“ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer’s disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. … If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer’s disease.”
This trial is ongoing. Meanwhile, they’ve just reported the PK data:
“This open-label pilot study investigated the pharmacokinetic properties of weekly oral rapamycin in 13 patients with early-stage AD. Participants received 7 mg weekly (11 patients) or reduced doses (2 mg and 4 mg; 2 patients) for 26 weeks. Blood concentrations were measured at four timepoints (pre-dose/Cmin, and 1-, 3-, and 48-h post-dose) during week 13. Moderate interindividual variability was observed across timepoints (coefficient of variation was 0.28–0.40), with the 48-h sample showing the lowest variability (CoV = 0.28) and strongest correlation with Cmin from the previous dosing (r = 0.72). Estimate of terminal half-life (68.9 ± 13.6 h) aligned with previous studies. Blood concentrations at Cmin were below immunosuppressive levels in all participants.”
Thanks for sharing. On the BBB crossing @John_Hemming:
The extent to which rapamycin passes the BBB is unclear. The drug´s high molecular weight (914.2 Da) and its status as an efflux pump substrate suggest limited permeability. One study of rapamycin in patients with amyotrophic lateral sclerosis showed no quantifiable levels of sirolimus in CSF using LC–MS/MS [15]. To assess whether LC–MS/MS could reliably quantify rapamycin in CSF, we developed a method achieving an LLOQ of 20 ng/mL. While further optimization might lower this threshold, reaching the single-digit pg/mL range—necessary to definitively rule out the presence of a pharmacologically relevant concentration—was deemed unfeasible. Given this, we elected not to perform any analysis of rapamycin concentration on the CSF data collected from the study participants in our trial. This constrained LLOQ should also be taken into consideration when interpreting the published dataset where no rapamycin could be detected in CSF of patients on the drug [15]. While some clinical data suggest BBB passage—such as rapamycin’s efficacy in treating cerebral manifestations of tuberous sclerosis complex in humans [21]—the question of its extent of brain delivery remains open. Given the expected low free concentration in CSF, one option for future research is to perform post-mortem analysis of brain tissue from rapamycin-fed laboratory animals. Alternatively, labelling rapamycin with a radioactive nuclide and perform micro-dosing experiments using positron emission tomography (PET) could provide further insights into its brain exposure.
There is another question which is where the CSF is tested as one would assume the concentration of any rapamycin in CSF would not be consistent particularly given the pumping proteins.