A DMOAD Definition, page-2

PART 2 - A DMOAD Definition

A very insightful paper on DMOAD, lets continue with the the topics covered, see main reference for the full paper below.



THE POSTIVE AND THE NEGATIVE

So yes, we understand what we need on the positive side, but we also have to tackle potential negatives that can crop up, of the bigger ones that normally plague pain related trials is the placebo effect.

"One of the greatest obstacles to understanding and interpreting treatment effects in OA clinical trials is the powerful placebo effect...".

Such a powerful effect that the researchers had to say this:


"Most candidate drugs have demonstrated treatment effects that do not surpass the placebo effect and thus fail to demonstrate statistically significant and clinically relevant improvements; to the extent that some groups have even suggested using placebo for treating the symptoms of OA".



Two things from that above quote:

POINT 1

What did we observe in terms of placebo effect and did we manage to trump it so far?





This last (red underlined) line kinda did it for me...ALL patients against placebo achieved favourable results.

Do you guys understand what that means? In the active arm, 100% achieved positive effect...



POINT 2

Wait, did someone mention statistical significance? I understand PAR need to be cautious when you have a P3 going on, but seriously, can you trumpet this enough? Does anyone out there understand what are the ramifications of this going forward with such a tiny subset of n?


Yeah Mozz...we may also get that in our dosing study, or perhaps, with our Phase 3 Part 2 002.

WHAT?

We have it already.....

...on what sort of numbers?


008

But 008 active twice week dosing only had 19 patients?!?!?









I will need a separate post on this...I'll cover it properly one day...Too much to do, so much to say!




ADVANCED EARLY WARNING SYSTEM


_AWACS?

Is there an engineer in the house? One of the reasons OA has progressed so markedly in so many is the fact that it goes undetected. As a Mozz example lets chat about the cartilage for a sec.

Cartilage lacks three distinct systems a number of other body structures tend to have, namely

1) Its Avascular (it has no blood vessel system proliferating through it

2) Its has no Nerves

3) It lacks any form of Lymphatic system

For this reason Paradigmers, when your cartilage breaks down, you have no knowledge of it...not for hours...NOT FOR YEARS!


This means by the time your surrounding fibres and tissues start also becoming inflamed and pain starts, its just way too late for most. The darned destruction is done...you're already too late...ENTER the biochemical markers! Dr Kraus, Dr Felson, I will one day meet you to discuss this in detail.


"One of the main weaknesses of plain radiography is the inability to capture early OA. By the time OA is diagnosed and confirmed radiographically, the disease has already reached a relatively advanced stage".

...and further...

"Current thinking suggests that once OA has reached an advanced stage, the ability to prevent further disease progression and even promote structural repair may be significantly reduced".


.
Now we get to see just how iPPS can play such a pivotal role in the Disease Modification, how it potentially will save many many lives and avoid a whole heap of pain and poor Quality of Life.

Yes indeed, the early detection of Diagnostic and Prognostic biomarkers will be key....I patiently wait to hear more of this at OARSI in just under 3 weeks from now. That's exciting me...but what our data says about iPPS's effect on the same is on another planet. When we finally get a hold of that data...be it via 6 month data release (008) or by a future peer review or indeed both...hmmm you may just find me pulling an overnighter at the pub (drink in moderation, bad for your liver, though I may just have a solution of sorts for an inflamed liver, lets not go there yet).


Hey hey, how did that image above get into this post?


_{Last drink for you Mr Mozz...you got research to drink do. Lucky Pool Director is on duty tonight, he will miss all this humour.}


Here is another quote from the researchers on the topic of biomarkers:



"... if we can identify a biomarker that reproducibly and consistently increases in terms of expression levels in serum before a patient begins to feel pain, early treatment can be initiated to slow disease progression and preserve long-term joint function".


