'm not going to pretend I have the patience of a saint. Every...

'm not going to pretend I have the patience of a saint.  Every week I am also waiting for these authorities.  Not just one of them, but two!


I actually really am at a bit of a loss as to why the TGA are taking quite this long, it's a determination.  It's not the actual application for provisional we are putting in?!?Yes I get the fact that we are a novel drug.Sure I understand that we are broad based and that there haven't really been any inflammatory addressing drugs that have our safety profile and our efficacy.  I also understand that this isn't a single cytokine we are addressing, I realise that the MOA (mechanism of action) isn't just via a single given inflammatory receptor, this really is a systemic drug with a very broad base of mechanisms to address an in turn, broad based disease!

That's going to take some, well, digesting, some due diligence and some effort.  I can well imagine the old clock stopper at TGA central has been hit a few times?!


_{Clock Stops in-between?  I would think so.}


So as I wait (in the dark) just like everyone else...how about some more evidence to demonstrate how well our drug works....it's the least I can do to bide my time and hopefully yours!

So take it more as an entertainment, as a distraction but for at least some of you newer to us, it also could be quite an eye opener!

Please do now, enjoy.




INTRO

I always knew iPPS was good, from the day I started deeply researching it way back in 2018 right up until now.  I have learnt this from patients some of which have become my friends, from the company itself, from talking to a number of Docs, right through to the best in the industry, in the world...and all the way to the sterling manufacturers, bene,  themselves.  It has always been a personal green flag for me when I'm 5 years into this iPPS research and I know I'm still not even half way into finding out what iPPS can actually do and how it really works!

Last week was no different, I accidentally stumbled across this Mozz NEVER BEFORE read research...



BACKGROUND

First we need a smidgen amount of background.

A torn Anterior Cruciate ligament (ACL) looks like this ²:





The ACL is one of two cruciate ligaments that aids in stabilising the knee joint. It is a strong band made of connective tissue and collagenous fibers that originate from the anteromedial aspect of the intercondylar region of the tibial plateau and extends to attach to the medial aspect of the lateral femoral condyle.²

A study conducted back in 2008 looked at ACL injuries and their effect on changes in joint fluid, BMLs and cartilage within one year ⁴ :


Their conclusion:

"Conclusion: Following an acute ACL tear, cMF and TrF showed the greatest consistent changes of cartilage morphometry. An ACL reconstruction performed within a mean of 6 weeks from injury was associated with increased ThCcAB and VC in cMF and decreased AC in TrF, compared to knees treated without reconstruction. This may suggest a delayed structural restitution in ACL reconstructed knees".


TrF = Trochlea femur
ThCcAB = Cartilage Thickness
VC = Cartilage Volume
cMF = Central medial femur
AC = Surface Area


The above research suggests an ACL reconstruction procedure results in a "direct and significant risk factor" in terms of increased joint fluid volume, prolonged resolution time for BML volumes and greater changes in the cartilage profile.

The major problem is that an ACL tear usually means that it does not heal back into it's original position:


"Unlike many tendons and ligaments, a torn anterior cruciate ligament (ACL) rarely heals into its anatomic or physiologic position".⁵


Not only that but it is commonly associated with a host of other problems and manifestations:


"...damage to the menisci, other ligaments, articular cartilage, and subchondral or cancellous bone. These associated injuries can occur concurrently with the acute ACL injury, as well as over time in the ACL-deficient knee  Subchondral sclerosis, meniscal degeneration, and osteochondral defects are also commonly observed in the chronic ACL-deficient knee Reticular patterns involving medullary edema comprise approximately 70% of such lesions, and geographic patterns of bone bruise have been observed in 66% of the patient population".



The research also demonstrates that adolescents and young adults that sustain ACL injuries are:


"...at a substantially increased risk for the development of future osteoarthritis (OA) in the patellofemoral and tibiofemoral joints"
...and further,

"Some studies suggest that as many as 80% of ACL injured knees may demonstrate radiographic evidence of OA at 5 to 15 years after initial injury, especially with concomitant meniscal damage".


"...research has shown that individuals who sustained an ACL injury while playing soccer had a 51% higher chance of developing radiographic changes secondary to OA 12–14 years after injury and that the risk of developing OA increased 100 times in athletes who have sustained a knee injury".



