PAR and the concrete base, page-4

POSTED 1/May/2022 "RESCUE ME"



ryptic subject thread? All will be revealed real soon...

The word 'Rescue' is defined as "The act of saving someone or something from a dangerous or difficult situation".¹

Buried fairly deeply in the midst of our visionary 008 study is a certain secondary endpoint. Tonight I explore just what this is all about and what we hope to gain from this somewhat lesser known endpoint!




NOT THE OBVIOUS EXPLORATORY ENDPOINT

I somewhat naively, back in 2018, thought that by 2020, maybe 2021 we'd start revenue and we'd be away. Yeah don't get me wrong, despite all the research I do and time that I spend, it doesn't mean that I'm oblivious to the fact that our timelines have blown out and from here, it looks like we are still ages away. BUT I'm not unhappy...


Why?
Because of two distinct reasons now:

1. We have gone from a fairly big scope to a very much larger one.·

• We have now added USA and Europe together, simultaneously ...and what about Canada, UK and Aus? · We have massively expanded our 008 program...broadened it...and it could just be quite a read out when it does read out. Forget "Read out", it might be a shout out. (Spec statement) ·
• We have included other programs like EAP and SAS which have helped along the way...not only as a look through, but it has no doubt helped a lot in our submissions to date and meetings with the authorities.·
• We've added to our basic trial, Hip OA and durational studies, all potentially label enhancing.

2. While our official timelines are still measured in years, there is a definite chance that it may be shorter....much shorter (spec personal views).


We NOW have a key potential accelerant...a Fast Track....This indeed could be a gateway chance to some other amazing designation and one could very include AA.

No not Alcoholics Anonymous...I'm talking Accelerated Approval, though I might need another scotch when we get whiff of any such sorta news.


I will have more to say on Accelerated Pathways later this month....just need more spare time to scribble down all my thoughts into a post coming to a thread near you, soon!

If today you were to ask me, Hey Mozz...$10 Billion per year revenue potential in 4 years or $20 Billion in 6....you know where I'm heading.

But WHY?

Isn't a shot at a quicker $10 B much better? Well yes and no. It is better and more certain and less riskier to have it sooner...but don't forget, we may not keep all of it, it could be subject to royalties and maybe some dilution effectively. I would rather wait for a joint market approach and really hit the revenue hard when we are approved. Doing it in tandem could be a lot of additional overhead, better to get it approved by a couple of the biggest authorities all in the one hit.

It also makes a lot of sense to have a global partner as the ultimate marketing and advertising message is consistent. Think of the consistency of McDonalds, you know what you are getting anywhere you go. Customers worldwide can relate to it. The same is true of a respected drug.




Above, Maccas...below, PAR one day?







Getting back to the endpoints, the more glamorous (well known?) endpoints are mainly covered, yes we have talked a bit about the usual suspects of TNF-A and the IL set (1, 2, 6, 8) and even those more obscure ones like CTX II and NO.

(...err don't know what NO is? Follow the below links).


NO Part 1

NO Part 2

(Psst: There is more to come on CTXII as well, I'm a few weeks out from posting that one).

We learnt that we have now included the structural endpoints of BMLS and Joint Space Width, exciting physical endpoints that will be measured with the help of MRI's in our main trial, 002. But one I haven't mentioned so far though it's been on my list to write about for some time now is plain ol' simple Rescue observation. Lets explore.



RESCUE ME

So what's all this about rescue? What is it, how does it work and how does it affect us?

Paradigmers, our PAR has set up an amazing study to really focus in on multiple biomarkers. The non HC'ian is generally oblivious to what 008 really is all about, what is it's aims. But Mozz, who cares about another scientific study....well... WE do...because it translates to hard core additional profit for us....yes I know there is almost no connect between our current SP and what we are worth, our potential...but do you really think this silly current SP will be so low always?

We are such a small group ...wait till the real big investors get wind...they will try to acquire more shares quietly...but at some stage the sellers will dry up....and the vast majority left holding shares will be the more educated ones, the ones that can actually wait for years and years and KNOW what's coming (my views).

PAR are also exploring such valuable structural endpoints as well as biochemical markers but look at this endpoint from within our 008 study.:




_{Rescue observation, one of the many Secondary Outcome measures in our main trial.}




What does this actually mean? Lets go through a worked hypothetical example.

