was a three movie series from the 80s and who directed it? None other than Steve Spielberg. A complete classic...
Ah but what does it at all have to do with us then?Well that series of movies had three parts...tonight we also look at three PAST positives and how they may assist us going FORWARD...
You know, I like the cutting edge latest reports, the papers, the studies. Reading the very latest findings in the OA world. But sometimes its just good to go over some of the older stuff to see where we have come from and what our science has said in the past.I really starting severely increasing my stake in PAR via solid iPPS research, just in the last two years. Back in 2018 Dec it was still fairly early days for me in terms of following
every announcement and
every lead though I've been a holder since IPO back in 2015.
But guess what, just the other night I was reading a past announcement that I hadn't really paid much attention to at all...this past snippet made me think that hang on, the future could just be a smidgen brighter than I originally thought.
Tonight, we go back in time to project our future with not one, but three potential positives... why our P3 results may actually be a bit better than what we have seen in the past to date.
Do enjoy.
Normally when you design a trial you want it fairly broad, you don't want to narrow it down too much. If you do, yes you might get a better honed result, it might be easier to get your desired result, but this limits you. Remember, its finally all about the approved
label. Too many companies are in a rush...they want an outcome soon and this comes at a cost of having to do so much work later on even further delaying the ultimate goal; meaningful revenue.
Yes sure later on docs can prescribe off label until more data is out...but at least initially, specially for a new drug, even if repurposed with a different mechanism of action, they will be reliant on the label, certainly the insurers will also be somewhat guided by what the agencies agree to.
So we don't want to go too narrow...but if one can eliminate lower classes of efficacy, then we do that by having exclusions.
Background out of the way, lets get to the three positives.
In a lot of cases, in terms of medicines, you want a consistent picture...you want consistent data. I don't need to impress upon you just how important consistent batch to batch sampling is. The FDA will only grant you a GMP if you can prove that your sampling is perfect batch after randomly audited batch. This normally would be a big part of the next step for us, working out manufacturing, ensuring that it is at GMP standard and then having provisions in place to ramp up and scale like you wouldn't understand.
We already have this well under control via our pals, Bene.
Sure starting off small but having to cater for even a tiny sliver of the OA market...lets go ultra conservative and say just 5% slice of the OA pie...in the USA alone this could be as much as 32 million x 5%...a massive 1.6 million patients...lets please halve this again to be further conservative....800,000...multiply this by up to 12 doses....you get where I'm coming from.
What about, simultaneously, in Europe? The numbers add up quickly.
Self Injector production is large scale these days with a number of medicines coming out in this format. 1 The same consistencies are required in terms of drug effect. Show consistency amongst the studies and trials and you have another big hurdle out of the way.
Paradigmers, lets take a look at our SAS results in the three batches that were reported on over time.Thanks again to our man in the west for highlighting this one for me.
I want you to note two very important points with the above table/chart.
A) Consistency - all three batches around that 45 to 49% level.
B) Improvement - progressively over the three accumulated patient numbers.
The figures are getting BETER over time. How is this possible?
Its only because of the following possible factors:
PAR learnt
what can improve the figs via the questions being asked of the patients,
how they were asked and PAR learnt a bit more on
whom should be excluded or included.
Just before we leave "Positive 1"...lets just go back again in the past, rewind to R & D Day 2019...
Dr Donna commented,
"Pain studies can be very challenging in terms of placebo effects" ...were her exact words.
She went on to say that..."... the CRO has worked with us to actually subcontract with a group that specialises in training of the patients and how they understand and answer questions about pain, they train the physicians and the sites about interaction with patients that do not lead to expected responses. And so this is a very specialised area in evaluating pain and controlling the placebo response."...and she further added..."...the CRO we have selected for OA is really top of the line for this kind of study".4These learnings will have been incorporated into the protocols for Phase 3. The results here compared to Phase 2 should be an improvement. Don't forget, the bulk of the SAS program took place after P2.