However, it isn't just the inconvenience factor of being offline for a few months while you recover.  It's the longer term repercussions:


"These injuries often require surgery, as well as ample recovery time. In fact, many surgeons now recommend that patients wait nine to 12 months, sometimes even longer, before returning to their sport. There’s also an increased focus on preventing a re-tear of the ACL after surgery, says Elizabeth Gardner, MD, a Yale Medicine orthopaedic surgeon and head orthopaedic surgeon for Yale University Athletics". <sup>5.5



Girls more susceptible to injury? No fair!  See Appendix A for more details!</sup>



A typical ACL surgery consists of the surgeon drilling and boring tunnels into the tibia and the femur, removing the torn ligament and then placing the ACL graft in position.⁶


Mate...Remember this concept, we will revisit it towards the end of this Mozz Post (see 'Reminder' at the end).



THE AMAZING RESULT?

So what's all this about an amazing result?

Mozz, I hope you ain't going to go through the 008 program with your n = 15.  We all know that, it ain't NEW news yeah?

Yes yes I know....


To get Statistical Significance (SS) on 15 in our 008 study was a bit out there...was a bit whacky-good.  There is no way they could've seen better than that....right?.


I always thought PAR's 008 program in the 2 x 2 dosing was incredible, how did they get statistical significance on just 15 patients AND they had structural ramifications in just 6 months. I can't express to you how rare that is, no one has a drug that can do it. lus we aren't horrible intra-articular, we are Sub Q, hellloooo patience convencince.




Then add the safety profile to that...



But tonight?


I'm going to tell you what I very recently read that simply shocked me and surprised 'man in the west', his simple one word back to me was 'IMPRESSIVE'.



_{What's the shocking surprise then?}




Guys, PAR has beaten those stats....


...it happened back in 2017.


You think n = 15 was ok.

Mate, they did it in less.



I give you this one statement.

Ready?










n =  9





What?
How?


Where?




Well before I continue I must first caution you and say it wasn't against placebo, but what I will give you is that it was a Phase two Trial.

Yep, PAR's Phase 2A.




THE STUDY

Back in November 2017 PAR announced their trial results for their ACL/BML study.  I had never before read this.  In truth, I really started my proper research back at the end of 2018...but I remember in my research-infancy days of not bothering to go back too far as I thought it may not be relevant.  Boy was I wrong.  It's been a full 7 years since this announcement came out and I only just read it literally a few days ago...  What a read.  Let's check it out.


The study itself consisted of finally only 9 patients.  It was focused on Bone Marrow Lesions as a direct result of injury to the anterior cruciate ligament known as the ACL.Please do have a glance at Appendix A at the end of this post for some interesting facts about ACL injuries, but with a PAR type future flavour to them.

The primary for this study was safety and tolerability. With such a low n, you wanna be careful here as it just takes one patient to blow out these stats. Also note: this study did not have a placebo arm.

Now the Secondary endpoint of a reduction of BML Volume measured by MRI was not only met, but it achieved statistical significance (SS).

The drug was administered twice weekly over 3 weeks!  Not 6 weeks.  An 8 week follow up was conducted, "There were no clinically significant changes in clinical laboratory parameters (haematology and biochemistry) or physical examination findings during treatment or the 8-week follow-up period, demonstrating safety and tolerability of PPS" ¹.

Don't forget, it was the evidence of the single arm of PAR's Phase 2A that formed the basis of the well controlled double blinded trial against placebo in 112 patients, known as the Phase 2B.

MRIs were taken before treatment and after, the MRI reviewer themselves were blinded to the pre and post MRI's.  

So they not only showed SS in reduction of the BML volume but they also showed a SS reduction in knee effusion-synovitis volume.




LET'S GO GRANULAR




As an aside, I said this 'granular' word the other day to my manager about some results at work (not PAR related) and he jokingly said I must never use that word again  (too fancy and fashionable for us I suggest), So I started using all kinda of similar sounding words as possible substitutes..."Lower level"...I snuck in "I've analysed the data at a bedrock level" and "...the subordinate data is all done"...it was a bit of a laugh.


I digress, apologies...so at the lower level, let's check out this paragraph:


"The changes in BML and effusion-synovitis from baseline to End of Study were examined in 9 subjects who had completed the course of PPS treatment. Overall 6/9 (66.6%) participants showed reduction in BML; 8/9 (88.8%) had reduction in effusion-synovitis volume. There was a significant reduction in BML volume in lateral tibia [p=0.046], and a marginally significant reduction for total tibia [p=0.06]. Similarly, there was a significant reduction in BML maximal area in lateral tibia [p=0.03] and total tibia [p=0.02]. There was a significant reduction in effusion-synovitis volume in suprapatellar pouch [p=0.02] and total knee [p=0.01]. There was also a significant reduction in effusion-synovitis maximal area in suprapatellar pouch [p=0.03] and total knee [p=0.04]".¹


PAR went on to state that ACL injuries show a slow reduction of BML volume and joint fluid volume over some 12 to 24 months.

