The Phase III Primer!

ell, it's been a long time between drinks.

What I mean by that is that I had covered what a Phase II entailed a long time ago. Finally, we are a genuine Phase III co. We have the green light to start...we are kinda just waiting for that official ASX ann of first patient dosing which should come quite soon.

But I know there are a number of new guys to us that don't know all that much about what a phase three really is and what it means for you and I.

Tonight, let's cover this phase of PAR's life, perhaps as a primer to the upcoming webinar for those that don't know all that much about what PAR and a Phase III actually entails.

Please tonight, enjoy.



THE PHASE THREE

A Phase three is the last real stage of a clinical trial program. (There sometimes is a stage IV but that's often post licencing to build up additional 'surveillance' data).

To make it to this stage III, it is a testimony to Paul and Co. The percentages aren't good for getting to the starting this stage AND it's even lower in terms of how many Australian companies make it onto the Phase III world stage.

Here is a very generic look at how hard it is to make it all the way through to approval ¹:

As indicated by the purple columns, it's getting harder to make it through all the way...



But what is the purpose of a Phase III? It's designed to test and observe how effective a given drug is. But it's more than just that.


It confirms efficacy

It seeks to determine this efficacy at scale

It compiles data to assist in labelling


Typically, a Phase II is more about confirming safety and usually it numbers in the hundreds. It's in a Phase III that typically the study looks at how the drug performs in the thousands of patients.


So why are our patients numbers so low?

Ahhh this is what I hope to hear more of on the upcoming Webinar - It boils down to Statistics.



OUR HISTORY



At a high level, and certainly not covering all the gory details and focusing more on the Reg and Clinical side... we basically performed two Phase two studies, namely 005 and 008.

005 back in 2018, had around 112 patients double blinded and had an emphasis on observing pain, function and other secondaries like BMELs.008 was a lot smaller with three arms but only a total of some 60 patients. In the 2x2 dose (see below) we had just 15 or so. Yet, this study was highly exemplarily achieving statistical significance or very close to it, on a number of endpoints and observables. That wasn't really supposed to happen. It was only supposed to be a study to link Synovium with Serum.

it did so much more than that.

While that was going on, PAR had to do a dosing study as part of the trials. This took time and effort and yes, expense. However, while that was happening, we were getting the results of the 008 program at 6 month and 12 months. Because 008 was so amazing, PAR spent the better part of a year pursuing the FDA to get the original Phase 3 design changed with revised protocols. We will hear more about this later next week. Just one example was a change of the primary measure. It's still Pain but instead of WOMAC, it is now ADP.

Two Mozz © notes here before I go on:

1) WOMAC is still in the picture, it is now a Secondary
2) Aren't PAR taking a big risk by changing it to ADP? Well no...for two reasons:

A) I believe it is the FDA that have worked with PAR to incorporate this into the revised P3

B) ADP measure works better when a trial consists of only a Placebo and an Active, as opposed to a Comparator and the Active. (That's when Womac may become more insightful or deemed to be a better measure in pain trials). At the end of the day, we want good Patient recall and consistent observations, ADP may do this when there is no other active. It has also been said that ADP can remove some of the 'noise' that WOMAC may generate. As a final point here, there is also some evidence of pain measures such as ADP working well with other measures like Rescue Medication, see also below ².

It has a lot to do with Patient recall of pain. We may hear more about this in the upcoming webinar.

Anyway, so PAR did the hard yakka and changed a lot of the protocols. It reminds me of how insightful they were with the 008 program. Remember this program too changed mid-stream. That was hugely risky, adding a new arm, adding a new site and extending out the 008 trial from 6 to 12 months. That cost us.

It cost us time, it cost us money...it elevated our risk. But at the end of the day, so prolific this program was that it gave us the one thing that will literally accelerate our future revenue curve...

It achieved, after at least 9 to 12 months and at the price of a number of us getting frustrated and having to further support the Co. with cash mind you....it gave us an Upgrade.A lot have also forgotten or don't realise all the events that also happened including as part of the 008 program the insightful Canine study.

Take the briefest look at just one subset of info from the Canine Study:


Mate, I could do a separate post on this one massive announcement alone, but in the chart above, take a look at Cartilage Volume... there are a number of points to note in just this one chart:


A) Active goes the opposite way compared to Placebo over time.

B) See that Week 26 above? That's NOT actually Week 26....that's THREE YEARS!....Yep, in human equivalent time. You are literally observing what iPPS does over a much longer duration of time. Can you just imagine the readout after Day 404 in our P3? That'll be just one year...imagine the headlines at three years?

C) A third amazing thing to point out in the chart above is the Effect Size...Yes it was great to get a LARGE effect at Week 8 (Canine time)...but look at the Three year mark (Human equivalent)...it's still a medium effect even out to then.

Yeah PAR mixed it up in this ann by reporting on the Drug Effect Size rather than the P values. It was a nice change.

