NASH: regulatory considerations for clinical drug development and U.S. FDA approval.

Nonalcoholic fatty liver disease is a growing public health crisis, with phenotypes from nonalcoholic fatty liver to nonalcoholic steatohepatitis, currently known as NASH, which can progress to liver fibrosis and end stage cirrhosis. NASH is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus. There are still no U.S. FDA approved drugs or biological treatments for NASH or related liver diseases. Despite official agency guidance, the regulatory pathway to ultimate product approval is unclear, due to both the extra-hepatic factors that contribute to NASH, as well as the organizational structure of FDA, with its traditional separation of therapeutic indications within discrete review divisions. There is hope that continued evolution of the regulatory process will lead to the ability for clinical trial endpoints supporting NASH treatment approval to include both liver-based and traditional metabolic measures, independent of specific FDA division review.

Targeting neurons in the gastrointestinal tract to treat Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. OBJECTIVE: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. METHODS: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. RESULTS: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10-7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. CONCLUSIONS: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.