steoarthritis just ten or so years ago was assumed to mainly centre around cartilage. It's in more recent times that the scientists have realised that it's a much more encompassing disease the embodies the
entire joint and surrounds. Tonight let's investigate one of the more telling biomarkers but not just from a science text book or paper, from a practical angle. Perhaps one for the newer investor to PAR to delve more into what this biomarker is and importantly what we have that can address it!
Do now enjoy.
BMLS - AN INTRODUCTIONOriginally Bone Marrow Legions (BMLs) had the limited definition of an increased water content within the bone marrow itself. Since then, further research has illuminated and broadened the definition:
"A study to correlate ill-defined MRI signal changes with histologic findings by Zanettti et al. suggested that several histological abnormalities were found in subchondral bone including bone marrow necrosis, abnormal trabeculae, bone marrow fibrosis and bone marrow bleeding".1BML's themselves can be classified into two broad groups, with and without cysts. Think of a cyst as a small sac like pouch that's full of liquid or pus. Within that classification, there can be BMLs that can be traumatic and non traumatic.
All nice and lovely to get a textbook definition but what about sighting one? I laugh sometimes at some of the images as you get an MRI and you have all these little red and yellow arrows supposedly pointing out the damage and I for one can't tell the difference between any of the shading! Clearly I'm not a radiologist yeah?
Not me!But I did find one comparison where you might start to get the idea of this shading. Shout out here to
@adherent as his arrows and images have been a lot easier to decipher, I might include one in an appendix below as an example as I know there are at least some new readers to PAR HC that prob haven't ever sighted any of Adherent's excellent examples!
Here is a generic difference of presence of BML's on the LHS and none on the RHS:
1.5
Yeah kinda hard to see if it weren't for the arrows AND if we weren't aware of what we are looking at, but that faint white (barely there?!) discolouration in (a) above is what we don't want, build up of excess fluid. Pic (b) depicts no BMLs present.
(Hey one more shout out, this time to Paul, what a sterling job he did in the last couple of pressos. I loved the simple explanation for OA manifesting through the joint in the Share Cafe pres. and of course how he tackled ol' Alan K with his somewhat aggressive questions).
But it is not the mere presences of a BML that can be the problem, it is more the knock on effect. Again after many years of research the boffins are learning more:
"New evidence shows that subchondral bone degeneration, including BML and angiogenesis, occurs not only at or after cartilage degeneration, but even earlier than cartilage degeneration".How strong is this correlation BML to cartilage degradation? Have a read of this one:
"At 24 months, significant correlations were seen between the loss of cartilage volume and oedema size change in the medial condyle (20.40, p = 0.0001) and the medial tibial plateau (20.23, p = 0.03), and the changes in cyst size in the medial condyle (20.29, p = 0.01). A multivariate analysis showed that the oedema size change was strongly and independently associated with medial cartilage volume loss (20.31, p = 0.0004)"2The incredibly small p values in the above statement were derived from just 86 patients. In other words there is a high degree of correlation between reducing Bone Marrow Lesions and not only cartilage Vol increase but importantly, the absolute progression of OA
It was Dr David Felson, a prior consultant to PAR and indeed one of the leaders in the OA space with more than 1000 peer reviewed papers to his name and some 148,000 citations, that stated:
"...almost 80 % of OA patients with knee pain had BMLs while only 30 % of patients with BMLs did not have knee pain".2.5Paul and Dr Ghosh knew there was a strong relationship many years ago, even before Paradigm Bio was born.
3
Excerpt from Par's original prospectus.
But even before that Ghosh was well aware of BMLs:
The patent below was originally filed in 2012.
From the above patent, Ghosh stated that based on other's research the high level sequence of events involved:
1. Failure of subchondral trabecular bone (as exists in BME lesions)
2. Following the above step, mechanical stiffening would generally occur
3. Reactivation of centers of secondary ossification (calcified cartilage) due to the disorganized repair
The above three steps could typically be the primary causation of OA...
