ot what you are thinking...
Nope, tonight it's not about the Man....it's about about PR ---->
Peer
Review!
Well it's always going to be at least
partially about the Man, I wouldn't be writing this if
he hadn't gone ahead and pursued this wonderful molecule, formed a company, funded it and forged incredible liaisons and stuck with it over the years. Was he tempted to sell out at a peak of $4.48 or whatever it was? I doubt it...he knows the real value of this co. I reckon there are only a few of us that actually do as well. (Darn it side note, can't resist...even today, not 4 hours ago from finally posting this post...there are many at Lovisa Chadstone, Victoria tonight...the stock went from $2 IPO to $32..in ten years. Remember, PAR IPO'ed 9 years ago...we address PAIN...not BEAUTY.
Well actually we do address beauty too...it will result in less wrinkles/bags under eyes and wound repair...that's beauty..
Ten years, $2 to $32...what will PAR be in another few years?INTROI have read a few Peer Reviews in my time, this is one of the handful that were next level. The best thing about this one? It's ours!
Often Times I read a great paper and I truly feel like instead of paraphrasing it, mate I should just include the lot. But that would put some of you to sleep and then I make myself redundant...we can't have that. Tonight I document our MPS I peer review...it's freshly out. 11
th March 2024.
MPS I Peer Review - out now!Yes I understand that the MPS program is now on the back burner and most likely PAR will pursue it through a viable partner or later when we are cashed up sometime in the future...Yes I also understand that it's now all about OA and the funding to get us through the major market of OA (and PAIN!).
However, you will see later in this post there is a fair bit of overlap between what came out of the MPS program and our chances of success in the OA realm.
Please enjoy this one tonight it's a bit of a stunner and of course, like usual I won't just parrot feed you, I'll point out
why I'm excited about it and the relevance to us going forward.
BRIEF OVERVIEWMPS I is a nasty disease...I mean they are all nasty, diabetes, heart disease...cancer....but MPS and the strains are really bad symptoms...any relief a drug can provide here is going to be a bit special.
Now MPS is on the back burner, but do plough through this Mozz post cos there are a number of little snippets,
, easter eggs as some of you will know them by, that will add a decent amount of colour to what you and I actually own.
Don't for a second think we have given up totally on the MPS program....the takeaway here is two fold...
We still have a very viable program that will get developed one day and will give a lot of relief to many a suffering patient.
There is cross over, overlap between MPS and OA...read on for more!
THE OPENERIt's a special job, task and place, for the opener bowler in cricket terms...breaking the ice...they have a number of various options at hand...to mix it up to the opening batter. No batter wants to go out quickly at the start of a game, in the very first over! The bowler has a good chance to be able to strike some fear...
Opening first ball...
In the same way, its right at the opening, the introductory paragraph, that we get some gems from this remarkable peer review.
"The GAG reduction, anti-inflammatory, analgesic, and tissue remodelling properties of pentosan polysulfate sodium(PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT".That's quite an opening over..it's going to be quite a match...
ANALGESICWe often forget that this is primarily (and I use that word deliberately due to our Primary endpoint) a story about Pain. For there are no real safe painkillers, specially if you are talking about using one for the longer term, for a frequent usage profile. They have side effects...in the end they may prevent a decent amount of pain but it will come at a cost.
TISSUE REMODELLING Anything that can remodel the tissues automatically makes it a candidate for a prize winning cup! How many drugs do YOU know that can actually SAFELY remodel tissues?
No no, not this kinda tissue (re) modeling...put that tissue away...I'm talking groups of biological cells, NOT Kleenex!The arresting of joint Inflammation is another big one for us...again, there is nothing on the market that can do this.
As if the above statement wasn't enough...check out this next statement:
"Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type 1 (CTX-1) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks".Ok I know there are a few of you reading this that are about to turn it in for the night and are yawning profusely.
DO not yawn.
DO not turn it in.
Wake up and smell the
dollars flowers....
