Latest MND Webinar information on Monepantel, page-33

Hi Lastly and all,

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370%2823%2900213-4/fulltext

Preliminary results announced from the recently completed Phase 2 Healey ALS Platform trial38 indicate that CNM-Au8 treatment did not slow ALSFRS-R change following 24 weeks of treatment.

Why my thoughts,

1. It is absorbed slowly via the first pass metabolism.

2. It requires prolonged dosing to reach therapeutic levels

3. Not metabolised by the liver, instead via regional tissue .

4 Bioavailability is 1 to 10% as compared to MPL 31%.

5. The levels not consistently quantifiable in human whole blood samples until 3–4 weeks of continuous daily oral dosing at 30 mg.10 Tissue levels do not reach equilibrium until >6 months of daily oral dosing .

6. First 12-weeks of active treatment represented a subtherapeutic period window whilst drug became therapeutic.

7. Therefore, orally delivered CNM-Au8 is blood brain barrier penetrant, albeit at low levels.

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Ok lets have a quick look at the problems of nanocrystals crossing the blood brain barrier effectively.

This article helps.
https://www.unsw.edu.au/news/2024/05/bypassing-the-blood-brain-barrier

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Now let's have a squiz at efficacy of CNM-AU8.

1.No PRO-ACT data base control to compare long term results.

2. Instead of PRO-ACT they used random slope models.

3.Neurophysiology was not collected consistently during the OLE (6–8 assessments per group per visit), so did not provide meaningful data for evaluation. "I wonder who dropped the ball there".

4. Study size underpowered to meet full statistical endpoints, they needed approximately 27 more patients.

5 The absence of significant differences in MUNIX measures may be explained, at least in part, by inclusion of bulbar-onset ALS participants, where the placebo group did not exhibit an appreciable decline in limb-innervated muscles over 36 weeks. (" I have rabbited on before about trials combining limb onset and bulbar, some may remember my rants. It really changes the P values of the intended treatment.)

6. Another limitation was the selection of MUNIX as the primary endpoint, as well as the selection of the four muscles innervated by the spinal cord motor neurons.

7. Neurophysiological techniques require extensive training and expertise, without which excessive variability may occur. Related to point 6.

8. Combining bulbar with limb onset in a subset to achieve a reliable endpoint may not work as the muscles in " point" 6 are not as affected in bulbar v limb onset ( if that makes sense)

9. They did not incorporate site level stratification effects on their sample size estimates, which may have contributed to the underpowering of this study.

10.Primary and secondary endpoints of the trial were not reached, it is important to cautiously interpret the exploratory endpoints and OLE outcomes suggesting potential benefit favouring CNM-Au8 treatment, and for the purposes of hypothesis-generation only.

References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314176/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494002/

In summary it comes down to statistical significance in my book.Monepantel is the autophagic drug of choice. The main problem with MND ALS is the removal of protein aggregation. Regeneration of synapses is futuristic and can be of benefit some time in the future. The research goes on.

Kpax