COMPETITION AND US

We don't often see PPS being mentioned in a DMOAD context, its a fraction too early but this is slowly changing. This paper finally mentions us, its a bit high level but at least we scored a mention. Competitors mentioned Tanezumab and Sprifermin amongst a number of older ones as well as a few up and coming ones. (See Appendix A)

The researchers are adamant that most if not all categories must be met in order to have the gold std of a DMOAD to be bestowed:


"Taken together, sprifermin is still a promising pro-regenerative therapeutic candidate, but it cannot qualify as a DMOAD because it does not appear to have any significant impact on OA pain symptoms. The clinical development of sprifermin has since been halted".


The researchers go on and state that despite some successes, no candidates in OA have received this grail like title of a DM. One of the reasons is that in the FDA assessment of OA drug guidelines, no structural outcomes have actually been defined or implemented. In fact the researchers go on to say that patients do not complain about their structural evaluation results but rather the joint symptoms and pain.

Here is an example they put forward:

"Sprifermin is a representative example of a biological drug caught in this dilemma; even though sprifermin showed significant differences in structure improvements, there was no significant effect on patients’ pain or functional improvement in phase II clinical trial".


This is why potentially the data on iPPS is indeed wholistic covering a broad range of markers both symptomatic as well as physical and even from a PGIC point of view. Certainly it is envisaged that a multi modal drug displaying its broadness on addressing the diseases on multiple fronts has indeed a better chance of success?

Indeed as the researchers argue,


"Currently, OA is recognized not simply as a result of intra-articular cartilage degradation but as the product of complex interactions between several tissues in the joint".


Again, the all encompassing nature of OA must be addressed via multiple prongs:

"In keeping with this shift in perspective, studies have aimed to elucidate the pathogenesis of OA and identify clinical outcomes focusing on various tissues, including knee joint cartilage and subchondral bone, synovium, menisci, ligaments, and peri-articular muscles and nerves. Alongside these pre-clinical studies, there has been growing recognition of the need for more effective assessment outcomes that can combine structure and function to achieve more successful clinical trials and reduce medical expenses".



Again, bringing it back to iPPS...the researchers mention "...inflammation influences the pathogenesis of OA, but not all OA subtypes are driven
by inflammation". Its a perfect iPPS recipe, yes address inflammation predominantly, but its all of the many other wonderful direct and indirect mechanisms where our drug will really shine to result in that all important DMOAD label.



PAR'S DMOAD SETUP



Paradigm knows what they have and where this is going, I suspect it will be quite an eye opener at the preeminent OA conference that's OARSI.

PAR now have three separate sessions that will assist in getting the word out:

1) Poster

2) CTS

3) Theatre Session


But it doesn't stop there, did you know PAR are working on multiple fronts. They know just how many patients may end up taking our drug one day, patient convenience is a big factor and through the use of auto injectors we may find the vast majority of OA and other inflammatory conditions may get treated this way.

Par also has sought to strengthen the tie up with Bene.

DMOAD may not end with OA, it could translate quite nicely into other inflammatory conditions in a DM sense, subject to future studies and trials of course.

Indeed we know the real ramifications that if we prove we are DMOAD even in a slice of the population, we go to the top of the class, first in line treatment and automatically the revenue gets multiplied. Multiplied not just by sheer volume of additional front running patients but from a chargeable price per course sense as well.

Yes we have some ways to go, but also yes, our time on the Global stage draws materially closer






As always, DYOR recommended





Mozz





APPENDIX A

Look out for the Orange Star...PPS finally gets a mention!








REFERENCES

MAIN REFERENCE

1] https://journals.sagepub.com/doi/10.1177/1759720X221085952?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

OTHER REFERENCES

1.5] https://www.arthritiswa.org.au/news/a-breakthrough-treatment-for-osteoarthritis-%EF%BB%BFcould-delay-the-need-for-hip-and-knee-replacements-2/
2] https://clinicaltrials.gov/ct2/show/record/NCT04809376
3] https://app.sharelinktechnologies.com/announcement/asx/7d8b2863c7cf454551f389cf7428c338
4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787673/#:~:text=In%20liver%20disease%2C%20saturation%20of,that%20amplifies%20the%20inflammatory%20response.
5] https://app.sharelinktechnologies.com/announcement/asx/fa31694b6b5919adc469e18a683a3c83