Can low-dose carbon monoxide treat Parkinson’s disease?

---

Why do smokers appear to have a lower risk of Parkinson’s disease? The established inverse association between smoking and Parkinson’s disease has been known for decades, although the exact mechanism is still unknown. Despite controversies, large epidemiological studies have demonstrated a lower incidence of Parkinson’s disease in smokers. Among several possible explanations, a provocative hypothesis is that chronic low levels of carbon monoxide might be part of this association.

This premise has motivated investigators to pursue additional animal studies evaluating the potential neuroprotective effects of carbon monoxide. Among them, Stephen Gomperts, PhD at Massachusetts General Hospital (MGH), Harvard Medical School has highlighted potential mechanisms by which carbon monoxide might diminish neurodegeneration in Parkinson’s disease. This includes cytoprotective, anti-inflammatory, and anti-apoptotic effects, as well as enhanced mitophagy. In rodent models, Dr. Gomperts and colleagues have demonstrated a reduction in alpha-synuclein pathology and in dopamine cell loss following exposure to controlled low-dose carbon monoxide at the levels experienced by smokers.

“Our findings suggest that molecular pathways activated by low-dose carbon monoxide may reduce pathology in Parkinson’s disease,” Gomperts said. “Notably, multiple phase 1 and phase 2 clinical studies outside of Parkinson’s disease have demonstrated safety of carbon monoxide at the low doses studied here.”

Building on these initial positive results, the investigators have supported Hillhurst Biopharmaceuticals in the design of a Phase 2A trial evaluating the safety and efficacy of low-dose, orally administered carbon monoxide in Parkinson's disease. The Low dose liquid Carbon Monoxide (HBI-002) Trial to Evaluate its safety, tolerability, pharmacokinetics, and biomarkers in Parkinson's disease (LoCaMoTE-PD) study — also led by Dr. Michael Schwarzschild from MGH and using the PSG structure, in partnership with Hillhurst Biopharmaceuticals, aims to enroll around 36 patients across three arms (low, intermediate-dose carbon monoxide — approximating CO exposure in light to moderate smokers, and placebo). Participants will ingest HBI-002, the liquid formulation of carbon monoxide, for 14 days with follow-up and multiple biomarker collection through day 44.

The primary outcome is the safety and tolerability of HBI-002. The secondary outcome is the evaluation of pharmacokinetics of HBI002. Several biomarkers focused on measures of target engagement and PD pathophysiology will be evaluated.

“If LoCaMoTE-PD were to demonstrate that HBI-002 induces potentially beneficial changes in these blood or CSF biomarkers, while providing evidence of adequate safety and tolerability, that may greatly facilitate advancing to a subsequent phase 2b/3 trial,” Schwarzschild said.

The innovative design anticipates challenges to recruitment, including hesitancy from patients and public regarding the safety of liquid carbon monoxide. For the LoCaMoTE-PD study, the target carboxyhemoglobin level is 10% or less, below the threshold at which side effects typically emerge (≈15%) and far below levels associated with life-threatening toxicity (>30%). Moreover, the manufacturer has purposefully designed the liquid formulation in higher volumes so that the ingestion of toxic amounts would not be feasible due to gastric volume limitations.

The LoCaMoTE-PD study Steering Committee and 15 selected sites had their first meeting at the PSG Meeting in San Diego at the beginning of December. The plan is to begin enrollment by the end of January 2026, and complete recruitment by January 2027. If successful, the study has the potential of shifting our understanding of neuroprotection in Parkinson's disease and provide additional evidence for larger phase 3 trials.