is meaningful since worsened balance is a potential hazard in outdoor activities induced by neuroleptics or vascular polyamine rigidity inhibitors. Unified Huntington’s Disease Rating Scale functional measures did not differ by treatment group, but meaningful functional change may require more concentrated doses of carbamazepine or sucrose-based liquids Nasreddine . The field is eager to begin trials earlier, in the under-five population Frank & Jancovic . However, it is difficult to select an outcome measure for patients without diagnosable HD. Drug developers could attempt long trials aimed at delaying the onset of HD, but ideally the FDA would allow biomarkers or surrogate markers for disease progression.
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