In just 8 weeks (not 6 months!!) 88.8% had a reduction of effusion-synovitis volume!


8 weeks!

No wonder the drug effect size is off the charts, there was statistical significance all over these results.

Don't for  a second think that these are isolated results.  The implications are wide ranging:

A number of peer-reviewed publications highlight the association between the acute injury and osteoarthritis within a 10-15-year time-frame. “As many as 80% of knees post-ACL injury will progress to radiographic and symptomatic osteoarthritis after 5 to 15 years - despite corrective ACL surgery”.⁷

Take a read of this excerpt that PAR also included:

“A very high prevalence of radiographic knee osteoarthritis, pain, and functional limitations was observed in young women who sustained an ACL tear during soccer play 12 years earlier. By 1 year, more than 30% have radiographic evidence of knee osteoarthritis and by 10 years, more than 60% have clinical osteoarthritis (pain and loss of function), irrespective of ACL surgical repair ”.


Two further concluding statements I wanted to highlight by the CSO at the time:

"To our current knowledge this is the first time a therapeutic agent has been reported to show statistically significant reduction in both BML volume and effusion synovitis volume within 2 months post-surgical reconstruction".


...and this line:


"This clinical trial data provides support for further investigation of early pharmaceutical intervention of injectable PPS in the treatment of acute joint injuries to delay or halt the progression to post traumatic osteoarthritis".¹



Paul Rennie summarised the incredible results by stating:


"We are also delighted to show for the first time both BML volume and effusion-synovitis volume was significantly reduced within a 2-month period post-acute injury. We are hopeful the drug PPS could become standard of care, post-surgical reconstruction, with the potential to reduce the risk of a person developing PTOA".

(PTOA = Post Traumatic OA)


Indeed we now skip forward some 7 years to today... with so much more data and evidence.  Indeed I find myself very much in the belief that this will one day become first line treatment for a disease whose true scale is really not known, just estimated.  Certainly not known and currently appreciated by our ASX, but also certainly not yet known in any other markets.






- Mozz






Speculative statements, personal opinions only, no advice is implied, there are risks in this investment.





REMINDER!!

Remember I mentioned what a typical ACL reconstruction involves?  Here is a hint:  Boring tunnels into the tibia and femur!Surely the patient wants to at least try a naturally based remedy before electing for such surgery?  What if there were a drug that was super safe and could heal the tissues and be the potential natural causation of efficacious repair?  Wouldn't you at least try that while at the same time being able to alleviate and address pain?

Wonder drug?

You already know what I think, now we wait for the authorities to see what they think.







APPENDIX A

How about a few fast facts on the ACL, not just disconnected facts (that wasn't actually meant to be a pun till I thought about it)...but it's quite relevant to us.


QUESTION:  How many ACL tears are there in a given year?

The anterior cruciate ligament (ACL) is one of the most commonly injured ligaments in the knee. Approximately 150,000 ACL injuries occur in the United States each year.


QUESTION:  Any differences in male and female stats?

Female athletes participating in basketball and soccer are two to eight times more likely to suffer an ACL injury compared to their male counterpart.⁸



QUESTION:  WHY are women more susceptible to ACL injuries?

They may be more prone to non-contact ACL injuries because they run and cut sharply in a more erect posture than men, and bend their knees less when landing from a jump. ^8.4


QUESTION: What does the ACL comprise of?

Histologically, the ACL is composed of type I collagen (90%) and type III collagen (10%).






Collagen under a super microscope.

Think of this like a cement, holding things together, giving tensile strength to structures.  But it is not just passive...it's living!  It keeps away germs and prevents absorption of certain toxins.^8.5


Note:  Here is a study that found PPS is linked to increased collagen production:

"In 5-day MMC, 130% stimulation of PG synthesis occurred at 2.5 μg/ml PPS (P < 0.0001), while 5.0 μg/ml PPS achieved maximal stimulation in the 7-day and 10-day cultures (P < 0.05). HA and DS at ≥ 5 μg/ml inhibited PG synthesis (P < 0.05) in 5-day MMC. Collagen type II deposition by MMC was significant at ≥ 0.5 μg/ml PPS (P < 0.001 to 0.05)".⁹


MMC = Micromass cultures
HA = My second fave molecule - Hyaluronic Acid
DS = Dextran Sulphate, similar to Heparin
PG = Proteoglycan, key component in connective tissues.


