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Initial STOMP-AD Trial Results Published, Not Yet Enough Data for Firm Conclusions to be Drawn


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Posted 18 May 2023 - 07:22 PM


The initial results from the first five patients enrolled in the STOMP-AD trial were recently published as a preprint paper. This clinical trial assesses the outcome of a (possibly too low) dose of the senolytic combination of dasatinib and quercetin in Alzheimer's patients. The hypothesis to be tested is that the age-related increase in the burden of senescent cells in the brain is important in the onset and progression of neurodegeneration. Animal models of inflammatory neurodegeneration have shown considerable improvement following clearance of senescent cells, and a range of evidence implicates senescent cells in aspect of brain aging.

Because only a few patients have completed the trial so far, there isn't too much that one can say about the results, but they do confirm that the treatment passes the blood-brain barrier as expected, and is relatively safe. The researchers observed changes in inflammatory markers consistent with a reduction in harmful senescent cell signaling, but not in a statistically robust way given the low number of patients. They did not observe any useful outcome in measures of cognitive function, which is unfortunate.

There is some thought in the community that the doses used in the Mayo Clinic sponsored trials of dasatinib and quercetin are too low (e.g. 100mg or 125mg of dastinib and 1000mg or 1250mg of quercetin). The Betterhumans clinical trial conducted a few years ago used higher doses; unfortunately nothing has yet been published on this, I believe. Nonetheless, one would have hoped to see some improvement in cognitive function in these patients if cellular senescence is a major mechanism in Alzheimer's disease and other forms of neurodegeneration. We will have to see how the rest of the trial data looks as it emerges over the next few years. These trials are not moving rapidly, and there is definitely room for independent efforts to test these senolytics in other conditions and many more patients.

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease

Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy.

Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study.

Our study was not powered to examine target engagement, but instead designed to collect exploratory data on baseline to post-treatment changes in markers of cellular senescence and senescence-associated secretory phenotype (SASP) both in CSF and blood. Change in IL-6 was a prespecified secondary outcome. The analyses revealed a statistically significant elevation of IL-6 in CSF after treatment. Plasma levels modestly increased, but did not reach statistical significance. The treatment-induced changes in IL-6 may reflect senescent cell apoptosis whereby IL-6 was directly released from senescent cells upon their lysis; alternatively, apoptosis may have initiated an immune response to clear the cellular debris.

Recognizing that IL-6 is a pleiotropic cytokine, we simultaneously performed a broader evaluation of cytokines and chemokines to better infer the treatment effect. CSF analyses indicated baseline to post-treatment decreases in adaptive immunity markers, TARC, IL-17A, I-TAC, Eotaxin and Eotaxin-2; and chemokine, MIP-1α. A similar pattern was observed in plasma whereby treatment was associated with a decrease in adaptive immunity markers IL-23, IL-21, IL-17, IL-31, and VEGF54; and chemokines, MIP-1α and MIP-1β. Given that senescent cells secrete these molecules as SASP factors, the observed reduction support a decrease in senescent cell burden post-treatment.

In CSF, we observed a significant increase in GFAP levels from baseline to post-treatment. CSF GFAP levels are presumed to reflect reactive astrogliosis and demonstrate elevations early in the neurodegenerative disease process. In our study, it is unclear if increases in GFAP reflect or an acute response to treatment. Coupled with the elevated CSF IL-6 data, it is tempting to speculate that the concomitant increase in GFAP may reflect apoptosis of senescent astrocytes. Supporting evidence for this would require additional blood and CSF collections, weeks or months after the end of treatment, to determine if increased GFAP and IL-6 were transient or sustained responses to senolytic treatment.


View the full article at FightAging




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