In Part 1 we saw some pretty super evidence of Pentosan working in MPS rats...In Part 2 we build on this and watch out for a bonus...it may actually make a lot of you sit up and wonder...
BANG
Let's start off Part 2 with a BANG.
I have often said that the application of Pentosan early in the piece will have merits. I've read it in a number of papers...I don't need to really go into the science too heavily, just look at the Researcher's next topic headline:
"Skull and Dentition Changes in the PPS-treated MPS VI Rats"
Yeah kinda nutty, after MicroCT and Radiographic analysis was performed the researchers found that there were:
"...significantly longer skulls and snouts in the PPS-treated MPS VI rats compared to the untreated MPS VI littermates".
Their words not mine.
PAR guys, maybe I shouldn't be too amazed cos didn't we see this cartilage analysis in our very own 008? While that's true, I'm still jaw smacked. Yeah its prob me...yeah a few of you will tell me Mozz.....we want our SP to go higher. Do you think I don't know that. It will come...there are real tangible efforts being made behind the scenes that will steady the ship and material progress will be made. I can't say when a deal will be done...I can say that as each and every month apsses...well our chances of a deal not only go up....they get richer. I mean a more commiserate deal that's well worth of what our drug can do....read on.
Let's see those skull and snout lengths as a chart:
KEY:
All three treated groups of rats achieved statistical significance at 9 months.
DENTAL WORK
"Dentition abnormalities are a common finding in MPS patients".
The researchers investigated dental properties of the rats. Again, take a read of the observations:
"In the PPS-treated animals a greater degree of alignment was seen between the mandibular and maxillary molars, correcting the malocclusion".
"The tooth mineral densities also were significantly improved".
Take a look at that one statement above, diagrammatically....
Another table that was a standout is the following. The way to read this is that you want the values to approach 100, or be as close to 100 as possible:
That there above is what I call a decent score card...what other drug can do this? Helllooo MPS partners....
It's like I feel I need three skills here... 1) Discovery (Research) 2) Do whatever I can to help my company 3) Hold......and wait....and be patient.
BONES
In terms of bone pathologies:
"As in the femurs, trabecular abnormalities were observed in the untreated MPS VI vertebrae in all of the parameters, most notably in the spacing (Spa; ∼152% of normal), tissue mineral density (TMD; ∼67% of normal), and bone volume density (BV/TV; ∼71% of normal). Within the responder group positive changes were observed in the vertebrae in most parameters, most notably in the bone volume and tissue mineral density. Trabecular thickness also was normalized, and changes were evident in the trabecular spacing. There also was an increase in the vertebrae heights".
Remember, I love seeing that word normalized...
Positive observations were also noted in the spine:
"In all PPS treated groups there was a modest decrease in the NZ length and increase in the NZ apparent modulus relative to MPS VI, and the effects of PPS generally increased with duration of treatment. Failure load and stiffness of the untreated MPS VI vertebrae also were significantly lower than those of normal vertebra, and these were slightly improved following treatment".
...along with...
"Reduced intervertebral disc height in PPS treated animals is further supportive of improved collagen integrity".
...and further:
"Several serum inflammatory markers are highly elevated in MPS VI rats and other MPS animal models, and were significantly reduced in the PPS-treated animals. This included TNF-alpha, MIP-1alpha and RANTES/CCL5, all components of the TLR4 signaling pathway. We also report that AGEs, another class of inflammation markers that trigger oxidative stress and other damage, are elevated in the serum of MPS VI rats, and were significantly reduced by treatment. Overall, these findings are in accordance with the known anti-inflammatory properties of PPS, and show that it is effective even in animals with GAG storage, which is known to stimulate the inflammatory response".
As a summary of the bone observations, the researchers pondered that it may also be the multiple ways PPS works suggesting the vascular proficiencies:
"It has been further suggested that because of the vascular effects of the drug it could decrease the rate of subchondral bone necrosis and sclerosis. Recently, PPS has been shown to promote the proliferation and chondrogenic differentiation of adult human bone marrow-derived mesenchymal stem cells as well. Thus, the positive effects of PPS on the skull and other bones in the MPS VI rats could be due to any of these effects, and our data clearly show improvements in inflammation and factors that promote chondrogenesis".
MOVE ME
Motility is basically an organism's ability to move...be it waking swimming, wriggling as examples.
The researchers found this area to be the most prolific stating it like this:
"One of the most striking and significant clinical observations in all of the treated rats was the effect on motility".
"We hypothesize that PPS treatment likely led to a significant reduction in pain of the MPS animals, contributing to the increased motility. A reduction in pain also is the most prominent change in IC patients treated with PPS".
As a few of us here at HC have suggested and myself personally hearing it ...we often tend to forget just how big PAIN is and how little there is symptomatically to address it. DM will come, but it will be the sheer pain relief coupled with Pentosan's extreme safety profile that will put us on the map one fine day.
