Post #: 75475423@QuiltmanI agree.I perceive that Nicky will be...

Post #: 75475423
@Quiltman
I agree.

I perceive that Nicky will be juggling multiple pre-clinical curve balls to see what lands where, how hard they hit, what gets inferred by the results, what bounces well, what crashes and burns, and what the next steps are after those aspects are all assessed.

I reckon it’s likely that we’ll see the design of the pre-clinical models before any potential results. Nicky may be running and repeating some fast cell lines which may inform other modes of trialling, which also may inform further avenues of investigative research and further testing, which may then inform other tests that take two or three months to run. Any of which may help if early enough to inform and support or further refine the design of the Healey Platform trial, or refresh the adaptive design, as well as investigating other neurodegenerative diseases Alzheimer’s, Huntington’s, and Parkinson’s.

There’s a lot of moving parts, and a lot of time is needed to generate the series of reliable and reproducible results. A quick insight into what Nicky has defined in post #: 75054203 that has helped to shape the best path forward, to give us robust data, in a timely manner. Those results will come out progressively over the next 3 or 4 months. Note of absolute caution and restraint:

The very last thing we want to do is to rush the pre-clinicals, or to have expectations of results way before their time.

Experiments generate data that yields insights into target-binding ability, modulation of targets, further confirmation of zero contra-indication against riluzole, or specific targets of the insoluble beta-amyloid plaque aggregates, the soluble neurotoxic amyloid oligomers, chronic inflammation, hyperphosphorylated tau tangle deposition, where any reductions in any of those will confirm the MPL mechanism of action and give insights into levels of efficacy. e.g. exploring blood-based biomarkers for AD, where the aetiology remains poorly understood, any modelling of the pathology of the disease hopes to gain a greater understanding of the cause and progression.

And those three ND’s are different — Parkinson’s and Huntington’s involve motor and cognitive symptoms; Huntington’s also causes psychiatric symptoms. Alzheimer’s disease primarily affects memory and cognitive function, often appearing as progressive memory loss, confusion, and difficulty with problem-solving and language. Although these diseases share some similar characteristics, they differ in their primary symptoms, progression, and underlying causes.

Using published data in those key diseases of interest, Nicky is:

“building on this already established knowledge, each experiment is set up to employ appropriate reference compounds, positive and negative controls, inhibitors and inducers, which are used in an orchestrated manner to help us map the ‘on’ and ‘off’ signals down a pathway, subsequently enabling us to monitor if, how and where monepantel might be working.

Other typical endpoints that are used in these types of experiments in addition to the above might include: cell viability, assaying levels of key transporters associated with neurodegenerative diseases e.g., EAATs, which transport glutamate, the major excitatory neurotransmitter, measuring mitochondrial function, length of neurites, electrical activity of neurons, measuring markers associated with inflammation (like cytokines), measuring reactive oxygen species, and assessing the morphology of cells under the microscope.”

There are so very many possibilities …

“We’ve got the ability to turn on autophagy in those other neurodegenerative diseases by using monepantel.” MT

In addition, we do know that the preclinicals have another very specific target — that is squarely faced at providing the exact type of data that big pharma want to see. That has been very clearly stated by MT.

Also stated by MT is that Nicky’s work allow the opportunity “to extend the value of the whole enterprise by looking at the MoA of monepantel, ... or exploring the opportunities for monepantel in other neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s”.

Any successes will further de-risk monepantel in the eyes of small, medium and big pharma who are known for very calculated and precise risk taking into the billion $ levels, and I’ll say it very clearly — they do not need certainty — they need clarity against their own internal modelling of risk profiling.

“The failure rate for disease-modifying AD therapeutics in clinical trials is currently 100%.”

https://www.sciencedirect.com/science/article/pii/S2772417422000164 August 2022

Even small successes will generate considerable interest, particularly as we are in the beginning of the end-game.

Compare what other companies may have spent, or are considering spending, and how long it takes, to where we’re at.

https://www.mckinsey.com/industries/life-sciences/our-insights/fast-to-first-in-human-getting-new-medicines-to-patients-more-quickly

https://www.nature.com/articles/s41582-024-00989-1

The players in this space are:

AbbVie Inc.

Merck & Co., Inc.

F. Hoffmann-La Roche Ltd

Gilead Sciences, Inc.

Biogen

Pfizer Inc.

Novartis AG

Johnson & Johnson Services, Inc.

Teva Pharmaceutical Industries Ltd

Otsuka Holdings

and I’ll throw Sanofi into the mix,

with the leading contenders being:

Biogen

AbbVie Inc.

Merck & Co., Inc.

Novartis AG

Source: https://www.expertmarketresearch.com/reports/neurological-disease-treatment-market

We are uniquely well placed in pole position with 1 clinical trial to go before potential accelerated approval.

cheers,
Ice