hen I first ever heard about PGIC some years ago I always kinda,...

hen I first ever heard about PGIC some years ago I always kinda, *whispering now*, thought it was a little airy fairy...




An airy fairy measure compared to the rest?


I mean out of all the endpoints and observables, we want to see concrete measurables like raw Pain go down. We want practical Function to go up and even those urinary and serum biomarkers should change for the better. Ie. hard core endpoints. How I am as a patient, isn't that, well, airy fairly subjective?


Tonight we not only cover this concept in more detail, we will see how this PGIC measure stacks up and why I have yet another reason to feel super confident on the pathway going forward.



INTRO

I'm no engineer but if I were, I'd be more focused on the structural reverberations. I'd be asking not only How this bridge is being made but what's it's tensile strength, how long does it span and indeed what is the integrity along with it's durability. How long will this bridge last? Are we building a new bridge to last only for a few months for instance? And what is the backup/redundant systems built in if it does have a moment ...a moment of structural failure.



Actual structural considerations? Isn't that the one and only important thing?



So PGIC never really rated personally too highly for me, specially a number of years ago. When I saw PGIC as a reportable measure, my Mozz eyes seem to slip quickly to the next paragraph...

But what is PGIC anyway?

It's the Patient Global Impression of Change.

How do they reckon their lives are before, and after, a course of iPPS?

To be perfectly honest with you, I only found out the distinct meaning of our PGIC results just a few months ago.

I'll get to that in a Mozz Story soon.



IT'S NOT JUST PAR


This PGIC measure isn't just coming from Paul and PAR as a nice additional measure to have.

It's a well regarded measure in the Pharma industry and there is a distinct link between the PGIC improvement and the improvement in pain for example, here is what one researcher group found:



"Higher PGIC scores were significantly (p<0.001) associated with greater improvement in pain, PGA, FIQ, HAQ and the body map".


and further....


"Regression analysis confirmed a significant (p<0.001) positive association between improvement in all disease severity measures and PGIC. Baseline disease severity and follow-up duration were identified as significant independent predictors of PGIC rating".¹



It's the authority at the highest level that alludes to it:


"In the FDA document titled Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices, and Biological Products for Treatment Guidance for Industry , their own guidance discusses the distinct discordance between between structural changes and signs/symptoms/function, the lack of standard definitions of disease progression, and, correspondingly, the absence of endpoints to reliably assess the ability of a product to alter OA disease progression".²


The guidance also goes on to state that finally it is the translation to a clinically meaningful benefit to patients that is key.


So important this PGIC measure is that it is not merely an observable, it's a Secondary Measure. Within the Secondaries, Paradigmers, PAR together with the FDA have made this a KEY Secondary Measure.



TRUMP CARD





Err...not exactly...


So what I'm asking is, how will we perform in the measure of PGIC in our upcoming P3? Well it's one of the key measures I patiently wait for, we might get a sense of it at interim....We might have to wait till the full result is out ...but it's one measure I am longing for and I think it will....well, ...trump!


What gives me the confidence?

The stats.



It's alllllllll about the stats!


Remember, when n is low and p is low, this can only mean that the resultant observation is less due to chance and more due to the actual empirical effect of the thing being tested, yes iPPS and the drug effect size.


So in our prior studies like 005 and 008, n was terribly low......so very low.

This means that when we bump up n (in our upcoming 012 for example), the p value will get even further suppressed all things remaining constant.
What were the numbers in the past key studies?

Before that, to give you a rough context of how powerful our drug is...

Phase I - usually around 10 patients
Phase II - anywhere from 50 to a few hundred
Phase III - usually several hundred to several thousand



Ghosh Study, n = 54
005 n = 56
008 n = 19

...and our future Phase III ?
012 n = 233

(I have listed n as active, the above were all double blinded so total patients you should double n approximately, ie Ghosh study above, the PBO was actually 60 patients while the active was 54, 008 had three arms of about 20 each)³.



Guys, 012 is more than 4 times the size of 005. Remember, as n is increased, all else being equal, the p values will fall. In other words you get more statistical significance. We want the lowest possible p values.


So what p values did we observe in the past?


Remember, to begin to be somewhat statistically significant you want p to be less than 0.05. In other words with n being fairly low, 0.02 for example is a good result...ie. lower the better.


Right, ready for this?

Look at these results, I did and though I already had some sense of the low p values attained in the past studies in the back of my mind, I still fell over while compiling this post and i'm walking thru the house with my hand covering my mouth.



Ghosh Study P value was 0.006


Note: patient global assessment at 4, 8, 12, 16, and 24 weeks, p was that anemic at ALL of those time points!





Helllloooo Paradigmers, is anyone reading this?





005 - The PGIC p value was 0.0062

The above is not a typo, I checked it twice just in case I got it wrong!

Actually here is a screenshot of the ann:






Right, then we had the wonderful 008 program. But the thing was that 008 was underpowered statistically, to show not much other than a loose link with how iPPS performs in the Synovium as opposed to the Serum. What if any link was there between these two areas, is the question it was trying to answer.



PGIC was measured in this study but with n even lower (some 19 patients compared to 005's 56) it would be a tough slog to get p values lower than 005.

Right?





Wrong






OMG
p value was 0.005



Mate. Yeah as I'm typing this I'm shaking my head. I still feel we are so, so under the radar. Even at this "late stage".


Please someone, articulate this to your nearest Big Pharma or Bio Pharma Funder?
If you want, tell them to come to HC and I will tell them what that means and what our future SHOULD be like (spec statement not advice).



I don't know who is going to end up funding us but I'm fairly certain they are gonna do alright when this baby lands and the rubber hits the proverbial tarmac.



When will we land this PAR Jet? When does the rubber meet the road?