I know this post is really aimed at the investor that has joined our ranks more recently, but c'mon, even for a longer (crusty? ['seasoned' is a better word]) PAR investor like me, that's amazing to revisit this sort of data again! Mozz note: There is much more incredible data in that Canine Ann. Want a read? Try Reference 3 below in the Reference section if you are new and are interested.

Yes things take a long time. Yes it can be frustrating waiting for revenue...waiting for the next milestone! But like counting the days for a massive new building to rise from the foundations....well, one day it's going to happen for us (DYOR).



Mozz mate, wake up, PAR is starting to move... (upwards!).



A lot of data from these studies were used in the formal application to modify the P3. This is the sheer insightfulness and indicates the long term nature of PAR. A lot of companies firstly wouldn't have bothered to do these ancillary studies and would just be content resting on the laurels of Pain and mere Function.




This is SO not PAR staff...they have worked harder than any staff I know...
Once we achieve stardom, you and I both need to sincerely thank them!




PAR knew it would cost them in terms of time and money and effort...but they did it anyway to sure up the long term future. Once they have this P3 out of the way, it will be so diamond hard robust. Tell me what deal we will get after a snippet of this raw evidence at scale? (Speculative statement, subject to passing a P3).


Just take a look at the below 008 data...⁴



Take note of the Purple and Orange indicators (Mozz drawn)...Purple is the result at Day 112...that's also our upcoming Interim readout day number! The orange circles show the lovely separation we achieved. This would be lovely anyway, but made all the more sexy because it occurred in just 15 patients.

Fifteen patients.


Our P3 active cohort is some 15.5 times that!

Hellooo, anyone...what will our p values be like then? After n = 233 or even n = 466. Mate.

PAR were also asked by the FDA to have a fairly aggressive monitoring process put into place with 002 (The original Phase 3) Part 1 process along with a number of other clinical and non-clinical data submissions. It was a long process.

I often wonder why the FDA made us jump through so many hoops. My main rationale is because they know or at least suspect that if we are indeed as successful as we purport ourselves to be and the drug sails though, the uptake on this medicine is going to be something.



THE UPGRADE

So what's all this about an upgrade?

So important this upgrade is, I had to include it in a separate section to draw attention to it. I will never forget this point.What was the upgrade? Adding structural endpoints that were observables in the 008 and converting them into SECONDARIES in our Phase III. This will never be lost on me. So important this is, as it will go onto the label once we pass and get a license.

This, as I have stated before, gives us four things, four golden keys



1) Potentially higher charge for the drug as it is now DM.




2) Better Market Penetration rates...patients won't just take this to address and alleviate pain, they will take it for two separate other reasons:

A) To halt or reverse the course of the disease
B) As a potential prophylactic, to ward off the disease before it takes hold. Eg Tear an ACL? Take iPPS to arrest further damage along with repair. Some may just take it to improve the inherent quality of cartilage and their joints! Some may take it as the know in advance that they are loading their joints excessively.




3) Better Insurance cover from payers




4) A better BP (Big Pharma) distributional deal


Most investors don't understand what the potential really is here. They see daily, the disconnect of the share price. They see that after every piece of good news we fall back into a rut in terms of the valuation. This cycle will break one day. Yes it might take some pretty hefty milestones to be achieved and certainly a commercial validation...but this day isn't, at least in my eyes, years and years away from now.


WHAT ARE THE SPECIFICS FOR US?

In a snapshot, let's take a look:

n = Number of patients to be dosed = 466
Arms = How many groups are there? = 2, Placebo and an active
Dosing = 2mg per kg, twice weekly
Sites = Around 65 spread across USA and Australia
Harmonisation = This isn't just the USA (and Australia), if we get a license, it automatically gets granted for Europe, UK and Canada.

PRIMARY Endpoint = Pain
SECONDARY = There are a few, let's list some of them :

Validated measures of pain and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
> 30%, > 50%. Pain, Function and Stiffness measures
Patient Global Impression of Change (PGIC).
Rescue medication usage.
Structural joint assessments via MRI and X-ray imaging.

OBSERVABLES = Included a number of Wet Biomarkers (see Appendix A) and Time off work measure

...and a number of other variables.

Note: At the time of this post the clincial.gov website was down for maintenance so I actually couldn't pull all of the Secondaries!



STATS

Statistics plays a huge role here. Ultimately what do we want? We want to pass our Primary and a good lot of our Secondaries. The way the stats work is that the best chance of success is at the end of the 12 months...we get to see how the two cohorts performed against each other. We are looking for two things here:

1) That we attain statistical significances on the measures and...
2) We achieve a clinically meaningful figure!

Those two above point go hand in hand, one without the other isn't great.

However, we have built in, an Interim Readout.

So the Interim Readout occurs when 50% of our patient numbers are at day 112, so our full n is 466, half is 233. So that last 233^rd patient, when they finish 112 days after their first dose, we then collate all the data and have a top line read out. At this stage, it is supposed to happen by about mid next year. However, if we get p values at 0.05 well that's good, we can no doubt continue, what I hope to see are p values UNDER 0.05, hopefully a lot under.