One of the world's experts, Dr V Kraus is jointly charged with Dr D Hunter by the FDA to find out what indeed is the single best or group of biomarkers going forward that will ear-mark the course of OA itself.
So far they have found, *clears throat* the single best individual biomarker out there from a prognostic of view is
CTX-II.
What does this mean?
It means if you measure your baseline CTX-II and if you find that it is increasing, you have OA....conversely, you not only halt BUT you manage to decrease it.....you are literally
reversing the course of the disease.
The above statement eludes to this. Hold that thought for a bit, we'll revisit it soon.
THE CURRENT STD OF CAREWithin MPS the current std of care includes treatments such as Enzyme Replacement Therapy ( ERTS) as well as Hematopoietic Stem Cell Transplantation (HSCT), but the good effect of these treatments wear out in time and "...neither treatment alleviates the progressive arthropathy and pain experienced by people with MPS I ".
In addition, none of these two therapies reverse the course of the disease.
PROPERTIES OF IPPS?As mentioned in the paper:
- Fibrinolytic
- Lipolytic
- Anticoagulant
- Anti-inflammatory effects
- Blocking effects of TNF
- Blocking effects of the proinflammatory IL-1
- Reduction of Pain
- Reduction of GAG accumulation
- Inhibition of NF-kB (this in turn reduces inflammation mediated by GAG build up.
- Increase inflammation and this plays a role in cartilage destruction.
Now do you guys get the overlap between MPS and OA?This article (See Ref 1 below) points to some pretty awesome observations...in MPS...but there is overlap...a lot of overlap between MPS and OA.
Let's take a look at the results:
2MWTThe results of the 2 Minute Walk Test showed improved function from baseline to Week 49 representing an 8.2% - 105.1% improvement and a 11.6% - 71% improvement from baseline at Week 73.
Subject 2 had the greatest improvement here at Week 73, it was a whopping 58.1% better! Paradigmers, what you must realise is that these guys aren't babies. I mean it's later on in life that they are trying out Pentosan. I have a distinct suspicion based on my research that if they tried it from early onset...the results would be even MORE genuinely prolific.
9HPTRemember, tests such as the 9 Hole Peg Test aim to show that the drug these patients have taken make a material difference compared to them not taking it...
Subjects 1, 2 and 4 showed between an 8 and a 26% improvement to Week 49. On the non dominant hand function, Subjects 1-3 showed between a 9.1 to 33% improvement.
Again, I know a few of you get bored with numbers and stats...let's just see how all this looks on a chart yeah?
In case you are wondering, Subject 4 actually got Covid through the trial, hence the result.
GSGC Gait Stairs Gower Chair.
In this test iPPS resulted in improved functional performance in all 4 subjects representing between 22.2% and 36.4% improvement:
Significance?
p = 0.007
Remember...we are literally witnessing again the benefits of the drug...yes it is MPS, but yes also that there is overlap in terms of musculoskeletal pathologies, reduction of pain and thus improvement in functioning.
PROMISIn terms of Pain Interference and Fatigue there was a significant decrease (improvement) from baseline at Week 49 among all subjects at Week 49 (p=0.001) and 73 weeks (p < 0.001).
PGICPatient Global Impression Of Change
GAGSAt Week 73, Subject 3 experienced a 68.4% decrease in MPS I GAG fragment. At Week 73 the decrease in 3 subjects was significant at p = 0.04.
BIOMARKERSRightio..let's get stuck into it...so remember the biomarker CTX II, its one of the single most prognostic biomarkers for OA.
How did this one perform?
"Cartilage degradation biomarker serum CTX-I decreased in all subjects at week 49". Sure, but, was the decrease a relatively strong percentage?
10%, maybe a 15% decrease?
Nope...it was 34.2 to 45.8% decrease!
Man, that was CTX-1, but what about CTX-II, CTX-II was an even stronger result!
I give you a 48.2% and 49.6% in two respective subjects. In the third subject the decrease was 43.1%.
I nearly fell over when I saw the next statement...
"
Urine CTX-II decreased in all subjects at Week 49 as shown in Figure 7C, representing a 56.1 - 92.4% decrease from baseline".Huh?