The observations that the researchers saw in these treated rats was most pronounced in their new movement profiles after treatment with Pentosan and this further observation supported that:
"There also were clear changes in the articular chondrocytes that suggested improved articular joint function, which together with improvements in bone morphology and spine biomechanics might be partly responsible as well".
THE BRAIN
As if the above is not enough. We know MPS (in particular MPS III) affects neurological pathways, just see what the researchers had to say about PPs in this domain:
"Also, although the current study focused on the non-neural effects of PPS in MPS VI rats, the drug has been shown to have neural effects as well. In experimental animals PPS has been administered intraventricular and shown to inhibit the formation of protease resistant prion proteins in the brain. It also has reduced neural inflammation in patients with Creutzfeld-Jakob disease. Neural inflammation is an important component of many disorders, including MPS, and reduction in inflammation has positive effects in several neurological lysosomal storage disease animal models. PPS also has been shown to protect the blood brain barrier against amyloid-beta induced toxicity, and as well as to protect against ischemia-related neuronal death".
WHAT AM I HOPING FOR?
Well I always wondered why are PAR doing a Double blinded study in this Rare/Ultra Rare indication?
Now I know why...because it's a well controlled study and it might just allow for early selling if a Reg body like Anvisa like what they see!
Guys, again like we saw with the last two announcements...we potentially will get a number of readings soon....
Take a look:
Yeah like all of the above but did you also notice the last point there above..."Pulmonary Function"?
That's what I'm talking about...not just one function/benefit..multiple... I'm glad they are broadening the base of observables...it will help a lot when they have those discussions with the authorities.
So what do I wanna see in this space? Well we have seen this 4 patient trial (JB Hennermann et al):
Wouldn't it be terrific to see something like this...(see below)
(Note, below data entirely for demonstration purposes, not actual data!)
Ie most of the thirteen lines falling? Perhaps a couple of lines going up, maybe they can be the placebo ones? We will just have to see...
See also Appendix A for a brief overview of GAGS but also Appendix B which will give you a sense of what I'm hoping for...
Mate.
HOWDY PARTNER
One day an MPS partner will assist PAR in taking it to the streets...well MPS patients.
My point here is that the researchers also suggest that while ERTS might have their merits, there is scant evidence if at all, on the cartilage and bone pathologies...
"While in our previous studies ERT was effective at reducing systemic inflammation, it had little or no effect on the cartilage and bone disease in MPS VI rats, and limited effects on motility. This was improved by anti-TNF-alpha antibody therapy, and we hypothesize will be even more significantly enhanced by combined PPS treatment".
This is what PAR need to suggest to any party they are talking to, the extreme advantages of PPS over and beyond ERTS. Yes it may also assist and work symbiotically and in harmony...but at the end of the day......
...well at the end of the day we are going to give the chosen partner a suite of benefits that will be NO MATCH FOR ANY OTHER COMPETITOR.
FOMO?
Sell it PAR..sell it to the prospective partners...utilise the upcoming MPS VI Data and just create that auction...create that fear of missing out.
THE MOZZ BONUS
Paradigmers, all that you read above...was based on the evidence that was found by the research team.
I just have one final sentence to leave you with in addition to all the evidence we have seen so far and are still yet to discover...
Ready?
ALL of the findings above in Parts 1 & 2 were based only on the oral version of PPS.
Mozz
DYOR required
ps: In case you are brand new to us..oral has only a bioavailability (uptake into the ultimate tissues) of circa 5%...SubQ injectable PPS is more like 20%.
Imagine the above potential results utilising the iPPS version....This is gold.
APPENDIX A
GAGS
I did some background research for this one and re-read a paper on GAGS. Full form is Glycosaminoglycans. Some time ago these long sugar chains were thought to be limited to cell hydration and structural scaffolding...
Turns out their function is much, much broader5....
Let me list a few:
Cell Signalling
Regulation of cell growth
Promotion of cell adhesion
Wound repair
However these chains pile up and accumulate if, like MPS you lack the enzymes required to break them up...that's when it gets nasty and leaves a whole trail of destruction...cellular dysfunction and death is the height of devastation.
APPENDIX B
Oh wouldn't it be so good if we could see a hint...Don't you just love hints? Hints are so much better in the case of PAR and iPPS because we know just how consistent the results can be if you get that dosing spot on!
Well.....let's do it...
Do what?
Have a look at a hint....
Where was that from? Our own MPS I Poster at the ICIEM Conference in Sydney Nov 2021.
Remember my paragraph on Mobility...well here is the evidence that we uncovered in the same poster:
Take a look at this reference for further "hints".
Cell Signalling
Regulation of cell growth
Promotion of cell adhesion
Wound repair
(20min delay)