Targeting the Enteric Nervous System to Treat Constipation in Parkinson’s Disease

Camilleri M, Subramanian T, Pagan F, et al. Oral ENT-01 targets enteric neurons to treat constipation in Parkinson disease: a randomized controlled trial. Ann Intern Med 2022;175:1666–1674. Constipation is the most common nonmotor symptom in Parkinson’s disease, a neurodegenerative disorder characterized by motor impairments attributed to the progressive loss of dopaminergic neurons located in the midbrain. The pathological hallmark of Parkinson’s disease is the neuronal accumulation of abnormal insoluble protein aggregates that have cytotoxic effects and are mainly composed of α-synuclein. α-Synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids. An established hypothesis is that α-synuclein first accumulates in neurons of the gastrointestinal tract before migrating to the central nervous system. This might explain constipation manifesting at early stages of the disease or in some cases even preceding the development of motor symptoms. Camilleri et al investigated the efficacy of a novel investigational drug, ENT-01 (an artificial compound derived from squalamine), for the treatment of constipation in Parkinson’s disease. Squalamine was first identified in the dogfish shark (Squalus acanthias) and is a steroid conjugate with a unique polyamine tail, giving it a positive charge. It was later found that, when squalamine enters cells, it binds to negatively charged phospholipid membranes, displacing almost any positively charged protein that is electrostatically bound there. Squalamine was indeed found to displace α-synuclein from the surfaces of lipid vesicles, thereby blocking its aggregation process (Proc Natl Acad Sci U S A 2017;114:E1009–E1017). Given its positive charge, squalamine has very low bioavailability (<0.3%) and this property makes it an interesting compound to target enteric nerves affected by α-synuclein accumulation. This phase 2b industry-sponsored trial included 150 patients with Parkinson’s disease and constipation. After a 2-week run-in, patients were randomized to either a high or low dose of ENT-01 according to the severity of constipation, or to placebo treatment. The dose of ENT-01 was gradually increased every 2–3 days until bowel movements returned to normal, and then fixed for the rest of the 25-day treatment period. All patients then switched to placebo for 2 weeks, followed by a 4-week wash-out. The primary efficacy endpoint was the number of bowel movements in the fixed-dose period and final analysis included 135 patients completing ≥7 days of treatment. Bowel movements numbered 3.2 per week in the ENT-01 group versus 1.2 per week in the placebo group (P < .001), although this difference promptly decreased 2 weeks after discontinuation (2.2 vs 1.2; P = .084). ENT-01 also improved secondary end points related to cognition and psychosis compared with placebo. These beneficial effects came with the cost of nausea (34% in ENT-01 vs 5% placebo group; P < .001) and diarrhea (19.4% vs 5.0%; P = .016). These adverse effects often led to discontinuation and could, therefore, limit clinical utility. In addition, it remains to be established whether beneficial effects can persist over longer periods of time and whether these effects are indeed attributable to a α-synuclein–related mechanism, because the immediate neuropsychiatric effects were unlikely related to altering α-synuclein.