PART 2 - PAR and the BML findingsIn Part 1 we went through a definition of BMLs, we saw some examples of what they look like and we concluded with NF-kB. We know that iPPS addresses this not only indirectly, but directly as well. We have seen this graphic a few times but look at those MOA's...they are so broad, this excites me a lot...its certainly not single targeting here, the ramifications are vast and so too are the future indications.
To do justice to BML's and the pathologies, it again would be post after post, I really am only giving you a high level view and showing you the relevance to us from my point of view. As a small sample, there could easily be separate Mozz posts on:
Tendinitis
Reflex sympathetic dystrophy
Postsurgical change
Radiation osteitis
Avascular necrosis
Subchondral insufficiency fracture
Transient osteoporosis BIOMARKER CONSORTIUMThe FNIH Biomarker Consortium is charged with the responsibility of coming up with biomarkers both wet and dry (wet being biochemical, dry being MRI observable structural type markers as an example)...The PROGRESS OA project takes a number of clinical trials in progress and attempts to link the observables to assist the consortium project, headed up by Dr Virginia Kraus and Dr David Hunter.
JSN in itself, according to the consortium wouldn't be feasible to follow, the duration is too long, the expense would be too great and finally what sponsor would support this expense?
7The consortium themselves agrees that BMLs are just one observable that will depict a most valuable prognostic observance of OA but there are many and I suspect PAR are heavily involved in collating data not just in our wonderful current 008 study, but will be obtaining these data from 002 and potentially a revised 003?
Some examples that have an immense scope for us as suggested by the consortium include:
- Articular cartilage integrity
- Marginal and central osteophytes
- Subarticular bone marrow abnormality
- Subarticular cysts
- Subarticular bone attrition
- Synovitis/effusion
- Medial and lateral meniscal integrity
- Anterior and posterior cruciate ligament integrity
- Medial and lateral collateral ligament integrity
- Intra-articular loose bodies
- Periarticular cysts/bursitis
THE MARKERA very important point here is that BMLs are not just an unwanted symptom...it can be used as a bio marker. Its here that there are strong implications for our future.
"It can also be a marker of disease progression or act as a marker for disease activity in certain conditions ... such as inflammatory arthropathy and osteoarthritis".7Or how about this quote:
"More recently Bone Marrow Lesions (BMLs) have been identified as a useful clinical phenomenon that may inform disease management " ..."BMLs have been associated with histological evidence of microscopic bone microdamage and are related to malalignment, pain and disease progression". 8Fellow holders, its the prognostic nature of the BMLS that excite me, here is another quote:
"Interestingly BML often appear before established joint degeneration occurs, and thus are possible candidates for the long-sought indicator OA that can be detected before irreversible cartilage degeneration".8Why indeed does this excite me? Because the addressing of BMLs might indeed be a prognostic surrogate. This is finally what the authorities want. This is what is required in the all important, the all exciting, Accelerated Application prospect for PAR.
If we know that BMLs can be a marker and can act as a legitimate surrogate, this saves us time ...this saves us a 5 year longitudinal study. Well we may still need to do the study but in the interim, we may indeed get a provisional licensing to literally begin work on saving thousands upon thousand of patients having to undergo potentially unnecessary surgery or at the very least tackle symptomatic conditions in the interim before the inevitable. I personally suggest there would be many cases where surgery will be avoided if broached early enough?
"There is already evidence that BMLs are strongly related to OA; their presence increases the risk of cartilage loss, likelihood of OA progression, and of development of knee pain".8Read the conclusion:
"In summary, clinical studies suggest that BMLs represent some form of mechanical damage in subchondral bone, and are related to joint degeneration. BMLs may also be a source of pain, and they appear to respond to mechanical (bracing) and biological (bisphosphonate) interventions. Thus targeting BMLs with novel treatments is a promising future strategy for OA".Indeed BMLs are certainly linked with progression of OA and manifest in a wider facet of abnormalities:
"Using MRI, Roemer et al. 35 previously demonstrated that progression of disease and the development of BML correlated with an increased risk of cartilage loss within the same subregion and that regions without BML were associated with a decreased risk of cartilage loss. Carrino et al. also reported that 87% of subchondral cysts were associated with BML abnormalities on MRI". 9There is further evidence from another research group that came to the following conclusion.
10:
"The prevalence and severity of BMLs are associated with less tibial cartilage volume and greater cartilage loss over 2 years. Moreover, severity of BMLs was positively associated with risk of knee joint replacement over 4 years. This provides further support for the importance of BMLs in identifying those with OA most likely to progress. Identifying factors that prevent or reduce the severity of BMLs may provide an important target in the prevention of disease progression and treatment of OA, and the subsequent need for arthroplasty".I will finish this section with one more paper, this one by one of the world's leading OA researchers, none other than the Good Dr David T Felson:
"Bone marrow edema is a potent risk factor for structural deterioration in knee osteoarthritis...". 11There is good evidence that addressing BML's will go a long way to addressing OA in general, it opens and it sets the scene for iPPS's performance quite nicely.
BMLs AND PAINWe are starting to get a better impression of just how encompassing this OA disease can be. One of the main areas is pain. Its this primary symptomatic phenotype that is one of our primary endpoints. Yes DMOAD has large potential, but finally, a given patient will always first address their upfront pain before they even think about anything further down the, well, track.
