ahh its just always so much more fun to research PAR and iPPS when the stock is
up. Yeah sure we are coming off a low base, yeah there are a number of us that have brought in higher but isn't it just
so good to get some confirmatory signals, some new buying...and actually retain these levels?
Look, the advent of OA is big enough. It affects so many people from so many communities and has plenty of unwanted and detrimental effects. It affects people
directly via pain, loss of function and a feeling of hopelessness. Why hopelessness? Because what can you actually take to get you out of pain and lack of function that's safe??
The current std of care is less care and a terrible standard to boot.
NASAIDS - Could stuff your gut, renal failure, increase chance of heart failure.
OPIOIDS - Highly addictive in a lot of cases, also will stuff you up
CORTICOERTOIDS - Mate, I'd rather have the slowly degenerative OA...these nasty villains SPEED UP JOINT DEGRADATION in a number of patients!
But you know what? OA also affects patients
indirectly by the increased chance and susceptibility to comorbidities. The lack of exercise, the lethargic feeling, the mental stress all play a toll on the OA patient. Its not like there are any safe and effective drugs either to temporarily stop the onslaught. Weight gain, increased blood pressure, cholesterol, depression these are just some manifestations that are possible once serious OA settles in.
Tonight a post after a super week...from $1.03 to $1.72..thats percentages I like to see after months and months and months of red and down trending.....As I keep imploring to you...the share price at these levels mean
NOTHING. There is a high disconnect. DO NOT LOOK AT THE CURRENT SP...it means nothing (my view only, not advice). YOU need to imagine...you need to forecast...you need to predict the future....what will the future be like for us?
Yeah its tonight that I'll tackle what the FDA are guiding potential sponsors, we'll broach some background on the true nature of why solutions haven't presented themselves and finally yes, we will cover a high level view of some of the science so you start to get an idea of just how compelling we are.
New guys to us? This is going to be illustrative. *rubbing hands together* I suggest a nice beverage as you read this...Chai Latte ...Red wine? Heck...why not a nice Botanical gin...
(Drink alcohol in moderation).
THE PROBLEM
OA is complex. I mean really complex, I have another post in the works to illustrate this a bit more...I'm prob 2 weeks away from this...
Its not just a problem of some damage, pain and loss of function and that's it. Nah... so much more complex than that and it manifests itself
early without our knowledge.
Although previous research focused primarily on changes in the articular cartilage, more recent studies have highlighted the importance of the subchondral bone, synovium, menisci, ligaments, periarticular muscles and nerves. Now osteoarthritis is viewed as a multifactorial disease affecting the whole joint.
THE FDA STANCE
Gee the FDA know the problem...they really do have to sus it out. It could potentially be rolled out to
millions of people...think about all the growth in OA...not just the people that have it officially diagnosed NOW. We know that governments around the world want to temper inflation to around 2 to 3%...OA rates grow at 8%!
Year in....
Year out...
Written in Aug 2018 1 , the FDA produced a guideline for potential sponsors in terms of endpoints when constructing Clinical Trials for OA..
Mozz Speak? Its a guide for Pharma companies that are developing drugs to treat the underling pathophysiologies and structural progression of OA. Yeah this is kinda an important guide when thinking about a trial design....
The FDA themselves know, this is a disease that has
nothing to address it:
"...treatments that inhibit structural damage or target the underlying pathophysiology associated with OA remain elusive and represent an unmet medical need".
Elusive indeed, but for how long?
Further through the guide, the FDA admit, this isn't a single targeted need:
"...there are several ongoing issues with developing such products, including the multi factorial and complex etiopathogenesis of the disease..."
My fellow shareholders...iPPS does not just work in
one way.
I need an entirely separate post to list them all...but we know the basics...we know it addresses the vascular system, we know it binds to certain proteins...we know it has a positive stimulatory effect on chondrocytes (cartilage formation). We also know that it has a lovely affect on the stimulation of higher weighted HA...but that's not all...what about NGF down regulation.
The magic of our drug...the magic of our investment is multi modal.
To further demonstrate just how acutely aware the FDA recognise that there is nothing out there, how about this statement from their own guide?
"...[The FDA are well aware of] the well-recognized discordance between structural changes and signs/symptoms/function".
This is what 008 and the enhanced 002 sets out to do...show the link...the link between iPPS's positive structural manifestations and clinical endpoints such as pain reductions and function improvement.
Again a further issue is:
"...the lack of standard definitions of disease progression, and, correspondingly, the absence of endpoints to reliably assess the ability of a product to alter OA disease progression".
My dear reader...this is the true spirit of 008....the observance of the biomarkers, whether they be Prognostic, inflammatory, Safety or one of the other BIPED classifications.
Again while researching material for this post I came across yet another peer reviewed research paper that singles out two distinct biomarkers as "...illustrative examples of Prognostic markers". 2
Medals for guessing the two biomarkers? There can be no awards for you if you are a Mozz Par Post follower:
COMP
CTX II
Mate.
How about this stat from the researchers:
"...showed that mean serum COMP levels (measured every 6 months in a cohort with knee OA), were higher during periods of radiographic progression and that on average, a 1-unit increase in serum COMP levels increased the probability of radiographic progression by 15%".
And that of CTXII?...
"Those with elevated levels of urinary CTX-II were more likely to develop worsening bone marrow abnormalities on serial MRI measurements over this 3-month interval".
You are new to us?
COMP and CTX II or just two markers being studied carefully in both of our 008 and 002 studies. Just do me
one favour.,..watch very carefully for these results to come out! These two are key.
