DAY 112 - PART 2
n Part 1 last week, we went over how Paradigm Biopharmaceuticals shifted from not just being a Pain and Function company but importantly, adding structural markers as secondaries to their Phase 3. Now officially accepted and harmonised FDA and EMA. But the shift did not just involve the authorities, it involved a time endpoint shift from Day 56 to 112. It is this concept I wish to cover more in Part 2 with some further evidence for your perusal!
Oh and do look out for some Mozz bonuses© right at the end!
Do now, please, enjoy.
LOOKING FOR CLUES
In Part 1 of this Day 112 post I also covered the fact that I want to see a relatively flat bell curve. In other words, I didn't want there to be an overly sharp drop off after we hit peak in the drug effect. I want the effect at Day 112 to still be up there!
It is one thing for PAR to demonstrate the drug works, it's an additional concept to show how it works against Placebo. This is always going to be especially tough as the placebo effect is even higher in Pain trials. It's another reason why we don't have a deal yet, there is a bit of skepticism, no doubt, as to what our results will be like at scale in an all important Phase 3.
Show that we are on track, or even better than most think at interim and all bets are off.....well, actually, on.
But I am Mozz, I want to see if I can get some sort of clue as to what are our chances of demonstrating some good effects in our P3? Yes I am being patient and waiting, but while I wait, it's a great chance while it's all quiet on the PAR stock market front to do some research. Find out more about how this thing works, why does this thing work and of course, how much does this thing work?
THE EVIDENCE
So as a reminder, what is our Primary? It is Pain.
Our 012 Phase 3 Study - What is the Primary?
Pain reduction. That's the ultimate test. Yes there are many other measures we will be testing, but finally it is pain that's key. Here is what I want to present tonight. Dr Ghosh's work.
In Ghosh's exceptional pilot trial conducted at Queen Elizabeth Hospital in Perth, some 60 patients were in the Placebo and a further 54 were in the Active. Let's take a look at how the Active patients performed in terms of pain:
The Pain trend was lovely, It was down...and look at the curvature, it was relatively flat, it didn't bounce up immediately and strongly, that's what ideally we want from the Active. Now I have deliberately hidden Placebo comparison in the above chart...I want you to guess what the Placebo was like....was it similar and also fell? Was it also relatively flat?
Well let me first take a rough stab at what it could've been like.
If I had to guess, I would HOPE it would look like this, see purple line in below chart:
So the above is Mozz's hopeful prediction...
OMG, what did placebo actually do? Sit down in your nearest chair....and brace for POSITIVE impact:
It went the other way, straight after the dosing regime, the Placebo group's pain got worse, so much worse compared to Active....Just look at it at Day 112 which is exactly Week 16.
See that double line: 
looking symbol, that's SIGNIFICANT at 0.014
Hellllllooooooo investors!
Take a look at the large canyon-like gap between those two lines - we like to call that... s e p e r a t i o n .
This is what makes me extra confident.
Imagine the data, when n is driven higher. I am so dying to see those p values, and I don't think I will be the only one waiting for it! The market will be holding it's breath for this read.
MORE?
Of course, there is more....
Now we know that PGIC is a pretty big focus for the FDA.
Why?
They want to know that it's not just one random positive aspect that a given patient is experiencing, it is a full panoply of desireale effects. A global impression. Is it benefiting the patients in multiple ways and on multiple levels? The FDA knows pain is subjective and yet it is a key, and yet it is not only a valuable and necessary endpoint but it is mandatory for a potential viable OA solution. However, finally, overall patient benefit in day to day activities makes a difference to a patient's life!
Take a look at this quote:
“Approvals for OA to date have been based on patient-reported outcome measures that assess pain and function. However, treatments that inhibit structural damage or target the underlying pathophysiology associated with OA remain elusive and represent an unmet medical need”.2
We know that PGIC were off the charts in other studies like 005 and 008 despite anaemic patient numbers...but what did Ghosh experience in the study from over in the West?
So let's do this again, and I'll make it somewhat interactive... what's your guess? If iPPS was half not bad I'd hope we'd get readings of above 0.4 on the Mean Change Y axis....
So perhaps some sort of Mozz guess like this (see next chart below), purple circles/lines are my guess, something better than Placebo group???
Rightio, what was your guess?Let's take a look at the actual results now, was our Pentosan anywhere near this 0.4 level on the scale and was there decent separation between the cohorts???
Yeah I kinda got you there, I didn't just erase the Active line in the first couple of figures above, I also erased part of the y axis scale altogether so you wouldn't have any clue exactly how much above 0.4 the result was!!!
Mate we featured in the 0.85's there at peak!
A number of other things to observe here:
1. Look at Week 16, Week 16...how many days is Week 16? Anyone?
Let me help you... 16 x 7 = 112
Helllloooo Day 112...that's the title of this post yeah.Look at the separation between Active and Placebo.