Two people, well actually two groups of patients, that both have OA.

Group 1 - Active, they get the real iPPS
Group 2 - Placebo - they get a sugar pill.

Both groups have their respective SubQ injection on the same day....






Both patients still have pain...but Group 1 feel just a tiny something going on, but can't quite qualify it.
Group 2 - Hmm also feel ok...better, umm maybe this drug really does work yeah?





Group 1 - Marked difference, pain has melted away, life is good Group 2 - Yeah I feel ok...pain still there but I'm pretty sure it is better.




Group 1 - Mate life is good, I'm going on another 10 km walk this morning, you coming?
Group 2 - Hmm I'm getting a bit weary...I think the pain is still there, I'm not sure anymore. 10 km walk? Maybe a 2 km walk today.




Group 1 - Mate, this stuff is great, life is good....yeah I'm still doing the 10 kms per day
Group 2 - That's it, I'm out, give me some NSAIDS. and now. The only place I'm jogging to is the closest taxi stand to take me to the Doc's to get me some of that NSAID pain relief. << RESCUE MEDICINE ACQUIRED >>





Group 1 - Gee this stuff is good....but there is some sort of niggling tingly feeling , still dong the kms though...wish I had this iPPS thing a few years earlier!






Group 1 - I can just feel the pain slowly coming back a tinge now....maybe rescue time in a month or two, right?








Ok all of the dialogue above is speculative and subject to trial/study observation etc. This is typically what the Rescue medication observable will strive to do. It will ask the question, at what point does the average Placebo patient have to give in and go back to the (nasty) std of care compared to the Active drug patient? If you can show this is statically meaningful, it will be a big bonus for us in terms of duration of effect and effectively staving off the nasties.

Thrilled? Yes, the insurers and the FDA and EMA authorities will be impressed.
Label? Bring it on.

BUT ...YOU are in a Mozz post, you know hypothetical dialogue is one thing... I love my piccies and charts.


Lets see this more visually....no no no not the above guy's log books....I'm talking their pain/happiness chart!The below is only my speculative musings, while it is not actual data, it is loosely based on anecdotal data. Do not rely on it, It does not mean that things WILL work out like the below (or the above for that matter).





(Single left click to enlarge)

What the heck is this?

This is a separate observation of how long our drug MIGHT last against placebo.. Its the duration aspect of the drug and how long we can stave off patients off the side effect ridden, so called, std of care. Yes it is what we MAY see as a Rescue Medication observation. Orange bars could be our active drug, iPPS group. The Grey bars are perhaps typically, the placebo group. Notice the steep drop off...where ours may plateau and subside much more gradually.




RESCUE MECHANISM - EXPONENTIAL DECAY


So how does this endpoint that we are going to study, work?

Well you take two groups, PLACEBO as well AS ACTIVE (the drug) and you record what both groups are feeling before the trial, WOMAC pain for example. You track this during the study...on average we see some positive effects by about week 3 or so...then it improves and finally plateaus. We should notice a long tail in terms of happiness (Think Quality of life) of an average candidate in the active arm.

BUT for the placebo, yes you will have some sort of psychological impact initially by roughly the same time frames, but what will happen is that the happiness levels will typically decay much more rapidly compared to the active (My opinions).

Another way to see this is via a line chart depicting Exponential Decays...here again is another example only:






I like to think about it as exponential decay...think of it like an egg and spoon race, but our egg is super glued to the spoon, while the placebo guys...they are on their own!


Remember, this is only my speculation, actual results could vary, perhaps significantly. I'm only eluding to what the results might be like and what is the purpose of the inclusion of this observation in our trial. From a payer's point of view, from an authority's (FDA/EMA/TGA) point of view, it could very well be quite revealing indeed coupled with the more empirical MRI/structural and biochemical observations. The complete story could very well be telling.

Lets take a look at the next section for more evidence about why I am thinking what I'm thinking.

