“Senolytic Therapy in Mild Alzheimer’s Disease: a Phase 1 Feasibility Trial”, 2023-09-07 ():
Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. 5 participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study.
D and Q levels in blood increased in all participants (12.7–73.5 ng ml−1 for D and 3.29–26.3 ng ml−1 for Q). In cerebrospinal fluid (CSF), D levels were detected in 4 participants (80%) ranging 0.281–0.536 ml−1 with a CSF to plasma ratio of 0.422–0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation.
Secondary cognitive and neuroimaging endpoints did not statistically-significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, p = 0.008 and t(4) = 3.354, p = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels (t(4) = −2.338, p = 0.079).
In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124.
Lowe commentary: …In fact, this exact combination was already reported in a Phase I trial in idiopathic pulmonary fibrosis earlier this year. That one had only 12 participants, but they were randomized (6 treatment, 6 placebo) and blinded, so there’s that. Now, 12 people isn’t very many to measure adverse effects in, but there seem to have been no serious ones in the treatment group. The team involved concluded that a larger trial was in fact feasible. But that wasn’t the first time that this combination had gone into humans: here’s a 2019 trial from Tbilisi on 64 patients. What’s more, this one reported improvements in systolic blood pressure after a stair-climbing test. And not long before that one was another trial in IPF (14 patients) which seems to have been the first-in-human for this combination. That one also showed improvements in physical performance.
So the combination of dasatinib and quercetin has proven itself feasible several times in humans—this latest trial is just demonstrating an abundance of caution as they move into Alzheimer’s patients and in measuring the concentrations of each drug as it crosses the blood-brain barrier. Or as it doesn’t—the investigators showed dasatinib levels in the cerebrospinal fluid of their patients, but not quercetin (although it was found in the peripheral blood samples). This is in contrast to several animal study reports that showed some quercetin crossing the BBB, but this does not appear to be the case in humans so far. Given all those phenolic OH groups, it’s not too much of a surprise.
…we don’t know how many of these cells were being cleared from the CNS versus from the periphery—given the lack of quercetin in the combination therapy getting into the brain, you have to wonder.
In general, Alzheimer’s trials have to last a lot longer than this one in order to be interpretable at all, and the authors of this paper acknowledge this. They seem to be attempting to find ways to formulate quercetin in order to increase its CNS penetration, but they’ve already started on a placebo-controlled trial under these conditions. They sure aren’t alone. Clinicaltrials.gov has 16 entries for dasatinib/quercetin studies, including 3 others specifically targeting Alzheimer’s patients.