A Synthetic Derivative of Squalamine Restored the Function of Enteric Nerve Cells in Parkinson Disease

In the phase 2b KARMET study, participants (n=150) with Parkinson disese (PD) and constipation treated with a synthetic derivative of squalamine (ENT-01; Enterin Inc, Philadelphia, PA) vs placebo had restored the function of enteric nerve cells. The change in complete spontaneous bowel movement (CSBM) from baseline to the end of the 3-week treatment period was significantly better in the treatment group compared with placebo (P=.0001).

The improvement persisted 2-weeks (P=.02) and 6-weeks (P=.05) after discontinuation of study medication. Spontaneous bowel movement (SBM; P=.001), stool consistency (P=.0001), ease of passage (P=.004) and laxative use (P=.03) were also significantly better among those treated with the squalamine derivative compared with placebo.

There were 13 participants who had psychotic symptoms at baseline (SAPS-PD score ≥4). In the individuals treated with synthetic squalamine (n=6), SAPS-PD score improved by 73% by the end of the 3-week treatment period and by 82% 6-weeks after treatment discontinuation. Participants treated with placebo (n=7) showed no improvement during treatment and worsened following treatment discontinuation. From the participants, 24 had dementia at baseline (MMSE≤26).

In the individuals treated with synthetic squalamine, MMSE score improved by 2 points during the 3-week treatment period, and by 3.5 points 6 weeks beyond the treatment period. Participants treated with placebo improved during treatment but worsened following treatment discontinuation.

According to Denise Barbut, MD, FRCP, Enterin's cofounder, president and chief marketing officer, "The continued improvement of bowel and neurologic symptoms for weeks beyond the brief treatment period suggests a possible disease-modifying effect."

Michael Zasloff, MD, PhD, Enterin's cofounder and chief scientist officer, added, "Aging itself compounds the ongoing damage caused by the accumulation of alpha-synuclein. Our preclinical studies suggest that the persistence of benefit observed with ENT-01 are a consequence of the reversal of certain aspects of the aging process."   

Following a 2-week baseline period, participants were stratified to start at high dose or low dose depending on baseline constipation severity and randomized to receive the synthetic squalamine or placebo. Dosing was escalated every 2-3 days and fixed for the remainder of the 25-day treatment period. All participants were then placed on placebo for 2 weeks, followed by a 4-week wash-out. 

There were no safety or tolerability concerns (n=150) with no deaths or drug-related serious adverse events. Adverse events, nausea and diarrhea, were largely confined to the GI tract and self-limiting.  

The orally administered targets alpha-synuclein (αS) accumulates in nerve cells of the gut (enteric nerves), preventing the nerve cells from functioning properly. The orally administered treatment displaces αS aggregates from nerve cell membranes as well as preventing their formation. Efficacy analyses were performed on all participants who had received at least 7 days of medication (n=136).