There is a fair bit of past evidence that alludes to this being a possibility, albeit perhaps a small chance because the hurdle is fairly high. I hope that PAR talk more to this on Thursday at the Webinar.



CONCLUSION

A phase three is a big one for us. We have done really well to make it this far and we have backers to enable us to progress at least until interim. Certainly if that interim lives up to the consistent results we have seen in past studies, well I think the future is going to be quite bright at or just after that Interim point. I really don't see any hurdles left after Interim! You get a fairly good result in 50% of the Cohort -v- Placebo and theoretically the end result should also match!

I'm very impressed with PAR they have such a comprehensive P3 program in place. The endpoints are broad. They don't just cover symptomatic endpoints, they are looking at structural as well. They aren't just covering one small slice of the Bipeds (See Appendix A), they are looking at a cross section. The proof is in the pudding, the stats are resulting in a very low n. As an investor, this gives me confidence.

I'm keenly waiting for this Thursday to hear more about the protocol changes and the probabilities of success...to garner even more colour about what we are embarking on...


...the final, most exciting, frontier.


The Phase 3.





- Mozz







DYOR implied





.APPENDIX A

Bipeds. The full form is Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic. These are markers, think of them as indicators of how your disease of OA is progressing or not.

So, for example, you could record, CTXII. (I chose that as an example quite deliberately as it turns out that this is one of THE most prognostic (Predicative) of all OA Biomarkers)! Mozz Note: Are you super new to us? I mean like you have joined us within the last 6 months, I have a special for you, see Appendix B, a totally must read if you are brand new to us.





THE BIPEDS


I've introduced those little red stars to indicate that we have seen these biomarkers work in our favour after administration of PPS/iPPS.

APPENDIX B

CTX-II. It's beyond the scope of this post to explain too much about what exactly this biomarker is, I will do a future post specifically on this Biomarker...but my point is, to be truly successful, we want a super educated patient and her/his Doc to do a test:

1) BEFORE admin of iPPS, we want them to do a baseline measure of various markers not unlike CTX-II.

Then we go to step 2

2) Take the full 6 week course of iPPS

3) Then re-record CTX II and other markers to see HOW iPPS has helped (Apart from the obvious PAIN relief, FUNCTION improvement...and that last one, STIFFNESS improvement)!

If the levels of CTXII drop, we are good to go, the patient is not only happy that their pain is dissipating and they have regained some of their joint function back, BUT, their future levels of degradation of the cartilage maybe be arrested. Now you start to understand that charging them $2500 USD may not cut it, get a genuine DM and you are $3500 USD plus.

New investor to PAR, don't fret, the ultimate patient doesn't pay for this out of pocket, the insurers pay. Why, pretell, would they pay? Because they are deferring/totally mitigating the artificial knee (hip) implementation, thats costs them upwards of $50 K USD. To spell it out, they pay just $3500 USD and save a sh!te load of payouts...rehab expenses...it would be a no brainer for them.



All very good Mozz, but wouldn't it be so good to have an EARLY read on what the levels of CTX II typically do AFTER iPPS treatment?

Wouldn't it be so nice if iPPS Beat the Placebo result in terms of CTX II levels....

I will go you one better:

How about this one new guys:


Yes, correct...Not only iPPS has a better CTX II result than Placebo...THEY GO THE OPPOSITE DIRECTION!
The Placebo cohort continues to disintegrate their cartilage, but the iPPS group REVERSE the levels of CTXII. The cartilage reduction is getting reversersed!

Did you notice the p values there? That indicates Statistical significance but on a totally crazy LOW n. Bump up the n, keep the Drug Effect size CONSTANT...the only thing that has to change, that will change is the p value...it will go down.

In case you don't know why I'm getting somewhat happy (excited) that the p values will go down as n goes up by a factor of 15.5 is because it could end the trial early.

That's not advice, maybe there is a lower chance/risk of that happening than I purport. Yes, DYOR








REFERENCES


1] https://www.norstella.com/why-clinical-development-success-rates-falling/
2] https://pmc.ncbi.nlm.nih.gov/articles/PMC8861226/3] https://app.sharelinktechnologies.com/announcement/asx/179203e8333a569490127ab50f672deb
4] https://app.sharelinktechnologies.com/announcement/asx/76393c2170325bd8cd425f9c4d0ffaae
5] https://southernstarresearch.com/guide-to-clinical-trial-phases/#:~:text=The%20primary%20objectives%20of%20phase,standard%20treatments%2C%20to%20continue%20monitoring
6] https://pmc.ncbi.nlm.nih.gov/articles/PMC3601706/
7] https://www.fda.gov/patients/drug-development-process/step-3-clinical-research8] https://www.oarsijournal.com/cms/10.1016/j.joca.2021.11.001/asset/8c8a385b-eaa1-4662-b6d5-c8ce6b80ac58/main.assets/gr1_lrg.jpg