We know the SAS read out was a great result was a great read. The final batch announcement came out back on the 3rd of Feb last year, 2021.
For those that are new to us and haven't gone back through our previous announcements, here is a recap:
Just look at that green arrow, an amazing circa 60% reduction in some categories, this by itself is wonderous, add in the multi decade safety profile and it becomes compelling.
But wait...lets just step back to that pic above for a sec, did you guys notice this, the red circle:
Paradigmers, here is the positive for us. Despite the above great results, that (12 weeks)
wasn't the single best point in time...it was actually Day 53 (Week 8). This is what Phase three will utilise.
Have a look below. Thanks to
@teddywestside88 for his assistance with this point.
Mate, the green arrows above depicts even better results, yes this has been incorporated into the P3 (See below), in fact it has been tweaked to Day 56. In the 4-6 KOOS stratum it works out to be around a 20% increase in mean change between week 12 and week 8.
Paradigm's Phase three protocols. (Single left click to enlarge).This alone should boost our P3 result by some factor.
Back to the Future came in three instalments, tonight I give you the third positive in terms of why our P3 might just be a fraction better than the results we have seen to date.
On Dec 18th 2018, PAR announced the great results of Phase 2 OA. A number of months after that Morgan's retorted by saying that while the P2 results may be ok, there is some evidence that the drug wasn't so good at higher stratum of pain participants. At the time I wasn't sure about what they meant. Now I know.
However, certain analysts at Morgan's are heavily biased against us in my view. They do not understand what the data means and the great ramifications this might have going forward.
Lets explore this.
Paradigm stated the following back then:
But Morgan's misinterpreted this. They incorrectly surmised that the drug isn't as good as what its made out to be...they falsely proclaimed the overall results aren't great.
In actual fact PR said this as well:
But PAR did not hide this, they were transparent, they concurred that the placebo effect/result in the higher stratum was also high by stating this:
All very good Mozz, thanks for the history lesson, but I don't get the big positive you are inferring?
That's cos I haven't stated it...here it is:
PAR folk...Paradigm used P2 as a learning exercise. They learnt a lot, they learnt more about the placebo effect and how it pertains specifically to us...they learnt what the best single day was on average to take to results from...but not only that, they also understood which was the best stratum of pain. Yes it was KOOS but its translates to WOMAC.
What I am saying to you is the Phase 3 results might just turn out to be better than Phase 2.
How?
Because in the top stratum of pain they had a higher placebo effect. PAR learnt that if they remove this stratum and focus on the best (4-6 KOOS) stratum then the lowering of the average due to higher placebo effect in the top stratum of pain will be somewhat mitigated:
In their words, my
orange emphasis added:
"The company is currently evaluating the full trial data for secondary endpoints to form final conclusions in this stratum (joint functions scores, BMEL Volume as per MRI and biomarkers). Based on what is known about subjects with severe chronic pain in clinical trials, combined with the Company’s own data it is likely that NRS Pain = 7+ subjects will not to be included in the Phase 3 study design, thus indicating that a phase 3 trial would likely return even stronger results than this trial by focussing on the moderate pain group i.e. NRS 4-6".EVEN STRONGER RESULTS in a phase 3? As a LONG term investor, it is this that I want.
Needless to say, I await the results.
Fellow investors, yes think carefully about your exposure and if you have enough (my personal views), sure, be comfortable with what you have...in my humble view...this is the time to review....for there are a LOT of exciting events and milestones to come in the next few months and years....review and contemplate....otherwise you too may just be....
DYOR
1] https://www.healthcarepackaging.com/machinery-materials/automation-robotics/article/21121179/burgeoning-autoinjector-market-demands-flexible-production-options
2] https://app.sharelinktechnologies.com/announcement/asx/4e6e9a6094fe8df04ee2 20205ba70966bda33]
https://clinicaltrials.gov/ct2/show/record/NCT04809376?view=record4] Paradigm R&D Day Presentation December 21, 2020 (1 hour 14 minutes 43 seconds mark)
(20min delay)