...and because of Paul's insistance the 008 study was compiled and executed. But PAR investors also had earlier clues and that became evident in the 005 study. We'll take a look at our studies soon.
PAIN?
Yes indeed, there is a connection between presences of BMLs and Pain. This was an interesting read in a peer reviewed paper:
"Bone marrow lesions were found in 272 of 351 (77.5%) persons with painful knees compared with 15 of 50 (30%) persons with no knee pain (P < 0.001). Large lesions were present almost exclusively in persons with knee pain (35.9% vs. 2%; P < 0.001). After adjustment for severity of radiographic disease, effusion, age, and sex, lesions and large lesions remained associated with the occurrence of knee pain".6Another study also found a strong relationship :
"The mean (SD) WOMAC pain scores were significantly increased in advanced OA 59.4 (21.3) and mild OA 30.9 (20.3) compared with controls 0.5 (1.28) (p<0.0001). MOAKS showed all TKR tissue analysed had BMLs, and within these lesions, bone marrow volume was starkly reduced being replaced by dense fibrous connective tissue, new blood vessels, hyaline cartilage and fibrocartilage. Microarray comparing OA BML and normal bone found a significant difference in expression of 218 genes (p<0.05)".
7Let's now get PAR specific, let's take a quick look at our own studies.
005A Phase 2 B with a Primary of Pain and Function, it was the Secondaries that were quite illuminating apart from the headline results:
"This represents a net reduction in the iPPS group compared to the placebo group of 65.8% for BML volume and 30.8% for BML area, respectively".
8Don't forget, that above sighting wasn't after 3 years of continual use of iPPS...it wasn't even after 1 year...nope, not even 6 months, that was sighted at just
Day 53.
That's profound. To get such a structural change in such a little time is actually remarkable. As if that's not enough, the chorot wasn't a thousand patients strong, not 300...not even 100... it was only 56 patients. No wonder I'm hearing statistically of this 98% chance of achieving SS when numbers bump up to 195 !
In terms of knee compartments it's the medial compartment that takes on the most load. This is one area you want fairly good observations of your drug. What did PAR observe?
"iPPS group was more likely to have BML regression compared with the placebo group in the medial compartment (50.0% vs. 27.3%, p=0.03) ."Later that year in 2019 after the above observations, we got the amazing announcement that not only we observed structural observations but the wet biomarkers were pointing towards a reversal of symptomatic knee OA, here is just one example:
To achieve statically significant results (The above COMP measure had a p value of 0.03) were obtained not in hundreds, but just n = 56.
008Ahh the old 008 - A truly pivotal study, as we know, was extended out to 12 months half way through the study. Due to this one study we find ourselves today resubmitting the entire Phase 3 based on the data observed in that study.
Yes it is tedious
Yes we need to be patient
Yes it's been literally months since we have had an update
Yes we are waiting on the FDA
...and yes we dont know if news will strike on Monday or in another 2 weeks or even a month from now *sigh*...
Imminent should mean days away...but it's the FDA yeah?
I'm totally...well...IMPRESSED, due to the wonderful and oh-so-consistent data obtained from 005 and 008 studies that has directly resulted in our n dropping by a full 17%.
I know there are at least a few readers wondering what that means. Usually a Phase 1 is conducted with 10 or so patients.A phase 2 is usually hundreds and a Phase 3 is often in the thousands. The original trial for Aspirin had some 20,000 patients:
Chen Z-M. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet Lond Engl. 1997;349:1641–169.
We were at 500 odd. We now are at just 390. It's LESS not more! How? Because we already achieved SS in just 15. Just 15 patients and the drug effect size was notable.
Ok let's have a quick look at some BML data.
Of course, it's time...time for what? You and I both know what it is time for.....a Mozz Quiz ®:
SPEAKING OF BMLS, IN THE 008 STUDY, WHAT DID PLACEBO DO AND WHAT DID OUR 2X2 DOSING ACHIEVE IN THE LATERAL FEMUR COMPARTMENT?A) Placebo had a reduction of 3% and Active reduced by 5%
B) Placebo reduced by 5% and Active reduced by 7%
C) Placebo all walked out and gave up, active reduced BML's by 11%?
