PharmAust is inching ever closer towards a Phase-2 clinical trial of its lead drug candidate monepantel (MPL) in people with Motor Neurone Disease/Amyotrophic Lateral Sclerosis (MND/ALS), after completing an interim pharmacokinetic analysis of plasma MPL and Monepantel Sulphone (MPLS) concentrations in Cohort 3 MND patients.

Pharmacokinetics is the movement of drugs into, through, and out of the body, essentially the time course of its absorption.

The patients received MPL at 6mg/kg, and the 24-hour intensive pharmacokinetics data demonstrated the presence of MPL and MPLS in all measured patients.

MPL was more rapidly cleared from the plasma of these patients, showing some apparent faster MPLS metabolism.

The average MPLS maximum levels following dosing were approximately 1.8 fold increased between Cohort 1 and 3, while calculated steady-state MPLS concentrations (Css) were 2.6 fold increased.

Therefore the more active ingredient, the higher concentrations in the blood, and still no serious adverse effects which points to a safe drug.

Good safety profile and absorption

Importantly, Cohort 3 patients are the same as those escalated from Cohort 1 which PharmAust (ASX:PAA) says allows for a direct comparison of tablet behaviour in the same people at different doses.

“Further to completing the treatment schedule for Cohort 3, we can note several encouraging outcomes: Firstly, we have a good safety profile and no serious adverse events, even after prolonged periods of dosing patients (4-10 months),” PAA executive chairman Dr Roger Aston said.

“Secondly, it is reassuring to see effective absorption of MPL from tablets and the metabolism of MPL into MPLS, which we believe the latter is fully active based on preclinical study data.

“Thirdly, it is encouraging that despite the challenges of dosing MND patients, the patients have generally adhered to the protocol and have elected to remain on treatment.”

“So far, these outcomes are consistent with previously measured biomarkers such as p-RPS6KB1 and p-EIF4EBP1 and p75ECD.”

Notably, p75ECD is a biomarker with predictive value in (MND/ALS) progression.

“Fourthly, independent studies have shown that one third of patients die within 12 months after first diagnosis, lending support to continue treatment,” Dr Aston added.

Importantly, 12 patients in this trial have survived between 4 and 10 months and are free of Serious Adverse Events. From previous announcements, one patient shows stable disease.

Results from the highly specialised testing of Neurofilament Light Chain (NfL) – a biomarker for ALS – are expected in the coming weeks.

Phase-2 trial planning underway

PharmAust’s preclinical cancer data suggest MPLS displays similar anti-mTOR pathway activity to MPL, suggesting anti-mTOR pathway activity between Cohort 1 and Cohort 3 has increased.

“It is hypothesised that decreasing mTOR pathway activity leads to increased autophagy and the removal of misfolded or accumulated proteins associated with motor neurone death,” the company said.

Over the long term and following repeat dosing, MPLS levels were increased by 13-64% for most patients.

This is noteworthy though that mortality for MND patients is reported to be 34% at one year from diagnosis. MND is invariably fatal with the average life expectancy of someone who has MND being around 27 months and more than 100,000 people die from the disease annually.

The final group Cohort 4 has now been approved to commence dosing by the trial Safety Committee, with the company now able to commence planning a Phase-2 trial.




This article was developed in collaboration with PharmAust Limited, a Stockhead advertiser at the time of publishing.


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