BASE CASE

Now Mozz, how are you coming up with this sorta data, granted it is speculative and guesswork... yes good question, lets explore....Plenty of evidence in the veterinary space so far..here is just one example:

1) Pentosan polysulphate injections: Also known as cartrophen or zydax, these are given weekly for 4 weeks, and last for several months. The injections contain a synthetic medication which draws more water into the joints, effectively thickening the joint fluid to provide a cushioning effect. If we can stop as much rubbing between the cartilage surfaces, the cycle of inflammation is interrupted which can delay the progression of the disease. Most owners notice a small improvement, particularly as the level of the medication in the body builds up, typically after injection number 2 or 3. ²

2) We know the pill format of PPS has very different characteristics compared to the injectable version, but even with the Pill format there is ample evidence of safety and tolerability along with efficacy over time (BPS = Bladder Pain Syndrome)"Pentosan polysulphate sodium is an effective oral therapy to control the symptoms of BPS with good long-term efficacy and tolerability". ³

3) We've also had a number of accounts over the years right here at HC. As a rough average the point of initial efficacy in terms of pure pain begins around that 4th injection. Harder to get an average sense of how long the wonderful effects last but from the few people I've managed to chat to it seems like the average duration is around 9 to 12 months. Don't forget, there are cases where there have been little impact to pain and there are cases where there has been NO pain for 4 years (@Happell, you are my go to).



THE ALTERNATIVE MAKES ME SO SICK

So in theory, we may see that the placebo guys drop off much more rapidly in this so called "Happiness" level, what I mean here is basically pain...

If I have a lot of pain, I'm not happy, I can't do my work, I can't do physical stuff, I can't sleep at night, I'm stuffed and tired and on top of that I'm in pain..some days more so than others....AND I'm sick of these crazy NSAIDS that I have to keep taking. I don't want to go near those opioids that are looming...

Fairly new to us here at PAR-HC land? A question to ask here is what effect does iPPS actually have on some of those above factors, walking, day to day functioning and the important one, SLEEP at night! (Mozz love's his sleep, 7 hrs and 25 mins a night? That's my optimum. Give me that and I will continue to post week in, week out).




<sub>Less than 6 hrs - I'm not your friend
7 hrs 25 mins - perfect
8 plus, must be a Sunday or a Public Holiday





Announcement - 3rd Feb 2021, Pain at night = highest scoring cat. Merits of proper sleep/rest at night are invaluable. Many of the body's processes are dependant on this ONE category! 64.6% was mean reduction of pain? Awesome.</sub>



SO how long do the effects of NSAIDS last⁴ ?
Take a look:






The above sounds a bit too frequent for me ,specially now that I know that one day we will have a much better ...safer...drug out there...



So how long do Opioids last? Do we really need to go here? ⁵




Some 90,000 deaths per year and specifically some 16,450 deaths due to prescribed deaths just in the USA last year alone. ⁶


So now ask, How Long does Pentosan in SubQ format last, this is the durational aspect we will be studying...The rescue observation will certainly be a other insightful indication to be explored.




CONCLUSION

A play in the Bio Pharma space is usually not for the feint hearted. It involves a number of skills and I'm not even talking about the company itself..I'm talking about us as investors!


- Fortitude

- Patience

- Understanding


Yes we all get frustrated when we know the potential, the science speaks volumes, the patients are shouting from the rooftops but our stupid (yes I want to use harsher words but @oxxa23 will have a field day not to say anything of the watchful moderators...)

IGNORE the disconnect...think of not now....think of the future..... Par is not a company that is sitting idle at times while they wait for FDA ...this is a proactive company....in my humble views there have been delays and have been times when we could've wanted faster outcomes... but they have more than made it up by their brute work ethos...their thinking outside of the square and their wonderful expansionary programs.

The Rescue observation is just one such subtle example of their attention to detail...are we truly aware of all that is going on in the background? Can we expect more glorious surprises from PAR during this amazing journey?


In my express views, they are killing it.



More to come.







REFERENCES

1) https://www.oxfordlearnersdictionaries.com/definition/american_english/rescue_2#:~:text=rescue-,noun,given%20up%20hope%20of%20rescue
2) https://www.monbulkvetcentre.com.au/arthritis-in-dogs-and-cats/#:~:text=Pentosan%20polysulphate%20injections%3A%20Also%20known,and%20last%20for%20several%20months
3) https://pubmed.ncbi.nlm.nih.gov/21470538/
4) https://www.getreliefresponsibly.com/use-pain-medicine-safely/adult-nsaid-dosage-chart
5) https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf
6) https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm
7)https://pubmed.ncbi.nlm.nih.gov/31066021/#:~:text=Introduction%3A%20In%20clinical%20trials%20for,the%20robustness%20of%20analgesic%20effect.