Nilotinib, a tyrosine kinase inhibitor, is emerging as a potential therapeutic option for Dementia with Lewy Bodies (DLB), a neurodegenerative disorder with limited treatment options. Data presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference from a phase 2 trial revealed cognitive improvements in DLB patients treated with nilotinib.
Phase 2 Trial Results
The randomized, placebo-controlled trial involved 43 patients with DLB who were administered either 200 mg of nilotinib or a placebo for six months, followed by a one-month washout period. The results indicated that patients on nilotinib improved by 2.8 points (95% CI, 0-6.34; P = .037) on the Alzheimer’s Disease Assessment Scale-Cognition 14 (ADAS-Cog14). Additionally, cognition, as measured by part 1 of the MDS-Unified Parkinson’s Disease Rating Scale, improved by 0.9 points (95% CI, 0-2; P = .044) in the nilotinib group compared to placebo.
While other cognitive and functional scores, including MoCA (1.5pts, 95% CI, 0 to - 3, P = 0.061) and ADCS-ADL, (-3.3 pts, 95% CI, -5 to - 1, P = 0.084) trended towards an improvement, the treatment was generally well-tolerated, with fewer adverse events reported in the nilotinib group (37) compared to the placebo group (74) (95% CI, 0.98-2.32; P = .054).
Nilotinib's Mechanism of Action
Charbel Moussa, PhD, MBBS, an associate professor of neurology at Georgetown University and a study author, explained that nilotinib was initially developed as an Abl tyrosine kinase inhibitor for leukemia. Its potential in neurodegenerative diseases was discovered due to its ability to induce autophagy, the process of degrading unwanted molecules and misfolded proteins in the brain. “Beyond autophagy, it also has anti-inflammatory effects,” Moussa noted.
Nilotinib's ability to inhibit discoidin domain receptor 1 (DDR1) in the brain, even at low doses, is believed to contribute to its therapeutic effects. DDR1 inhibition is linked to reduced tau hyperphosphorylation, increased dopamine metabolism, and improved amyloid processing. In previous trials, nilotinib has shown potential in reducing amyloid burden in the frontal cortex of patients with Alzheimer’s and DLB.
Challenges in Treating DLB
DLB presents unique challenges in drug development due to its complex pathology, which combines features of both Alzheimer’s and Parkinson’s diseases. Patients with DLB often experience a combination of cognitive decline and motor symptoms, making it difficult to find treatments that address both aspects without exacerbating either. According to Moussa, “For DLB, we need drugs that address both motor and cognitive symptoms without worsening either... This dual challenge makes DLB drug development particularly complex.”
Safety and Tolerability
The safety profile of nilotinib at the lower doses used in neurology patients appears favorable. “Across all trials... the safety and tolerability of Nilotinib have been comparable to placebo,” Moussa stated. This is particularly important for elderly patients with neurodegenerative diseases, who are often more susceptible to drug side effects.
Future Directions
These promising phase 2 results warrant further investigation in larger, multicenter trials to confirm the efficacy and safety of nilotinib for DLB. The potential of nilotinib to address both cognitive and motor symptoms, along with its manageable safety profile, positions it as a promising candidate for disease-modifying therapy in DLB.
