Ann: First Patient Dosed in MND Phase 1/2 Trial, page-168

Many SH interested in the science underpinning the current MPL trial will be aware that an Italian Phase 2 trial has been exploring the use of rapamycin (Sirolimus) in MND/ALS since 2019. While the full study is still to be published, I've located the abstract from an oral presentation delivered at the June 2022 European Netwrok to Cure ALS (ENCALS) convention in Edinburgh by principal investigator, Dr Jessica Mandrioli, of the Azienda Ospedaliero-Universitaria di Modena, which has just been published.

The abstract in question appears on p.49: https://www.encals.eu/wp-content/uploads/2017/03/Abstracts_ENCALS2022.pdf
Details about the EU trial can be found here: https://ichgcp.net/clinical-trials-registry/NCT03359538

Keeping in mind the context in which this high-level information was provided (it's NOT a journal article), some takeouts:
1. It's a high-quality study - multicenter, randomized, double-blind, placebo controlled.
2. Two doses of rapamycin were trialled over an 18-week period - rapamycin 2 mg/m2/day and rapamycin 1 mg/m2/day (as well as a placebo arm)
3. Patients were monitored out to 54 weeks.
4. Rapamycin 1 mg/m2/day reduced CD8 T-lymphocytes (p=0.032), IL-18 (p<0.001) and related inflammasome (p=0.023); slowed the rate of disease-related deterioration; and was associated with better quality of life in relation to the 'communication' domain on the ALSAQ-40 patient self-report (the ALSAQ-40 asks patients to score the frequency of a range functional difficulties they may have experienced in ther past 2 weeks across 5 domains: physical mobility, activities of daily living and independence,eating and drinking, communication, and emotional reactions).
5. Adverse events (AE's) were equally represented across all treatment arms, which suggests (more detail needed) that the trial did not encounter dose limiting toxicity. There may be a lot of reasons for this, including that the dose may not have been high enough to induce toxic effects, or even that the 1mg/m2/day dose was too high resulting in similar AE's to the higher 2mg/m2/day dose. It's just too early to tell based on limited info.
6. The lower rapamycin 1 mg/m2/day dose was identified as the most promising for further study, based on biological and clinical outcome measures, safety and plasma dosage stability. This may be due to a biphasic effect? Again, insufficient info to know.

So, a first peek at the first mTOR drug study in ALS/MND.

It should also be noted that, while MPL is an mTOR drug like rapamycin, the method of action and signalling pathways targetted by MPL are very different. So the rapamycin results, while interesting, encouraging and providing a first look at how down-regulation of mTOR signalling pathways might impact ALS/MND progression in vivo, it's by no means predictive of what we should expect from the current MPL trial.

Cheers

Densy