Toward More Efficient Clinical Trials in Motor Neuron Disease – Total Drug Exposure Analysis and Bulbar Biomarker Development

Motor neuron disease affects upper motor neurons in the brain and lower motor neurons in the spine and causes muscle weakness, atrophy, difficulty swallowing, respiratory failure, and death. The development of effective interventions for adult motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA, also known as Kennedy’s disease), remains a challenge. To date, many clinical trials have been conducted and most of them have failed. In this thesis, we analyzed a previous large ALS clinical trial using total drug exposure and searched for biomarkers that correctly reflect dysphagia in SBMA to help achieve more efficient clinical trials for motor neuron disease in the future. In my first article, we used a database of the clinical trial of ceftriaxone. Ceftriaxone, a β-lactam antibiotic, has been shown to increase the glutamate transporter that clears glutamate from the synapse. In the clinical trial of ceftriaxone for ALS, 514 participants in the United States and Canada were enrolled. The trial did not show significant clinical efficacy; however, treatment adherence may have masked potential efficacy. We found total ceftriaxone exposure analysis did not show overall efficacy of ceftriaxone. We concluded that failed clinical trials with intervention adherence problems may need total drug exposure analysis to assess potential effect of the medication. In my second article, we analyzed the results of the videofluoroscopic swallowing study (VFSS) in 111 consecutive genetically confirmed patients with SBMA and 53 age- and sex-matched healthy controls. Difficulty swallowing (dysphagia) is a major symptom of motor neuron disease, and often leads to life-threatening events such as aspiration pneumonia and suffocation. We revealed that dysphagia of SBMA is characterized by impaired tongue movement and nasal penetration, followed by pharyngeal residues, resulting in multiple swallowing sessions and laryngeal penetration. We concluded that pharyngeal residue and penetration-aspiration scale reflect major features of dysphagia in patients with SBMA.