Lighthouse Pharma lands major grant funding to advance Alzheimer’s drug into Phase 2 trial in patients with P gingivalis.
US biotech Lighthouse Pharmaceuticals has secured a $49.2 million grant from the National Institute on Aging to advance a Phase 2 study of its experimental therapy LHP588 in patients with Alzheimer’s disease who test positive for the bacterium Porphyromonas gingivalis. Widely recognized as a key pathogen in chronic periodontitis (gum disease), P gingivalis has increasingly been implicated in systemic conditions beyond oral disease, including cardiovascular disorders and neurodegeneration.
Research suggests that chronic infection allows the bacterium and its toxins to enter the brain, where they produce enzymes called gingipains that can drive oxidative stress, inflammation, and neuronal injury. These processes have been linked to hallmark features of Alzheimer’s such as amyloid-beta accumulation and tau pathology. Evidence from animal models and clinical studies indicates that gingipain activity can exacerbate feedback loops of inflammation and cell death, potentially accelerating cognitive decline.
LHP588 is a brain-penetrant lysine-gingipain inhibitor designed to selectively block the toxic protease activity of P gingivalis, reducing both bacterial virulence and load. The therapy builds on findings from an earlier investigational compound, atuzaginstat, which showed clinical benefit in a pre-specified subgroup of P gingivalis-positive Alzheimer’s patients. In Phase 1 studies, LHP588 demonstrated favorable safety, with no serious adverse events or dose-related concerns.
The randomized, double-blind, placebo-controlled trial, known as SPRING, is set to enroll 300 patients with mild to moderate Alzheimer’s and a confirmed salivary infection. By focusing on patients with a confirmed bacterial infection, Lighthouse says it is applying a precision medicine approach that parallels treatment strategies in other infection-related dementias, such as those associated with HIV or Lyme disease.
“This grant enables a rigorous clinical test of a truly novel mechanism of action in Alzheimer’s disease,” said Dr Marwan Sabbagh, Chair of the company’s clinical advisory board. “By directly inhibiting lysine-gingipain, LHP588 offers a targeted approach to intervening in the infectious and inflammatory cascade that may underlie the disease in P gingivalis-positive AD patients.”
Lighthouse CEO Casey Lynch added that the NIA funding was a “validation of the growing body of evidence connecting P gingivalis to Alzheimer’s disease and the potential of gingipain inhibition as a therapeutic strategy. We are proud to lead this pioneering trial aimed at modifying the disease process by targeting a known microbial driver of neuroinflammation and neurodegeneration.”