What did they achieve? Up til now I knew a result of a circa 20% drop in CTX II was outstanding...outstanding for two distinct Mozz
© reasons
1) Because Placebo's reading wasn't as good....well...not only did it NOT go down...it went up! Yes the Placebo cohort continued to suffer degradation of cartilage (that's what CTX II measures).
Ok here is a reminder:
The above is nutty...nutty because Active was the total reverse of Placebo...but nutty cos look at the
n. It's not in thousands...its not in hundreds, Crickey it's like 56 in 005 and 15 in 008. Fifteen. Hello, is anyone reading this?
15 and we got Statistical Significance??
Now you are telling me, some bloke in MPS got a reduction of CTX-II by
92.4% ??? And you are asking me if FDA will approve us?
(Spec statement, there are risks here, the FDA's ultimate decision is not guaranteed).
Seriously, no one on the entire planet has emailed, called, texted, LinkedIN or Reddit'ed saying:
"Hey Mozz, you know that you get excited by a MERE drop of 25% CTX II levels, that's nothing in front of a patient in MPS I Adelaide trial that got a drop of circa 94% yeah?"
*Mozz feints*
(Side note: you know who in Oarsi I'm going to show that figure to right?). I'm supposing SHE will have already seen it but I'm hoping she's forgotten and I'm feebly attempting to impress the world leader on OA for the second year running). (I impressed her with Adherents' MRI's last year for those that are reading this and don't know). ( I should update her on Adherent's supreme progress...a real pioneer in terms of back disc efficacies...what a great result, he is NO LONGER IN PAIN).
While on the topic of Adherent..here is a tiny quote from him that's worth repeating in light of the cartilage volume increases we saw on 008:
".. expansion of cartilage".
That's what he experiences.
New to IPPS? Curious, left click on this link:
ADHERENT2) They did this safely. That's not a throw away statement....there are
NO drugs that can reduce CTX II, one of the single most prognostic biomarkers of OA, SAFELY. None.
Let's now see those biomarkers graphically...these are quite the charts!
All CTX related data looks incredible, this is a very exciting release of data.
At the end of the day there are going to be a few of you who get lost in the science....all I want to say to you is that when I look at the above graphs, they are trending down consistently AND noticeably...this is an amazing observation and one that will have some definite ramifications in the future...hopefully the near future!!!
Tell you what, I'm kinda looking forward to out 008 peer review once its out, I think officially it will be out by the end of the year, hopefully sooner,but I quietly suspect the FDA will get a first look through the data when PAR submit it hopefully soon.
I'll tell you another thing, as your informal Retail Rep, I'm going to go into OARSI this time heavily armed with such data as above. My simple goal is to spread the good news, get feedback from these expert scientists and researchers to confirm what I'm seeing is real. Ie get them to scientifically PINCH ME!
MOAAs I said, this peer review was one heck of a read....the data and the results presented had my brain lighting up...
Mozz brain lighting up...ok ok so it's a little zoomed in then...(ie not to scale)Me brain lit up not just because of the absolute value of the data. but because how my brain extrapolates to what the equivalent 008 peer review is going to read...I have a post that's going to refer to this ...I'll try and get it done by next weekend.
The next statement that caught my eye in this amazing peer review was the following statement which gives you a sense of the amazing chain reaction pentosan plays....
"PPS also directly binds to NF-kB in the cytoplasm inhibiting its activation and therefore translocation into the nucleus. The inhibition of nuclear translocation of NF-kB results in the reduction of gene expression of pro-inflammatory mediators including inflammatory cytokines, IL-1B and TNF-A, which has the potential to reduce the joint inflammation and pain associated with MPS I".But they go on...
"As well, PPS results in reduced expression of the pain mediator nerve growth factor (NGF) in osteocytes from degenerating joints, which is thought to suppress the release of NGF in subchondral bone and potentially reduce joint pain"....and one more MOA statement....
