NeuroVoices: Charbel Moussa, PhD, MBBS, on Therapeutic Potential of Nilotinib in Dementia With Lewy Bodies

Charbel Moussa, PhD, MBBS

Dementia with Lewy bodies (DLB) is a complex and progressive neurodegenerative disorder that requires a multifaceted approach to treatment. There are currently no FDA-approved disease-modifying therapies, so typical treatment options have been aimed at managing symptoms, such as the cognitive, motor, and psychiatric deficits patients face. While the therapeutic landscape has been scarce, there is one treatment, nilotinib (Tasigna), that is making its way up the treatment pipeline.

At the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, investigators presented promising data from a phase 2, randomized trial of nilotinib in patients with DLB. The study included 43 patients who were randomly assigned 1:1 to either nilotinib 200 mg or matching placebo for a 6-month period, followed by a 1-month washout. Overall, the treatment was considered safe and well-tolerated, with a greater number of adverse events (AEs) occurring in the placebo (74) vs nilotinib (37) groups (95% CI, 0.98-2.32; P = .054).

In the study, patients on nilotinib improved by 2.8 points (95% CI, 0-6.34; P = .037) on the Alzheimer’s Disease Assessment Scale-Cognition 14. No differences were observed in MDS-Unified Parkinson’s Disease Rating Scale Parts II and III, but part 1 (cognition) improved (0.9 points; 95% CI, 0-2; P = .044) in nilotinib compared with placebo. 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.

Following the meeting, study author Charbel Moussa, PhD, MBBS, sat down with NeurologyLive^® to provide greater insights on the study and the mechanism of action behind nilotinib. As part of a new iteration of NeuroVoices, Moussa, an associate professor of neurology at Georgetown University, discussed the origins of the drug and how it came into development for DLB, along with some of the reasons for why there has been little drug success in this patient population. Furthermore, he gave insights on the safety and efficacy of the agent, and ways it can be optimized for future use.

NeurologyLive: What is nilotinib's mechanism of action and origin?

Charbel Moussa, PhD, MBBS: Nilotinib is a known tyrosine kinase inhibitor. It is FDA-approved as an Abl (Abelson) tyrosine kinase inhibitor for leukemia and has been in clinical use for over a decade. It’s really a blockbuster drug for leukemia. We stumbled upon this molecule back in 2007 when we were testing several drugs related to mechanisms we knew were important, particularly autophagy—the degradation of unwanted molecules, misfolded proteins, and other neurotoxic agents in neurodegenerative diseases that lead to neuronal death.

At the time, Nilotinib stood out due to its high efficacy in inducing autophagy, and its mechanism of action was already well-documented in cancer. Beyond autophagy, it also has anti-inflammatory effects. We replicated these findings in my lab at Georgetown University and in almost a dozen other labs worldwide. The mechanism has been confirmed in several neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and ALS models.

This combination—inducing autophagy and reducing inflammation—is highly desirable in neurodegenerative diseases. However, one challenge with Nilotinib is its poor brain penetration. When we began clinical trials in 2016, we saw some promising effects in patients with advanced Parkinson’s disease and dementia with Lewy bodies (DLB), even though these were small, open-label trials involving just 12 patients.

Over the years, we conducted multiple trials in Parkinson, Alzheimer, and DLB. Using genome and microRNA sequencing in cerebrospinal fluid, we confirmed that Nilotinib induces genes associated with autophagy in humans, has potent anti-inflammatory effects in the brain, and influences angiogenesis and vascular fibrosis. These findings suggest a robust mechanism of action.

One persistent issue has been its limited brain penetration—less than 1%. This is because the drug was designed for leukemia, not for brain-targeted activity. However, pharmacology studies revealed that while Nilotinib requires high concentrations to inhibit Abl in leukemia, much lower concentrations are sufficient to inhibit a receptor tyrosine kinase called discoidin domain receptor 1 (DDR1) in the brain. DDR1 controls processes like angiogenesis, collagen modification, autophagy, and inflammation.

Even at low doses (150–300 mg), we observed sufficient concentrations in the brain to inhibit DDR1. This inhibition was linked to several key effects: reduced tau hyperphosphorylation (a hallmark of neurodegeneration), increased dopamine metabolism, and improvements in amyloid processing. In Alzheimer’s and DLB, we even saw reductions in amyloid burden in PET imaging, particularly in the frontal cortex, which is associated with executive function.

In phase 2 trials, cognitive outcomes improved significantly in patients with DLB after six months of treatment with 200 mg of Nilotinib, without worsening motor or behavioral symptoms. Importantly, we also observed a 70% reduction in falls among the treatment group, which is critical for DLB patients. These findings provide strong evidence for its potential benefits, and we now aim to confirm these results in a larger multicenter trial.

What are some of the challenges with treating DLB and with drug development for this patient population?

That’s a great question. Historically, DLB has been overshadowed by Alzheimer disease and Parkinson diseases. If a patient presented primarily with cognitive decline, they were often diagnosed with Alzheimer’s; if they had motor symptoms, they were diagnosed with Parkinson’s. Only recently—perhaps in the last decade—have we come to understand that DLB is a distinct disease with its own pathology and clinical presentation.

DLB progresses faster than Alzheimer disease or Parkinson disease. Patients often develop dementia first, followed by Parkinsonian features within a year or two, whereas in Alzheimer’s, motor symptoms appear much later, and in Parkinson’s, cognitive decline occurs later in the disease. Other hallmark symptoms of DLB include REM sleep disturbances, hallucinations, and cognitive fluctuations. These unique features have helped differentiate DLB as a separate condition.

Pathologically, DLB combines aspects of both Alzheimer disease and Parkinson disease. There is widespread alpha-synuclein pathology (Lewy bodies), along with amyloid plaques and tau hyperphosphorylation. Clinically, it’s a mix of dementia and Parkinsonism that occurs early and progresses rapidly.

Developing drugs for DLB has been challenging because it doesn’t fit neatly into the categories of Alzheimer’s or Parkinson’s. For example, in Parkinson’s, we have a “gold standard” symptomatic treatment in levodopa. But levodopa doesn’t address cognitive symptoms, and over time, its effectiveness wanes. In Alzheimer’s, the focus has historically been on amyloid and tau, with mixed success.

For DLB, we need drugs that address both motor and cognitive symptoms without worsening either. This balance is critical. For example, if you treat motor symptoms with levodopa, you risk exacerbating cognitive symptoms. Similarly, drugs targeting cognition shouldn’t worsen motor function. This dual challenge makes DLB drug development particularly complex.

What does the safety profile of Nilotinib look like?

Great question. Tyrosine kinase inhibitors are typically used at high doses in cancer, where side effects can be significant. For neurology patients, particularly the elderly, we use much lower doses—about one-third of what’s used in leukemia. Across all trials, including those conducted by other groups, the safety and tolerability of Nilotinib have been comparable to placebo.

In this population, we haven’t observed any major adverse effects. This is crucial because elderly patients with neurodegenerative diseases are often more vulnerable to drug side effects than younger, cancer patients. By reducing the dose, we’ve mitigated the risks while maintaining efficacy.

Transcript edited for clarity.

REFERENCE
1. Pagan F, Torres-Yaghi Y, Hebron M, et al. Cognitive and behavioral outcomes in patients with Dementia with Lewy bodies treated with nilotinib. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT LB05