ndeed exciting times...
More so aimed at the new investor and new poster to PAR HC...we are at the gate...we have a golden ticket....the security guard is checking their screen....we'll know in 30 days or less if we're in....please enjoy:
VERY FIRST STEPWell the next thing for us to do now is....wait...
What, not more waiting...err yeah, get used to it...there will be a few times when nothing seems to happen....more on that later. The very next thing for us is to wait for either three things to happen:
A) We hear back from FDA within 30 calendar days....it could be sooner, next week...it could be in 2 weeks...it might not be at all!
B) If we don't hear back from the FDA then after 30 days (actually will be 31 or so to cater for time differences) we are free to start on our Big P3.
C) Clinical Hold is enacted - small chance but the FDA may want to ask us further questions or get something clarified...in which case everything is halted while we answer them and they question us.
NEXT STEPAfter that we are free to start in earnest.
Mate...the IND is OPEN and we are officially a GO...no R%ckets yet..that's for later...but it will still be pivotal...it is this point when we surface on a number of new radars and some of them will be big..think analysts and instos the world over...they will now know that we have passed a big hurdle of getting to the starting line of a P3 by the FDA...
Mate, just getting here was a big tasks of some 30,000 strides pages!Incidentally, don't forget we are also in harmony with the EMA...yes Europe...two massive markets at
once...in synchronisation....this is big news.Ok so where to from here Mr Mozz....ah that's easy...a study within a study up next:
DOSE ME UP BABYWhat is a dosing study? Why is this needed?The FDA have specifically requested us to do this first ...the aim is to find the minimum effective dose. What is the least amount of drug we need to subcutaneously inject into a given patient for our drug to work.
Why do this? Well really the aim is safety...I also suspect the FDA are well aware of HOW big this disease is globally...how many are affected...iPPS has the potential to make a real difference here to so many patients so the FDA are at an even more heightened sense of safety and this can be focused on by such a dosing study.
My second rationale for why a dosing study is required is to do with the Bell curve...this is not a drug (like most drugs aren't) that forms a linear path in terms of efficacy. Ie 2 mg/kg might be more effective at 2 injections per week compared to just 1.5 mg/kg with the same injection frequency...but this does not follow all the way up to 5mg/kg or 10mg/kg etc....it cuts out at someleveland in fact there are studies that not only show that the drug efficacy falls away at a certain level, it MAY become counter productive at higher levels.
Less this:
More this:
There will be basically four groups of dosings to kick off, we are looking for the minimum effective dosing regime, let's take a look.
2 mg/kg twice a week for 6 weeks
2 mg/kg once a week for 6 weeks
2 mg/kg less than once a week for 6 weeks
Placebo
Now the good thing here (as Scott Williams recently pointed out), usually we see AE's potentially as the dosing gets HIGHER...eg either at a say 5 mg/kg or perhaps it is still the 2mg/kg dose but increased frequency like 3 times a week etc...In the above dosing program we are to utilise LOWER dosings/frequency than what we have utilised in the past, so chances of AE's are
lowered.
Indeed we are within our NOEL
1 limit which stands for No Observable Effect Limit as evidenced by the toxicology studies already performed on animals. These toxicology studies are just one chapter submitted as part of the IND dossier. It is also possible that the lower doses will not demonstrate the levels of efficacy seen so far in our 2B and SAS results to date, but as Paul has said, these still need to be tested as required by the FDA.
Of course the less the required dosing, the better for us shareholders, again as Paul recently stated, it would serve to give us the same efficacy with less raw material. Not sure on the chances of this, there will be a trade off at some point, ie the bell curve. There might be some chance of a slightly reduced treatment regime for close to the current levels of efficacy...don't forget, a slightly favourable outcome in this area would make a difference of potential millions of dollars for us.....How?
Volumes in the future as well as Doc's time and payer's rebate levels over a number of future years of treatment, globally. Of course the current regime of 6 weeks of bi-weekly dosing at 2mg/kg will still be lucrative if we find we are already at the pinnacle of this observable bell curve.
