n the last few weeks I've been doing more research on what the FDA likes to see in terms of looking at candidates that satisfy an Accelerated Approval.
Tonight, lets investigate a possible pathway to this stairway to heaven kind of scenario.
The parallels I draw are for you to watch out for in terms of the Led Zeppelin song references (All references in Orange to make them obvious) in this post, its been voted as one of the best songs ever made, could one day we not have one of the best drugs ever repurposed?
Led Zeppelin the band, Stairway to heaven came out in 1971.
As one of the lyrics goes in the Led Zeppelin song, there is a tree by the brook...for us, it begins with Beechwood bark. We know the rest of the story...synthesis with sulphur and sodium to get the final product, an extremely complex process refined over not a few years, but literally decades...a process so complex that even generic manufacturers have so far failed to replicate exactly...this multi refined step process resulting in a complex molecule that is baked just right...GMP standard achieved and randomly FDA audited on yearly basis, its also ISO 9000 certified.
Indeed the forests will echo with laughter ..they've been there all this time sitting and waiting for us, sure the vets and pets have prospered but humans are a bit behind...our time is coming (my views).
Forests of beechwood...
What then can we offer the FDA to get them to consider us a bit quicker?
Paradigmers, what do the FDA want? At the end of the day they will look at an accelerated application if we can show them we have a surrogate biomarker showing its "likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments". 1
The good thing for us as investors is that OA is all encompassing of the joint. It affects many aspects, here is just a taste:
"In addition to loss of articular cartilage, OA also affects the entire joint and the associated pathologic changes have been recognized in synovial, meniscal, ligamentous, tendinous, and muscular periarticular tissues. Importantly, knee OA is also associated with substantial alterations in subchondral bone (SCB), including changes in histology, histochemistry, morphology and mechanical properties". 2
This is our sign on the wall...The best part about this sign is that it is means that all we need is one good biomarker, it could be structural, it could be biochemical. I suspect we are going to be presenting core evidence of a number of biomarkers...talk about going above and beyond.
In tonight's post we focus on one such biomarker, its a structural one.
Enter the BML.
Knee OA is all encompassing of the joint. Traditionally radiological evidence has been used to investigate OA but it is the more modern advent of MRI that is now leading the way.
"Compared to joint space narrowing on traditional radiographs, the presence of BMLs has been better correlated with severity of clinical symptoms as well as clinical deterioration".2
Don't forget we have added MRI scans before and after for patients in 002 and 003.
QUESTION: Up to what fold increase does the presence of BML's increase the chance of progression to total knee arthroplasty?
A) 1.1 fold increase?
B) Yeah I gotta do something about those A) answers....2 fold increase?
C) 4 fold???
D) 4.5 fold?
Yep, all of you were wrong again...up to 9 fold increase..
"Presence of a BML increases the likelihood for progression to a total knee arthroplasty by up to nine fold".2
We are measuring BML volume, grade and size in our trials, there is a direct link here between BML volume and pain levels, here is another quote from another source:
Changes in total knee BML volume had a positive association with changes in knee pain severity (P = 0.004)". 3
The Good Doctor (Dr David Felson, working for PAR as a world-renowned consultant in the OA space) also had this to say about BMLS and associated pain:
"Felson et al. noted that patients with knee OA are more likely to have pain if a BML is present (10). In this study, they reported 77.5% of patients with a BML had significant pain compared to only 30.0% reporting pain if no BML was detected (p<0.001)". 2
Now BMLS can change over time, they can increase and decrease in size and shape over a short period of time but look at how its the longitudinal approach that is relevant for us. The FDA's spirit of AA was to not make the ultimate beneficiaries of a new drug have to wait for long clinical trials to prove the efficacy. If there was some surrogate biomarker that can show safe and an efficacious pathway then this is a good way of getting good drugs out to the patients quicker while the main trials continue in the background. In fact the average AA designation has saved an average 3.4 years of waiting around before drugs have become available.
Getting back to BMLS, what are the longer term observations?
"...longitudinal studies have demonstrated that a BML is more likely to progress and increase in size over time rather than resolve in patients with knee OA".2
Its a perfect scenario that could result in the iPPS piper perhaps leading us to reason.
Indeed there is a relationship between BMLS and OA progression, as we wind down this road take a look from an engineering point of view how pervasive this OA can be.
KEY: SCB = Sub Chondral Bone SCBP = Sub Chondral Bone Plate
"The rate of SBA has been noted to increase exponentially following the development of a SCB BML. Recognition of a BML represents a critical point in the OA disease process. Retrieval analysis has demonstrated that the histology of a BML closely resembles the appearance of a stress fracture or bone non-union. These changes in histology are associated with significant loss of SCB mechanical integrity and inadequate support of the SCBP. Micro CT analysis of tibial plateau retrievals from our laboratory suggest that SCBP fracture may occur as OA progresses".
Failure of SCB to support the SCBP coupled with fracture of the SCBP likely explains the relationship between a BML, SCB, and onset of clinical symptoms.