THE MOZZ STORY

Rightio, definitely high time for a Mozz Story ^©...

At the end of last year I was chatting at night to The Man From The West and I was reflecting on just how delightful our results were from 005 and 008. I brought up the announcement on the 28th of November 2024 and reiterated how absolutely bl**dy fabulous was the fact that we had our revised protocols through.


I started stating to him that our structural observations in that same announcement⁴ had been UPGRADED (see orange underline below) from mere observables to actual SECONDARIES.




I then mentioned that PGIC was on the list of key secondaries (see red underline above). Not only that but it is a KEY SECONDARY MEASURE.... All of a sudden a big bright light bulb went off in Mr West's brain...he went super quiet and then like he was that Archimedes guy shouting out "Eureka" when he discovered buoyancy...








...Man From the West stopped me mid sentence and said:

"Mozz...this drug is systemic...the effect is all over...that's the beauty of PGIC. These patients aren't just feeling great about their knee...they are feeling great ALL OVER" !!


- Man From West December 2024




I definitely stopped talking and paused for prob a good 7 seconds and understood what he meant and the inference of this.It's like the clouds in me head parted and I could see the sun. Man from the West had hit the nail so perfectly on the proverbial head.




WHAT DOES THIS INFER?

PGIC is the total impression of life after, and because of, the iPPS drug in question. How do you feel the treatment has made an effect on your life?

It's all encompassing. How does the patient feel overall?

It dawned on me too, why exactly we are getting BETTER p values in PGIC compared to the sharp usually pinpoint or concentric-area pain reduction in just one joint, ie the knee.In other words, the patient's entire focus should be on the knee...that SHOULD be the one joint that they are focused on and thus it would get the best absolute result, a result of the lowest p value. But no. It's PGIC that is scoring even better. How is this Mozz-previously dubbed 'airy fairy' measure achieving a better result than a hard core empiricle measure of knee pain?

How is this PGIC measure garnering anemic and magnificent statistical significance punching way above the weight of the suppressed and minimal n patient numbers? Even in a study of just 19 (008) it is recording nutty low beautiful values???

Because the sum of all the parts trumps the one focused knee joint.

It's because this drug is acting holistically. Yes of course it is reducing the knee pain and that's impressing the patient, but crikey...it's affecting so much more...It's affecting their well being, that little niggling pain at the small of their back, their sore shoulder that's not as bad as the knee but certainly is contributing to a painful and tedious life. These guys are finally getting a good night sleep and that in turn is affecting their entire daily disposition. You get a good night of sleep as a result of pain all over coming down and you are a new person the next day after a restful night's sleep!



Finally, a decent night's pain reduced sleep!



Now this might sound obvious, but it's connected. Yes fix the knee pain and you have a good drug. BUT fix MOST of the other simultaneous pains and aches AND get a good night sleep as a result of it, well all of a sudden you not only have a physical spring on your step, your entire MENTAL disposition towards life is changing too!

The results in PGIC trumped against Placebo but they also were better than even the single joint pain focus...that's telling, and that is one of the best benefits for us. It's all encompassing and it's simultaneous. It results in a much better impression of the patient entirely.


What I'm trying to impress upon you is that yes, fix the knee pain in isolation and we can rate the drug as a solid 7 out of 10. But, you reduce basically MOST of the other, though lesser, pains at the same time....and get a better night's sleep as a result, you have a 9 out of 10 drug.First in line drug?I would suggest so, though it wouldn't be advice.

The FDA know there are two distinct parts here, symptomatic along with structural. A good solution will have both:



"Despite the limitations as a measure for DMOAD efficacy, delay in JSN has been reported for a small number of potential DMOADs to date. However the lack of associated symptomatic benefit in these studies has prevented any of these agents from being successfully registered".



Did you read that above, lack of symptomatic benefit. Jeepers, we have both. We have wonderful symptomatic benefit COUPLED with the structural positive changes. Get both with safety and you are ....done! That's not advice, thats pure FACT.

Now not only PAR is aware of this, the FDA know it too, that's why they value PGIC as a measure in clinical trials especially ones involving pain. They know it is one thing to perhaps alter a structure or reduce some pain, they know it is quite another measure when the patients THEMSELVES are feeling better overall!

This is an important measure to the patients but this is an important measure to the authorities. This is one of our best readings for any markers studied to date.



If the patients feels better after taking iPPS, there is one other class of entity that will also feel better...

The Insurers and Payers.





Get them to also feel good and pay, it will add spades to our ultimate value.










- Mozz












No advice contained in this post, there is risk with any investment.











APPENDIX A




PGIC measured over time in our latest 008 study - measured over a full year. Results were great over Placebo, but certainly these results were magnified when n is just 19 in the 2x2 dosing cohort of the recent 008 study. When n bumps up to 233 (active), you tell me what will the p value ultimately will be in this 'key secondary measure' ?

Anything less than 0.0005 and I'll see you at the pub.





REFERENCES

1] https://pmc.ncbi.nlm.nih.gov/articles/PMC4623367/
2] https://www.fda.gov/media/71132/download3] https://pubmed.ncbi.nlm.nih.gov/24678076/
4] https://app.sharelinktechnologies.com/announcement/asx/0f31b957e47b97890d4a933ff7b4577d
5] https://pmc.ncbi.nlm.nih.gov/articles/PMC3260466/
6] https://app.sharelinktechnologies.com/announcement/asx/63a249bdb0b4e5e1dc93c8ee2644f3a2
7] https://app.sharelinktechnologies.com/announcement/asx/0f31b957e47b97890d4a933ff7b4577d
8] https://app.sharelinktechnologies.com/announcement/asx/9fe3dc76fd51b4a6345f9b4542e23c82