NEXT STEP ?Once we have the dosing regime determined (we will not get details of what the determined optimal level is to ensure integrity and non biassing of future patient trials), the next step is then to begin recruitment into the MAIN trial...this is known as 002, also known as the Pivotal Clinical Trial.002 will kick off if all goes to plan around Q3 2021. While a statement/term like 'Q3' often seems ages away (at least to me)...it's 13 weeks from now.
Follow on study is 006 and that kicks off at the end of this year...Now there are a few combinations that will get covered here and no doubt this has been expressed as a complex flow chart somewhere in the depths of PAR HQ...you have combos like the first group who were on placebo in 002 will now cross over to 006 placebo....or they were Placebo in 002, now will get the real drug...ect etc
Here is a really simplified Mozz version:
Simplified Mozz version, note: not official in any sense of the word...for illustrative purposes only.So don't forget, this is not just a simple 4 way combo:
P - P
P - R
R - P
R - RKey
P = Placebo
R = Real dosing of iPPS
(Patient one has placebo in 002...then goes into 006 and has placebo again, this is represented by
P - P)
You need to also throw in the varying dosings in here too...add another factor such as dosing and all of a sudden you have many more combinations, all of this data gets compiled at the end.
CLUESYou get a sense that PAR really aren't doing the bare minimum, they are being very comprehensive and thorough. WHY? Why do this when it adds just so much time,..and so much cost....why bother getting it all verified and asking the FDA if we are on track?
It is for the future...it is ultimately for the broadening of the label...yes OA is big but a single trial might still result in a narrow label, you achieve a broad label here and mate, the numbers will be even more amazing, the numbers will multiply out. It's not just about the economics though, it is broadening the numbers of people that are eligible for treatment.
You show the Docs, the front line medicos, that this drug works...
that this drug works and it works well
that this drug works and it works well AND its safe
that this drug works and it works well AND its safe AND it can be used in multiple joints and MULTIPLE indications...you get the picture.
We need all of the above and it has to be statistically significant, clinically meaningful, better than placebo and also be consistent, thank you very much. We tick these boxes...
The TIME to do this painstaking work is NOW...its not after Read Out as an afterthought or after we start selling...its too late then...you don't easily build a two storied building on a certain foundation and then modify it by placing steel girders all over the place to get another couple of levels on top...nahhhh so much easier to pile drive first...takes ages I know...but the strength is there for future expansion, hands down that's the way to go to ensure a brighter future!
Now all of that is great...and it's a hurdle in itself...but you do all of the above AND IF you get ANY potential DMOAD....(Disease Modifying OA Drug)...then to me, this equates to the entering of WARP Speed ...yeah that's the bit where all those little twinkly stars becomes one long line and we travel at the speed of light.
DMOAD result will have this effect on my brain... Ok maybe I'm getting a touch carried away but the subsequent action in terms of:
Share Price
Exposure to new eyes
Write ups in scientific and other media, global type exposure
Mozz's Heart beats
...will be GOOD....will be exhilarating...
That's my point.
This step for us is called 008...there are two readouts to come, one interim around Q3 (yeah, that's the slated 13 weeks from now, can you believe it?), maybe let's say late Q3/early Q4...and then the final read out in 2022 maybe Q2/Q3.Not far away at all and this in my books will have
huge ramifications and will make these eyes of many new to us and large to us (instos) pop and wonder
how they missed buying into us much earlier??? Any of you reading this here post are already so much ahead of the curve...my views.
NEXT?Well the P3 commences, after 002 has started there is an overlap and eventually 003 starts, that's the confirmatory trial.
Left click to enlarge - 002 and 003 overlap.
Left click to enlarge - 2023 super busy time...Now when I look at the above pic I start off with MIXED feelings...
THE SLIGHTLY DISAPPOINTED MOZZ FACE:
Slightly disappointed because it is so f a r a w a y! Blah...2023 isn't any time soon....
THE VERY HAPPY MOZZ FACE:
BUT I know this is not ALL Paradigmers, mate the excitement is beginning and yes it stepped up today and there are parties all through this program up to and including 2023... let's explore...
