Cohort 4 can only proceed following a safety committee review of...

Cohort 4 can only proceed following a safety committee review of cohort 3. They review each dose level for AE's before giving the green light for the next (higher) dose. The only dose escalation currently being considered is from 2 to 3.

What we are waiting for is the release of the interim analysis results:

These results are based on the pharmacokinetic (how the drug is absorbed, distributed through the body, metabolised and ultimately removed) and pharmacodynamic (what effect did it have) studies of the 12 patients in cohorts 1 & 2.

The study record (https://beta.clinicaltrials.gov/study/NCT04894240?term=monepantel&rank=1) identifies 'secondary' outcomes (because this is principally a safety study, these outcomes are considered secondary) that will give an indication as to efficacy/drug effect. These include blood markers that will indicate whether the MPL/S is having the intended effect on mTOR, changes from baseline in functional rating scales used to track MND progression, respiratory function, imaging, and changes in blood/urine/CSF (central spinal fluid or cerebrospinal fluid) markers that serve as a proxy for disease progression in MND.

Of this latter group of measures, one of the most important biomarkers from a drug development perspective in ALS is neurofilament light (NfL) chain markers, which are used as a diagnostic tool in ALS (NfL chain levels in ALS patients are far higher than in non-ALS individuals) and, more recently, have been strongly associated with clinical outcome and disease progression in ALS/MND.

In recent decisions related to drug and device approvals in ALS/MND and a small group of other neurodegenerative diseases, the FDA has not only accepted NfL chain levels as a surrogate endpoint, but also as a prognostic tool that gives good insights into the likely course these diseases will take (particularly the rate of progression). (See https://www.medpagetoday.com/neurology/generalneurology/103672 and https://www.fda.gov/media/166326/download)

So, when the report lands, one of the key metrics to look for will be what changes (if any) in NfL chain markers were induced by MPL, as this is a key indicator of whether or not the drug is slowing disease progression.

With the right results, things could move very quickly indeed.

Cheers

Densy