ENT-01 (squalamine) KARMET

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Enterin Inc. (sponsor); Michael Camilleri (first author) and many US co-authors, including Michael Zasloff and Denise Barbut of Enterin. Funded by Enterin.

What happened

ENT-01 is an oral version of squalamine, a compound that the authors describe as inhibiting the formation of synuclein aggregates. Enterin proposes that it displaces synuclein from the membranes of enteric (gut) nerve cells, which reduces synuclein clumping there and restores gut nerve function.

• KARMET (NCT03781791) was a randomised, double-blind, placebo-controlled Phase 2b trial run from December 2018 to December 2021 (registry). 150 people with Parkinson's and constipation (the registry lists 151) took ENT-01 or placebo daily for up to 25 days, with the dose raised to a prokinetic dose, the maximum 250 mg, or the tolerability limit, then a washout.
• The primary aim was complete spontaneous bowel movements (CSBMs) per week: 0.7 to 3.2 on ENT-01 versus 0.7 to 1.2 on placebo (P < 0.001). Stool consistency, ease of passage and laxative use also improved.
• Nausea (34.4% versus 5.3%) and diarrhoea (19.4% versus 5.3%) were more common on ENT-01. There were no deaths or drug-related serious adverse events.
• Exploratory neurological findings were tiny: in 14 people with dementia per arm, MMSE rose 3.4 points on ENT-01 versus 2.0 on placebo; in 5 versus 6 people with psychosis, SAPS-PD fell from 6.5 to 1.7 versus 6.3 to 4.4. No significance tests are given for these.
• A follow-on open-label safety study (NCT04483479, 27 enrolled) was terminated early because of poor recruitment and retention in the pandemic, and its data were not analysed. A planned Parkinson's dementia study (NCT03938922) was withdrawn.

Why it moved us toward a cure

It is the first drug aimed at synuclein in the gut's nerves (landmark 257) rather than in the brain, putting the gut-origin idea (landmark 6) in a trial. It is included because it tests whether a gut-targeted drug can be given safely and whether it engages the intended neurons, not because it showed slowing. The company has speculated that gains persisting after dosing might hint at a disease-modifying effect; that is an interpretation, not a result.

Outcome

Open. The aim was symptomatic (constipation). No evidence of slowing exists, and I found no registered Phase 3. Whether a gut-acting drug can change brain disease is untested.

Sources

• Camilleri et al., Ann Intern Med 2022;175:1666–1674, DOI 10.7326/M22-1438, PMID 36343348 (abstract via Europe PMC) · NCT03781791 · NCT04483479 · NCT03938922 (API, 19 Oct 2026)
• Cure Parkinson's summary of the company's claims
• Not yet verified: the mechanism (it is the authors' and company's account); the origin of squalamine; the authors' institutions; any later Phase 2 or 3 plans (a 2023 Parkinson's UK newsletter mentioned psychosis and dementia studies, not seen in the registry).