D) Placebo reduced by 2% and Active stabilised?
Hmmmmmm...I wonder how many picked C)....so what's the answer?
Mate, the answer....
Let me just give you active first.... it REDUCED by a nuttty-good
38% on average.
Helllo, that's not 38% over two years.
It's 56 days, man!
How strong is our drug, to afford structural, morphological results in two months? Sorry, but that means a lot to me.
Ok ok all good Mozz, calm ya farm. What did Placebo reduce the BMLS by then?
It didn't.
Huh?
It
didn't reduce the BMLS...
...it went the other way...
Really?
It WORSENED BY a massive
47%In theory, one would expect 008 data compared to 005 to not be as prolific, to not be as stunning. Why? Because n in 008 was like 27% less of n in 005, ie barely over a quarter of the n!
Here were the results in terms of BMLS:
Say what you like but it is because of PAR staff that have worked so hard to even think of such studies to encapsulate such readings.This data has never ever been seen before. The way iPPS works and the results it is producing is indeed outstanding.
WHY DOES THIS MATTER?Well because it is all related and all contributing to OA.
The medial compartment is load bearing.
There is a nexus between BML and Cartilage disintegration over time.
Cartilage has no nerves but underneath it, at the subchondral bone, the bones have nerves all through them.
Have a read of this conclusion:
"Conclusion: These data demonstrate that bone lesions are prevalent in knee OA. The correlation of the oedema and cyst size increase in the medial compartment over time with a greater loss of cartilage volume in this area underlines the importance of subchondral bone lesions in OA pathophysiology".
7It matters a lot because we aren't just addressing pain and function. We aren't just addressing symptomatic phenotypes, we are addressing the underlying causation of the disease. We are assisting to regain a balance where the body wrests control over chronic inflammatory processes. The data is based on very small subsets but it still achieves SS. Take a look at one of the highest achieving measures across both 005 and 008 in the Appendix A below.
Like two halves of one of the Fabergé eggs....iPPS isn't that far removed from this concept...Like two parts of a precious egg....
...we are addressing not only BML's but we are tackling
both the symptomatic and structural ramifications of this disease..
It matters as we are about to hear back from the authorities. We get the Green light funding and/or a deal will be hot on our radars...then it will be all systems go for the final stage of our clinical program. Once the P3 starts in earnest, and we know how consistent the data is at the 2 x 2 dosing profile, this baby is simply...
...going to fly.
My views
Best to DYOR
APPENDIX AThe single best (p value) published measure, was PGIC - Patient Global Impression of Change
005:
008:
Considering the p values were fairly similar, don't forget the n in both studies, 005 was 56 but 008 was only 15.
Incredible results. One of you please remind me when Phase 3 readout occurs, I want to know what the PGIC p value will be when n is some 195 odd!
Incredible.
APPENDIX BPost by Adherent.