"Mechanically compromised SCB coupled with SCBP fracture likely is associated with deformation of the periosteum during weight bearing. Deformation of the periosteum has been demonstrated to be a very important source of bone related pain. Additionally, as previously noted, a significant increase in inflammatory mediators has been identified in BML affected SCB. The combination of bone inflammation coupled with structural compromise could explain why knee OA is associated with pain at rest, which increases significantly with weight bearing".
Like the lyrics on the song, we have had time to change our destiny. We value added by increasing the observables, the exploratory endpoints in our main trial. This is a big clue for us, we want to measure these structural endpoints and we gather data. This change was for the good. Yes I know it added time, yes I know it added cost...yes I know it added frustration to us...but I really do think we are all going to be much more appreciative of what PAR have done for the long term share holder....its pointing to a much much brighter future, a smoother path to registration and an incredible broadening of that all important label.
Change ...adapt....take into consideration....move...dynamic....nimble...flexible.
These are words that come to mind when I think of my investment in PAR. Guys, this is NOT a stagnant one tracked company...they are moving as news comes to hand...as the data gets back....
Change the road you are on....here is another example:
New additions to our 002. (Left click to enlarge).
Again like Zeppelin sings....
And a new day will dawn for those who stand long.
There aren't many of us PAR shareholders, my guess is no more than 17,000 odd. Of that my guess is that there are around 550 of us here at HC. My point here is that there aren't many of us,... literally just a small number of us know about PAR, know about iPPS, know about patients and what they have experienced. It really is a bit of a whisper still...
Winds of change are afoot...
Sand Diego Partnering Conference 008 Primary Result MPS VI Phase 2 Brazil Conclusion New CEO beginning work Deal?
Here is the thing, I don't know whether we will get an AA. If we are a chance for AA, I don't know when it could happen, I guess they would need a good amount of data to build up and present, perhaps a year from now isn't out of the question?
But I do know that even if we don't get an AA designation, but if our trials are successful, we still have a chance at gold..
"Since onset and severity of OA symptoms correlate closely with SCB changes and are associated with disease progression, it is reasonable to contemplate interventions that could prevent or reverse the described alterations in SCB. For example, pharmacologic means or surgical procedures that mechanically or biologically enhance SCB before a BML forms could delay or even prevent the onset of severe OA symptoms".
We already know iPPS shows efficacy against BML's...its a clue for us all.
What we have is a real chance at greatness, the signs on the wall, the whispering wind we hear, despite the stores seemingly like they are closed (lack of volume and positive share price direction)...
What do our shares give us? What have we bought? What could we one day be entitled to?
Well what does the song say...?
Well potentially.... are we...
...buying a stairway to heaven ....
DYOR
PRE APPENDIX A AND B NOTE
If you are young and have not heard this song, it is a must you hear this, its one of the best songs...do stick with it as it starts off slow but it really gets into itin the later stanzas - See Appendix B
APPENDIX A - Lyrics to the song
There’s a lady who’s sure all that glitters is gold And she’s buying a stairway to heaven. When she gets there she knows, if the stores are all closed With a word she can get what she came for. Ooh, ooh, and she’s buying a stairway to heaven. There’s a sign on the wall but she wants to be sure ‘Cause you know sometimes words have two meanings. In a tree by the brook, there’s a songbird who sings, Sometimes all of our thoughts are misgiven. Ooh, it makes me wonder, Ooh, it makes me wonder. There’s a feeling I get when I look to the west, And my spirit is crying for leaving. In my thoughts I have seen rings of smoke through the trees, And the voices of those who stand looking. Ooh, it makes me wonder, Ooh, it really makes me wonder And it’s whispered that soon, if we all call the tune, Then the piper will lead us to reason. And a new day will dawn for those who stand long, And the forests will echo with laughter. If there’s a bustle in your hedgerow, don’t be alarmed now, It’s just a spring clean for the May queen. Yes, there are two paths you can go by, but in the long run There’s still time to change the road you’re on. And it makes me wonder. Your head is humming and it won’t go, in case you don’t know, The piper’s calling you to join him, Dear lady, can you hear the wind blow, and did you know Your stairway lies on the whispering wind? And as we wind on down the road Our shadows taller than our soul. There walks a lady we all know Who shines white light and wants to show How everything still turns to gold. And if you listen very hard The tune will come to you at last. When all are one and one is all To be a rock and not to roll. And she’s buying a stairway to heaven.
APPENDIX B - The Song
Note: This rendition has some 81 million views...
APPENDIX C - Post Edit Acknowledgement
I couldn't resist this one lyrical line, dedicated to my contact in the west. You have provided me with MANY references and articles, food for thought. Need to acknowledge you by one line that caught my attention in this amazing song...
There’s a feeling I get when I look to the west.
Many thanks for your great research, thoughts and sending me ace articles and relevant material. Please keep it up well into the future and when we hit real share price strides...! I'm sure I can say this on behalf of the entire HC sister and brother hood.
Also need to acknowledge another guy, the guy with the boat.
Your head is humming and it won’t go, in case you don’t know.
Without you and your humming questions I couldn't reflect on as much as I do in terms of all things PAR...You are the anchor, in a good steadying way...
n the last few weeks I've been doing more research on what the FDA likes to see in terms of looking at candidates that satisfy an Accelerated Approval.
(20min delay)