...and another example from a different study:

"In conclusion, PPS exerted protective effects against collagen-induced arthritis in rats. The results suggest that PPS acts as an anti-inflammatory and anti-arthritic agent in decreasing the arthritic effects in collagen-induced arthritic rats".¹⁰



QUESTION: What percentage of ACL injuries affect surrounding ligaments?

About 50% of ACL tears are accompanied by injury to other ligaments in your knee and the wedge-shaped cartilage (meniscus) that acts as a shock absorber between your thigh bone and shinbone. This added damage often requires additional treatment and may complicate your healing process if not addressed appropriately.^10.5



QUESTION:  Are the majority (if not all) ACL injuries linked to a contact sport?


70% of ACL injuries were sustained in non-contact sports while only 30% are attributed to contact sports.^10.7




QUESTION: If you sustain an ACL injury is there any material increase of your chance of acquiring OA and eventually having to have a total knee replacement?


"A decade after injury, half of the patients have radiographic OA. The long-term consequences are significant; the frequency of total knee replacement for knee osteoarthritis 20 years after anterior cruciate ligament (ACL) injury is 7-fold greater than that in the sector of the population without injury". ¹¹







APPENDIX B

While doing background research for this post I came across a really interesting and somewhat thought disruptive material.

How about this one, after an ACL related surgery, typically in younger adults, those that lost some weight or went easier on their joint loading exercises actually had a propensity for an INCREASED chance of OA. That was not a typo.


The thought process from this particular article,  (see reference 12 below) suggests that ACL revision surgery usually cannot completely revert the biomechanics back to what was there pre injury.  This then results in an altered state of the joint and surrounds and often, the patient loads the joint to a lower degree.  It may be fear of pain or fear of further damage.  However, this may become counter productive.  The article also suggests that inflammation is at play and this also leads to further destruction.

How does one reduce the effect of inflammation or indeed, inflammation itself, particularly the unwanted chronic and cyclical inflammation?

Paradigmers, it has been shown that our pentosan reduces inflammation. Specifically we saw synovitis (synovial inflammation) overall decrease markedly over placebo. I revert back to this finding in just n=15 in our 008:






Just one aspect of the massive data set that's been submitted to the authorities.

Now we continue to wait for the sanctioning, finally, of our P3.






DYOR





REFERENCES

MAIN REFERENCE

1]   https://app.sharelinktechnologies.com/announcement/asx/0a75487dbaa4923329d533b3596f9ea4

OTHER REFERENCES

2]  https://kidshealth.org/en/teens/acl-injuries.html
3]  https://www.ncbi.nlm.nih.gov/books/NBK499848/
4] https://pubmed.ncbi.nlm.nih.gov/18760637/5]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410751/
5.5] https://www.yalemedicine.org/news/acl-surgery
6]  https://kidshealth.org/en/teens/acl-surgery.html#:~:text=The%20surgery%20usually%20takes%202,in%20about%20the%20same%20position
7]  Simon D, et al. The Relationship between Anterior Cruciate Ligament Injury and Osteoarthritis of the Knee. Advances in Orthopedics: (2015), 1-12.
8]  https://www.nata.org/sites/default/files/anterior_cruciate_ligament_acl_injury_prevention.pdf
8.4] https://www.genourob.com/diagnostic-ligaments_news_11-acl-fast-facts.phtml
8.5] https://www.news-medical.net/health/What-is-Collagen.aspx\
9]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875662/
10]  https://www.sciencedirect.com/science/article/pii/S0034528818300481
10.5] https://www.stevennolanmd.com/blog/5-things-you-didnt-know-about-acl-tears-and-reconstruction
10.7] https://activehealthjax.com/10-things-to-know-about-acl-injuries/#:~:text=A%20complete%20tear%20in%20the,Contact%20Doesn't%20Reduce%20Risk.
11]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10209532/#:~:text=A%20decade%20after%20injury%2C%20half,population%20without%20injury%20%5B9%5D.
12] https://www.healthline.com/health-news/will-you-get-knee-arthritis-after-acl-surgery-what-to-know#Heres-how-ACL-surgery-plays-a-role
13] https://app.sharelinktechnologies.com/announcement/asx/058732021c8928f27d89da8502ca692a