PARTY 1 008 to the rescue. In some ways, perhaps not totally, the interim and final read out of 008 will be magnificent and could possibly be in the same vein as the P3 readout itself? It could potential show for the first time ever that we have the power to halt, slow down and modify the trajectory of OA. This intitself is Gold...pure Gold to the share investor, to the future patient and of course to the authority...they will sit up when they see this data come out....and imagine it does it safely with little to no ramifications/dire AE's. Incredible is the word that lights up in my brain.
PARTY 2 Sure Party 1 is a big one, but there are other events, not limited to the potential of a regional deal, it's possible, sure the chances increase a bit more once Party 1 takes place....think of Party 1 as the start of a chain reaction...glorious. Imagine Japan works out for us later this year...it makes a whole heap of sense to me to do a regional deal of this nature, you can't tell me the Chinese aren't sniffing us out indirectly, just pray there is no hostile or big cheque offers...
I really don't know what it would take to persuade 51% of us to move...hopefully if this happens it is high enough...this could be the single biggest risk going forward..holding firm, knowing what we have...easier for you and I to know this, harder for the rest (apart from those really well informed or connected to the company or instos) to know the potential, I know a lot of them would be naturally in it for the quick buck. If we get taken over for even $2 Billion, it would be a sad party...yeah we'd get a pay out but GONE would be all that amazing incredible future revenue potential...going from market to market..indication to indication....oooh Dividends like Scott laughed about....Wiped. That $2B would not be near enough.
PARTY 3 Other data along the way such as a Twins (RRV/CHIKV) tie up for P3....perhaps more data on Heart...hey, DOD deal for P3 funding?
PARTY 4 MPS Program, are we forgetting about this one? Did you know we already have three patients with the first one probably hitting what, week 13 already? This is ongoing in the background and read out here might be sometime in 2022 !
PARTY 5 Mysterious party, 3 new repurposed drug potentials?
LABEL ME AND AN ACCELERANTOk Im feeling a bit better now, I know that we are a ways off of the real pointy end of the trials...again as Paul explained just rencelty, this finally has a lot to do with the label. That's the important part that allows us to be officially prescribed for a certain condition, in our case Knee OA...but there is the Hip study and of course 008 that we will eventually add. I believe 008 will require a separate clinical trial but that's to discuss in another post.
From the end of the P3 which results in a Read out through to the Registration can actually be as much as a year... BUT as our CMO has stated, PAR intends to apply for a Fast Track designation and this could speed things up, particularly in this last stage...we could knock off as much as 6 months in this process.
A further accelerant could be a different designation in addition to a Fast Track, perhaps a Break Through or a Priority. Empirical data from 008 has the potential to formulate a 'Breakthrough' case (my views). Certain extension studies like 006 will still need to take their course in terms of time. Such possible designations will give us a stronger focus, a separate review team from the FDA and will assist us in cutting at least some days off the overall program.
FINAL THOUGHTSThe beauty of this entire situation is that we are going to make some really big news going forward....we can tackle OA in so many ways...multimodal indeed...and this is the key to success...we will see the buying pressure increase, gradually...gradual is better for us as those crazy huge spikes in share price can be fun and thrilling but what goes up usually comes down at least a little at some point...a gradual building albeit with some dips and corrections is more healthier...and by stealth it will happen.
I say 'by stealth' as we may not even realise that retail are selling out to the accumulation of those really big hedge funds over time, and that in my mind will take place more and more frequently. It's times like this I'm glad there are only 229 odd million shares on the register...it sounds like a lot but for a company with our potential, you'd be surprised at how it's not really all that many....
As a few others have commented, it's cheap...it's oh so cheap...completely my views...but once others start learning and acquire a depth of knowledge that's even a fraction of ours....watch that pressure build. We are in for some fun times ahead my hearties.
DYOR, spec comments and views expressed above.REFERENCES1] https://www.zeomic.co.jp/en/glossary/antibacterial/40#:~:text=The%20NOEL%20(no%20observable%20effect,adverse%20effects%20on%20tested%20animals.
2]
https://www.medicinenet.com/script/main/art.asp?articlekey=98773] https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
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