Posted 9/8/2023
Link to original post:
https://hotcopper.com.au/threads/resolution-of-lumbar-bone-marrow-oedema.6739626/page-65?post_id=69257591------------------------
So I wanted to show another feature of my imaging that I haven't talked about before. I have (or perhapshad, see below) facet joint osteoarthritis. The facet joints are where the spiny parts of the vertebrae rest on each other. The facets have a layer of cartilage, which in my case of severe, stage 4, OA of the L4/L5 and L3/L4 facet joints, especially on my right side, had worn away. No cartilage.Here's a picture pointing out the relevant facet joints so you can see what I'm talking about:
Now take a look at the images for L4/L5. Remember dark is more dense tissue like bone, light is less dense like water, nerves or cartilage:
Look at the right facet joint, before treatment, indicated by the arrow. There is no cartilage here. It's basically bone on bone. It's a very degenerated joint. But, after treatment, and continuing to today, there is dramatic restoration to a much healthier joint structure, indicated by the bright line. This is joint space widening, which I believe is a structural marker PAR will use to show DMOAD.The question is, what is filling the space in the joint? It can't be just fluid, these are load bearing joints and fluid alone won't hold them apart. It has to be some form of hydrogel, like a crosslinked hyaluronic acid, or polyglycoside. Or, dare I say it, cartilage? I never hoped for that but its consistent with the imaging.----------------
REFERENCES1]
https://www.researchgate.net/publication/24270509_MRI-detected_subchondral_bone_marrow_signal_alterations_of_the_knee_joint_terminology_imaging_appearance_relevance_and_radiological_differential_diagnosis1.5]
https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/1471-2474-12-1982]
https://pubmed.ncbi.nlm.nih.gov/17728333/2.5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996250/#:~:text=It%20was%20reported%20that%20almost,et%20al.%2C%202001
3]
https://announcements.asx.com.au/asxpdf/20150818/pdf/430lk4gt2h6c26.pdf4]
https://patents.justia.com/patent/201400246145]
https://pubmed.ncbi.nlm.nih.gov/11281736/6]
https://pubmed.ncbi.nlm.nih.gov/17728333/7]
https://pubmed.ncbi.nlm.nih.gov/28705915/8]
https://app.sharelinktechnologies.com/announcement/asx/9fe3dc76fd51b4a6345f9b4542e23c829]
https://app.sharelinktechnologies.com/announcement/asx/9fe3dc76fd51b4a6345f9b4542e23c8210]
https://app.sharelinktechnologies.com/announcement/asx/1801a407c6bff2b2200d2ab1a15c725911]
https://app.sharelinktechnologies.com/announcement/asx/63a249bdb0b4e5e1dc93c8ee2644f3a2POST SCRIPTNot sure how many of you read right down to the bottom.
It's like those Marvel films, rewarding the audience for staying right till the very end after all the credits for a little taste of what's to come as an easter egg..
This Mozz post nearly didn't happen tonight...I usually make a back-up...I did so this time...but while copying over the references, both my original (Primary) AND my Backup went into the circle of death and froze...(that's never happened before). Every 5 mins I got the HC message WAIT or EXIT message... you select Exit and you lose
everything.
I felt like Sir Isaac Newton...he had a dog called Diamond and late one night the dog accidently bumped the table while Isaac was out of the room...the candle on the table got knocked over and
twenty full years of Sir Isaac Newton's work went up in flames. Gone! There was no
Google History backup for him!
Isaac came rushing back and instead of turning the dog into pure mince meat, he simply patted him on his innocent head and said words to the effect "Diamond, if only you knew what you had done" ...
Ref: https://commons.wikimedia.org/wiki/File:Isaac_Newton_laboratory_fire.jpgThat's patience. How many of us have that much patience??
That's kinda like the patience we too need not only when 4 hours of HC post goes up in flames but it's taking longer than 3 plus full months for the FDA (and TGA) to get back to us! I'm sure the stats will say that out of every 10 HC Par readers that read this, only 3 or so will actually be convinced that greatness is still possible after waiting for so long...
Luckily I found a way to recover this post and so I could post this one out tonight....the alternative would've taken me all day tomorrow if I could be stuffed reconstructing it.
Not for a second comparing me to anyone great, but my point is that sometimes we just gotta be terribly patient. (The best person I can think of is Warren B.).
Not easy when things take so much longer than they should.
My heart sinks when I lose 4 hours of work, but does that compare to a number of months?
Tell me, does that remotely compare to 20 years? I know this isn't for everyone. But if I look to the future, I like what I see. I just need the fortitude to have more than just a handful of shares to enjoy this ride IF it all works out.
If you can wait a year or three...I suspect we have a higher chance of success with this one, it's only my personal view.
I could be wrong and you really ought not to rely on just one poster. Do your own research and work out for your very own self if this is a stock for you, if you believe the chances of success are greater than the chance of failure and if it's genuinely for you, if it makes more sense to put ya hard earned cash into some other stock?
I scourer a lot of plays in Aus and USA. I just can't find anything else that's at all terribly close.
Not advice
(20min delay)