2. Hello Statistical Significance (SS). At Day 112 it's 0.001 !!!
This isnt in a study where Active n is like 100, it was 54 patients. The clue I talked about early in this post was about trying to guess what the separation and what we might be able to expect at Day 112 (as opposed to Day 56 for example)....the SS achieved here at Day 112 is amazing. It will be even more prolific when n goes up to 117 ! (Active at 50% of the total trial population). I don't want to even begin to think about what a measure like PGIC will be with some 233 Active patients at day 404 ! Here is a friendly reminder from way back in 2018 (And yes, I have been watching this stock since then):
3. The Errors Bars being displayed are on the conservative side. They aren't just recording separation by taking the average. In Placebo they are taking the best cases, on the Active they are taking the worst:
Those Mozz introduced red arrows above would be the approx average points showing even more separation between the two cohorts!
BONUS TIME
It's been a little while since I've done a bonus section, tonight I have not one bonus for y'all but THREE!
First bonus, let me show you another couple of charts:
.
Doesn't it all start with getting out of bed? A new day. How much better, how much more productive are we when we have had a good restful relatively pain free night of sleep? To get out of bed more easily, with less pain, with less OA stiffness...isn't that just the great start to the day that we all want? There are 630,000,000 sufferers of OA. I want some of them, as a direct consequence of iPPS, to feel like the active cohort in that above chart. I'm a long term investor for this exact reason.
Let me break for just a sec...here is a Mozz Story©. I know a person. They are a good friend. I would actually need to do a separate post on how much pain this individual has experienced and how pronounced their injuries have been. I remember a number of years ago they told me what their sleep at night regime was like. They went down to the details of how many pillows they needed to rest their sore knee on to get sleep.
Yes this individual tried iPPS.
I know a lot of new guys would not have seen the below SAS table:
Yes I originally circled the above n a HC post dated 12th March 2022, here is the link:
https://hotcopper.com.au/threads/what-do-they-want.6637828/?post_id=60159097
Yes, red circled above, that's a 64.6% drop in pain at night. It was the single best category reduction.
Oh and yes, my pal got to a point of NO PAIN! Considering they had some 11 ops....and a whole host of prior medications that failed? This was quite a result.
Now back to my post...
Interim is something to look forward, the years after that is what I am ALSO looking for, waiting for.
Take a look at this chart:
Hello green circle and green underline of delight....this is what I'm talking about. We hit these sort p values and it is -SO- Game Over... err... in a good way, we get promoted to next level!
Ok Mozz, what are the other bonuses?
Well bonus two revolves around a statement (one of many mind you) in the Ghosh paper where he states this line:
"In other studies, 2 or more intra-articular 50-mg injections of NaPPS into the joints of 14 patients with rheumatoid arthritis patients with OA were associated with a clinically significant increase in synovial fluid hyaluronan MW of 70% to 83%, probably resulting from a direct stimulatory effect on synovial fibroblasts".
Mate, did I read that correctly? He actually states that the increase of synovial fluid Molecular Weight hyaluronan of some 70 to 83% ??? Longer term readers to Mozz will know just how important the higher molecular weighted blend of HA is. There are essentially two blends, a lower molecular weighted and a higher. It is the higher weighted blend that has profound shock absorbency properties (elasto viscosity) that we need our aging synovial capsule to contain. (This granular knowledge is actually better than any bonuses that any shareholder needs, my personal views and of course not advice). There is only ONE molecule from within the body that is responsible for the natural internal production of such a blend of HA.
Those 70 to 83 percentages are off the charts. He goes on to state:
"The MW and concentration of hyaluronan in the synovial fluid of joints affected by OA are reduced, and the normalization of these parameters by NaPPS could serve to improve the rheologic and cartilage-protective effects of synovial fluid, as has been found with the intra-articular administration of exogenous high-MW hyaluronan. Cartilage hyaluronan and proteoglycans have also been found to be preserved in the joints of animal models of OA after IM administration of NaPPS".
FINAL BONUS
I got one more last one for you before I call it a night.
Guys, we saw in this Mozz post some pretty good clues about what MIGHT happen....if all goes well, the read out next year could be quite a read out....worse case, in my mind, we are simply allowed to continue onto Day 404 and we get a readout after that. The stats, the separation, the evidence to date is compelling. But listen to this, with all the data presented above....what was the dosing used by Dr Peter Ghosh and associates that gave us such prolific and distinct results?
All that great data above in this post was based off only 4 weeks of 1 x 3mg/kg (ie 3 mg/kg per week which is 12 mg total per kg for the entire initial course) ...not 6 weeks of 2x2 (ie 4 mg/kg per week which is 24 mg total per kg) which is the dosing in our P3 trial. Our P3 will have effectively a stronger for longer dosing regime!
Our results, at least in theory, should comfortably beat what we have seen tonight.
- Mozz
Speculative statements presented above. Future data not necessarily indicative of past performance. There are many factors that govern a P3. There are risks at this early point in time. Always DYOR and don't over commit in any one given investiture. I own Paradigm shares, options and CFD's. I'm quite happy about that.
MAIN REFERENCE1]
https://pmc.ncbi.nlm.nih.gov/articles/instance/3965979/pdf/main.pdfOTHER REFERENCES2] https://www.raps.org/news-and-articles/news-articles/2018/8/osteoarthritis-fda-drafts-guidance-on-developing
(20min delay)