This is just a phase 1b trial (so small sample size, and very early in the process) but I find it interesting because of the encapsulated rapamycin being used. I wonder how the bioavailability compares to rapamune or all the generic versions of rapamycin. This seems to be a key issue…
The company behind this study is, I think, the group that is a spin out of UT Southwestern that first developed eRapa for the mice trials of the NIA ITP.
Results of a phase Ib trial of encapsulated rapamycin in prostate cancer patients
At low doses, rapamycin inhibits cell proliferation and angiogenesis while augmenting CD8 T-cell responses, cumulatively producing an antitumor effect. Oral rapamycin is limited by variable bioavailability. Encapsulated rapamycin (eRapa) incorporates submicron rapamycin particles into a pH-sensitive polymer, improving bioavailability and allowing for consistent and lower dosing. Here, we present results of a phase Ib trial evaluating safety and treatment effects of eRapa in patients with low-grade prostate cancer (PCa).
Results: 14 patients were enrolled; 3 in cohort 1, 3 in cohort 2, and 8 in cohort 3. 2 patients withdrew for non-dose limiting toxicity (DLT) (grade 1-2) adverse events (AEs) in cohort 3, leaving 6 evaluable. A single grade 3 DLT (neutropenia) occurred in cohort 3. No AEs > Grade 1 occurred in cohorts 1/2. Peak serum rapamycin concentration ([Rapa]) was 7 ng/mL after a 1 mg dose (2h after administration). Stable trough levels (2 ng/mL) were established after 48 hrs and persisted to 13wks. Central memory CD8 T cells and CD3+/CD56+ NK cells were more prevalent in cohort 3 than other cohorts at 1m (p = 0.027 and p = 0.041) and 3m (p = 0.023 and p = 0.049). There was no significant change in PSA level; no patients clinically progressed on therapy. In cohort 3, there were no differences between baseline and 3m QOL assessments but there was a suggestion of withdrawal effects at 6m.
Conclusions: Treatment with low dose eRapa is safe and well-tolerated. The dose of 0.5mg daily produced stable serum [Rapa] through the duration of treatment and resulted in a positive immune impact. Further investigation with low dose and/or intermittent dosing of eRapa as a preventive agent in PCa and other indications will be required to establish clinical benefit.
Benefits of eRapa™ over rapamycin and current rapalogues include:
Enhanced bioavailability improves drug absorption, allows for a lower therapeutically effective dose, and improves its toxicity profile. eRapa™ consistently provides approximately 30% more drug than generic rapamycin (Emtora Biosciences unpublished data);
Less interpatient pharmacokinetic variation reduces need for therapeutic drug monitoring and limits adverse events;
Targeted delivery to the duodenum, lower intestine and colon delivers the active ingredient directly to the site of active disease in GI indications. eRapa has a systemic effect and a local (GI) effect.
That’s from the company’s web page, last updated in 2020. Guess we’ll have to see if any or all of this pans out…
Seems interesting. IDK if if fits into longevity protocols, but seems really good strategy for cancer.
encapsulated rapamycin
An orally bioavailable nanoparticle-based formulation composed of sub-micron particles of the macrolide antibiotic rapamycin incorporated into a pH-sensitive poly(methyl methacrylate) polymer, with potential immunomodulating and antineoplastic activities. Upon oral administration of the encapsulated rapamycin, the nanoparticle specifically delivers rapamycin at the tumor site. Rapamycin binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate a complex that binds to and inhibits the activation of the serine/threonine kinase mammalian target of rapamycin (mTOR), a key regulatory kinase. This may suppress mTORC1 activity. In addition, inhibition of mTOR may modulate central memory CD8 T cells, CD3+/CD56+ natural killer (NK) cells and CD8 T-cell responses. This may kill tumor cells. Compared to the administration of rapamycin alone, this formulation improves oral bioavailability of rapamycin with more consistent rapamycin levels, thereby allowing for administration of lower rapamycin dosage, which improves and minimizes rapamycin’s toxicity. Upregulated in some tumors, mTOR is a serine/threonine kinase involved in regulating cellular proliferation, motility, and survival that is located downstream of the PI3K/Akt signaling pathway.