A show stopper - get a drug that addresses pain safely and we will go a long way along the success path.According to one research group:
"There has been growing evidence of BML correlating with recurrent pain and pain severity in several studies, particularly in large-joint OA"...."A significant correlation was seen between the presence of larger BML in painful knees as opposed to non-painful knees".9Another paper found:
"People with knee OA who have BMLs are 2–5 times more likely to have knee pain than those without...".12BML AND CARTLIAGE LOSSAs I stated below, we are getting a better sense of the interconnectivity, cartilage loss has definite associations with BMLs:
"There is a strong association between BMLs and structural progression in the same compartment42, and 81% of knees with medial compartment progression have colocalised BMLs".
12As one domino falls, the next begins...
"Increasing medial BML size is associated with progressive adjacent cartilage loss, and medial compartment BMLs are strongly predictive of total knee replacement".
12Our data from 008 has just come out and it was telling, but what will be the future findings, I'm talking 008 12 month, I'm talking meaningful discussions with FDA and EMA and other authorities, I'm then talking about the findings from 002 and any future studies, we are really, really only just beginning our more exciting journey...
"Prediction of joint space narrowing by baseline BMLs might be at least partly explained by associations with baseline cartilage damage43. OA pain is also associated with synovitis31,46, and synovitis is associated with more severe cartilage pathology".
12I really do envisage a Big Pharma one day dedicating a whole stack of resources to our joint venture...or at least PAR will have such crazy large funding pools for the furthering of multiple indications via multiple studies....
Yeah one day it will be more than just a couple of staff in the Reg and the Clinical teams...it will be much larger numbers!CLINCIAL UTILITY?The interesting thing I'm picking up via researching Pentosan is that it has a number of different mechanisms of action. In fact we are witnessing many different benefits all at the same time. Sure we are only concentrating on Pain, Function and searching for a DMOAD effect which looks clearer as we progress, but there are a lot of other pharmacological benefits, specially when you start zooming out a touch and realise that the common overlap with a lot of these indications is PAIN...and INFLAMMATION.
How vast are some of these future markets for us? Do we really stop and think about this?I really can't impress upon you enough just how vast these spaces are. Yes of course we have to approach this one hurdle at a time, one milestone at a time..and it seems to be a very slow moving vehicle for many...we seem to really take one step forward and a couple backwards...but when you think about it, we really are progressing, there are only so many forward steps we need before some really big hitters will start having that FOMO...When that sets in, it will be too late for a lot to even think about coming back...
My views of course.
I like this next quote...it summarises how I feel when I read the various templates set up by researchers or the FDA themselves, no one really is contemplating a drug on the market that can do it all in OA...AND do it safely in the OA space.
12
Not all treatments that reduce BMLs have been found to reduce pain, and treatments that can reduce pain associated with BMLs, such as exercise, analgesics and weight loss, might do so without reducing BMLs. The Golden Chalice would achieve both.
Pentosan, in the injectable Sub Q format really is showing us all an early glimpse that it can do
both in a good number, a good percentage of the lucky few that have tried it so far.
ENTER THE MAGICAll very good Mozz...how long must I wait for us to see how iPPS performs on your said, Bone Marrow Edema Legions??
Please Hot Copper PAR folk...tell me how long I must wait for good BML data?Well, we have the data ALREADY!
No kidding. I think most of you will remember it...but I know there are a few that have missed it....
Let's look at this graphically first, then we can go through the numbers to remind the few that have forgotten!
Ok So IPPS BMLs fell by a decent 17%, that was just after a mere 6 months...one initial course...Structural changes after such a short period of time is fairly unheard of, and to see this with supreme safety profile (
NEVER been seen before)...anyway, what did Placebo fall by??
(We can't do a Second Mozz Quiz, PB would have a fit....forget about Ham sandwiches, he'd throw me out of the club for good).Here is a hint for you new guys to us.....
...errr....ummm...Placebo
didn't fall....
........it went
up...a few percentage points? Perhaps 2%? Maybe 6%?
Take a look:
This Mozz chart single handily was the reason I added last week. Not advice, you must do your own research and work out if this makes sense to you. BML progressed in the placebo cohort DESPITE the placebo effect...yes placebo can affect structural objective observations.
Yes the same chalk and cheese difference between the active and placebo in the lateral femur, a decrease of 38% in active -v- INCREASE of 47% in Placebo...
This was profound.
BML's indeed are a potentially amazing bio marker for the progression of OA. We are, again in just my opinions, lucky to be getting such incredible early hints...
-Mozz
Remember to DYOR
REFERENCES1]
https://www.ncbi.nlm.nih.gov/books/NBK559176/2]
https://onlinelibrary.wiley.com/doi/full/10.1002/jor.238443] https://my.clevelandclinic.org/health/diseases/24622-bone-marrow-edema#:~:text=What%20is%20bone%20marrow%20edema,edema%20is%20bone%20marrow%20lesions.
4] https://my.clevelandclinic.org/health/articles/21199-lymphatic-system#:~:text=They%20include%20protecting%20your%20body,fats%20and%20removing%20cellular%20waste.
5]
https://pubs.rsna.org/doi/full/10.1148/rg.20201901736] https://pubs.rsna.org/doi/full/10.1148/rg.2020190173)
7]
https://link.springer.com/article/10.1007/s00256-023-04284-w8]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607515/9] https://www.emjreviews.com/rheumatology/article/drilling-down-to-the-bone-evaluating-bone-marrow-lesions-in-osteoarthritis/
10] https://academic.oup.com/rheumatology/article/49/12/2413/1790955
11] https://pubmed.ncbi.nlm.nih.gov/12965941/
12] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255125
13] https://www.sciencedirect.com/science/article/pii/S1063458422008597#:~:text=BMLs%20might%20contribute%20directly%20to,OA%20pathology%20in%20different%20compartments.
14]
https://app.sharelinktechnologies.com/announcement/asx/63a249bdb0b4e5e1dc93c8ee2644f3a2
(20min delay)