"Finally, PPS also inhibits cartilage-degrading enzymes that are related to the joint dysfunction observed in MPS".Guys, its like I have been listening to everything in MONO for my whole life and all of a sudden someone introduced the concept of STEREO....I'm blown away.
Going from Mono to Stereo?What I mean by that is that I, on one side of the large wall, hear and see the
theory...this cytokine goes down...this TIMPS goes up....This space increases by micrometres, and this BMEL reduces in size grade and profile. Morphology this, Cartilage Matrix regenuviation that.
BUT....but my dear readers, on the OTHER side of the wall I get crazy amazing stories of patients that were in pain and could hardly walk...that after iPPS they are NO LONGER IN PAIN and can walk better....these poor patients are sleeping at night for the first time for not a week...but for YEARS!
Paul R. once said to me (well ok it wasn't on a one to one basis, he said it to the room)...these dogs that are having PPS are now acting like puppies, they are bouncing up and down, they have more energy, they are like NEW DOGS.
Mate...I need a drink, I have to pause....I'll. be right back
I used to watch Dave Allen as a kid, I didn't get all the jokes back then...but I watched a highlight the other day at a mate's place in Sydney, was a blast. There must always be a little humour in our lives...The science is heavy as it is!Ok I'm back...
no there won't be more typos in this paragraph compared to the previous ones...As I've said a few times before, we can see the benefits iPPS has with MPS and how it will and has, translated into OA. In fact it is the off-labelling scenarios that often makes me stop think just how big this opportunity will be one day. We need to build some of this into our models. What models they may turn out to be.
One last fact about CTX-II before we tackle another topic...
"CTX-II levels in urine, serum, or synovial fluid are increased in KOA patients with higher radiographic KL grades".2GO BEYONDA future frontier somewhat after we cross over and are accepted for OA...has to be the realm of CNS and neurocognitive observations as a result of iPPS.
I've posted a couple of posts on this in the past, perhaps the most remarkable one was of the canine MPS study that Dr Simonaro headed up, I will post it at the bottom of this post for those that haven't come across it...the video is quite a watch! (See very end of next post in Appendix B, if you are a BIG LT fan of iPPS, it's a must watch!)
The Peer review suggests that some of the observed biomarkers "...may also play a role in CNS involvement". CNS is short for Central Nervous System. With the UA-HNAc levels (A GAG fragment) decreasing significantly, this attests to the fact that further research here needs to be done, it has been associated with better cognitive outcomes and reduced GAG nonreducing ends in the cerebrospinal fluid "positively correlated with neurocognitive improvements".
As I said, see the next post!
CONCLUSIONThe peer review itself summaries it very well,
"This study confirms that PPS reduces urinary GAG excretion, relieves pain, and improves some measures of joint range motion. It also provides some new information on the effects of PPS over the longer term (72 weeks vs. 24 weeks) on function and quality of life and examines it's effects on biomarkers of inflammation, pain, and cartilage degeneration in patients with MPS I".They also went on to conclude that:
"In a survey of MPS patients, 69% reported pain, with 40% having pain scores high enough to be considered significant pain. Pain has an important impact on quality of life and has been associated with depression and other psychological issues in patients with MPS"."Decreases in pain were reported by all four subjects in this study".In case any of you at all are wondering why I included that last quote, to make it obvious, n =4. They
ALL got pain relief.
This is why I'm a holder, for the long term. (Usual caveats here, just because I reckon we are a good bet, doesn't mean you should back it)
What I'm also saying is just wait for the OA Peer review. Yes we have been waiting for a while...but I believe it wont just contain Pain and Function observables that we predominantly saw in 005 (Phase 2B)...it will include a good dollop of 008. If you guys think the above MPS write up wasn't half bad...you really aint seen nothing yet in my view as well as Paul's....
The MPS I Peer Review was a hell of a read...but it's 008 peer review that will really just blow the roof off the FDA house !!
My views and of course, DYOR
REFERENCES1]
https://onlinelibrary.wiley.com/doi/full/10.1002/jimd.127152] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10288416/
(20min delay)