THE FDA CLUE
Guys, wouldn't it be nice to get some sort of clue....
Whaddya mean Mozz...
I mean If the FDA were to actually state publicly, what it would take them to consider an Accelerated Approval?
What does the biggest Pharmaceutical market administrator want to see?
I would love to know what would put any given company into serious contention....
"To accept structural endpoints as valid outcome measures for accelerated approval, there should be substantial confidence, either based on empirical evidence from randomized, controlled comparisons from clinical trials and/or based on a comprehensive understanding of the disease process and product mechanism of action, that an effect on the candidate structural endpoint will reliably predict an effect on the clinical outcomes of interest."
Substantial confidence in controlled comparisons from clinical trials coupled with an understanding of a mechanism of action that there is some effect on a structural endpoint that will reliably predict an outcome of interest.
Mozz Speak please....
I give youBML
Size
Grade
Width
...and maybe add in Joint Space Width...
Fellow investees....do we have evidence of this already????
Anoter PAR announcement...
The above from a PAR announcement...
Guys, Remember, BMLS that stay the same size is one thing....the
enlarging ones are quite something else.
THE GOAL
Yes Mozz, I understand the FDA want some solution...but what is their real goal...how do WE (and please don't forget by YOU owning shares of PAR means YOU are the owner of this magnificent company....) as shareholders, we must understand WHAT are the GOALS of the FDA...
Simple...read their bloomin' guide!!!
"The ultimate goal of treatments related to inhibition of structural damage or targeting the underlying pathophysiology associated with OA is to avoid or significantly delay the complications of joint failure and the need for joint replacement, and also to reduce the deterioration of function and worsening of pain".
We are well aware of the association with BML presence and the pathology and progression of OA (ROA = Radiological OA):
"The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.6%; lateral: −1.9%/annum vs −1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5–2.4; 95% CI range 1.1–3.4)". 3
Its what the FDA know and want...some solution, that's safe that addresses or better yet, arrests the progression of OA and thus brings down the real chance of joint failure and ultimately replacement.
A SMALL TASTE
Just a small sampler for you guys to understand just how prevalent the evidence is....and we will do it in the form of one of my favourite formats...
Question: What is the relationship between Radiographical Osteoarthritis and annual percentage loss of medial and lateral tibial cartilage volume, as well as a significantly greater incidence of joint replacement surgery.
Let me restate that like this...
How many times greater if you have OA show up on an X-ray is your chance of needing a joint replacement eventually?
A) Its going to be something significant...lets go 3 times the chance.
B) 6 Times, Double answer A is a good guess.
C) 8 times the chance?
Guys, the answer is
24 times!!!
"...people with ROA had a greater annual percentage loss of medial (1.7% vs 1.3%, P < 0.001) and lateral (1.7% vs 1.4%, P < 0.001) tibial cartilage volume, as well as a significantly greater incidence of joint replacement surgery (9.6% vs 0.4%, P < 0.001)". 3
Yes the P value was significant, my emphasis added above
You and I both now know that OA starts a long time before radiological evidence...as I have said before, if you have OA, one day into the future, mate, they are going to highly recommend you have a dose of iPPS as a prophylactic...it will be this concept that will be highly accreditive in terms of revenue, it will make our drug front line.
Paradigmers, the key to success is to simply show that our drug...OUR drug...can avoid, or at least significantly delay the complications of joint failure....not increase the rate of joint failure like corticosteroids do, not simply do nothing but letting OA progress...by ADDRESSING OA.
How and when will we know this?
My guess is in 008 (maybe 56 days...maybe 6 month read out?)...and 002.
AN FDA GUIDE CONCLUSION
Finally how does the FDA conclude their guide?
"At this time, the ability of treatment effects on common measures of structural progression to reliably predict treatment effects on direct measures of how patients function and feel, has not been established. Therefore, FDA welcomes efforts to address the above considerations and is open to work with all stakeholders on such programs".
WE ARE INDEED NOVEL
Oh so novel...Nah I don't just mean that we are the first in terms of an OA solution...
Heart Failure
MPS
RRV/CHIKV
Hay Fever
Let me just take one of those above...Heart Failure. In terms of heart failures, there are two types, one without preserved ejection fraction, and the other with preserved ejection fraction.Want to know more on what this means?
Read this if you haven't already (Single left click on the hyperlink:
PAR's EXCITING FUTURE INDICATION
50% of all heart failures fall into the 'with preserved fraction' group...how many cases is that?
64,000,000 cases per year 4
How many possible drug solutions are offered in this space...?? There must be a few...
None.
There is nothing...
Novel?
iPPS is the only possible drug at the moment that is showing some efficacy here.
Yes, its peer reviewed.
Yes you own a novel drug.
Paradigmers, we have something unique, we have something that works, we have something that's novel, we have something the FDA are going to realise is quite incredible.The share price in my opinion has just
begun its appreciation....as Paul Rennie said at the very, very end of a marathon 2019 AGM...
"YOU HAVENT SEEN ANYTHING YET IN TERMS OF OUR PERFORMANCE..."
- Mozz
DYOR applies
REFRENCES
1]
https://www.fda.gov/regulatory-info...hritis-structural-endpoints-development-drugs
2]
https://www.sciencedirect.com/science/article/pii/S1063458406001038
3]
https://www.oarsijournal.com/article/S1063-4584(17)30855-5/fulltext
4]
https://amj.amegroups.com/article/v...to the last searchable,(11.61 per 1,000 YLDs).
(20min delay)