DAY 112

DAY 112 - PART 1



onight, a very specific post on Day 112. What does it mean, what evidence can I find, what might Mid Next year look like and do we have to wait that long?

Do now, please enjoy.






THE SHIFT

Paradigm Biopharmaceuticals of Australia used to be just about merely Pain and Function. The word 'merely' is kinda misleading as a drug that's safe, effective, and that's durable and that materially decreases pain and improves function isn't a 'mere' thing! There are NO drugs out there that decrease pain safely is what I'm inferring here.

But PAR have shifted. This post is more about the shift to Day 112 but if you are new to us and don't know a lot about what we have, know that we have also shifted from Pain and Function to now incorporating Structural modifications and potentially, disease regression. It is a big shift in that sense. Paradigm spent the better part of an entire year to incorporate revised protocols which were recently accepted by the FDA. It's a massive win for us.

I've already stated it a couple of times but again, most have no idea that positive structural markers that were always only ever mere observables are NOW FORMALLY Secondaries. I'm guessing there is at least a good 55% of readers here that do not know the difference. A Secondary, if achieved, makes it onto the label. Who cares? Who reads the label? The Doctors and the all powerful American (and Australian) Medical association (AMA), it is these guys that commend iPPS to the General Practitioners. Thats what will result in extra Billions for us one fine day. Remember, most Docs are simply guided by what appears on their PC screens. Most don't research iPPS and what it actually is!!

How do I know? I have a very good childhood friend who is a well respected GP with many years of experience, he came over when my dad passed away not 4 months ago to visit me, I chatted to him about OA, he was dumbfounded about what I had to say about OA and the efficacy of iPPS!

The market definitely does not understand just how pivotal it could be if we get consistent results mid next year.

So the Day 112 shift was a revision from the peak of the Drug Dosing profile. Peak was circa Day 56. So why would Paradigm apply to change it to day 112?Mainly for commercial reasons. Any Doctor would rather prescribe a drug that has efficacy at Day 112 as opposed to Day 56. Day 56 is shortly after the last dosing. It makes sense to change that from a commercial and business sense to Day 112, especially if there is longer duration of effect!



THE BELL CURVE?

So we know that iPPS has a half life of around 12 hours or so - this needs further study to get an accurate figure. But what I'm more interested in is how much "tailedness" is the data distribution of SubQ PPS over time based on the std dose of 2x2 over 6 weeks. The reason I want this is because of Interim. I want to know that shifting our focus (endpoint read) from Day 56 to 112, well is that a conceptually steep drop off? If it is, then I know we need to power the trial even more to compensate for the drop off.


Ignore the data labels and figures below from this non PPS bell curves, focus on the actual shape of these example bell curves...




I want iPPS's drug effect to last, I want the duration of effect...I want placebo to have more of the sharper bell curve shape and then just deteriorate quickly and sharply after the peak. I want and need there to be a material separation between the two, placebo and active signals. If we get this separation, we will be successful.

At the end of the day, this is a multifactorial study.

What I mean by that is that we can't just get a fairly good p value on one measure and we are done....

So, what then do we need??



WHAT DO WE NEED?



PAR, FDA, Patients, DSMB, Investors, what do we all need for a successful trial?


Well I'm kinda talking hypothetically and focussing on Interim. But really we want an anemic p value, something lower than 0.002 would be nice (at Interim). It's usually a tall ask to achieve under 0.002 as that's quite a magnitude better than the ol' 0.05 at Day 404. At the end of Day 404, I'm not all that much worried, I reckon we have a huge chance of success of achieving under 0.05. In fact, a drug effect size of anything near 0.39 or better equates to a greater than 98% chance of success. That's a strong statistical statement...

But that's not all that we need.

Importantly, we need an immaculate safety profile, it's one area I'm very confident in.

We also need some decent p values on other measures, a few secondaries, specially the key secondaries. A good result in regards to PGIC is almost a must. In fact PGIC and Function, as you will soon see, have already been off the charts in prior studies, so again, I'm even more confident of these. The PGIC is a major focus of the FDA. Pain can be somewhat subjective, how a patient feels overall is an important and valid measure. The FDA know this.


So we know as PAR stated in the Prob of success Webinar, they are basing the Drug Effect Size off a pooled result from both 005 and 008. Here is where we have some really ace advantages up our sleeve that should help us to outperform:


1) ADP -v- WOMAC

It has been said that for Active -v- Placebo, ADP is better, but Active -v- Active Womac might have advantages¹.
In terms of ADP, there are some real strengths for us:

A) Patient recall is much better with ADP, a few minutes or hours versus up to 7 days recall from Womac!
I can't remember what I was feeling three days ago let alone 7 days ago!

B) ADP is straight forward, one question, pain out of a scale of 0 to 10. Easy peasy. Womac is a number of questions.

C) Electronic diary that prompts you, this is perfect for the patient that's busy. This is a great way to quickly remind them to answer on the spot, submit and you are done!


Example of device that could be used in the upcoming trial (not actual example).

D) The continuous daily data formulates a rich data set, this should lead to not only a clearer signal but tighter std deviation in terms of variability. Get this, and the separation between cohorts becomes more distinct. Achieve that and you get lower p values.


2) Learnings

PAR learnt a lot from 005 to 008. They managed to learn a lot about the placebo effect and how to control it further. Other learning such as the precise inclusion and exclusion criteria have also been finessed.


3) 002 Assisted

This Stage 1 of 002 program certainly showed the FDA that the best signal was obtained from the 2x2.But it also helped PAR to ascertain which were the single best clinics around the USA and even Aus. PAR will use this to their advantage almost like a test run.



THE CRUX - DAY 112

Bursting through Day 112 - Interim Readout?


Rightio, i've saved the best to last.

What I really want to know is what is the drop off after peak on the efficacy cycle? Is it a steep gradient fall?Is it more gradual? The more gradual the drop off, the better for us at Interim. I want that Day 112 effect to be potent as can be.I dunno about you guys and if you are across what Interim can mean, I promise that's not being patronising, the longer term Mozz readers know me.I certainly know the market is completely clueless, but they will catch up... If they actually knew what was coming, there is no way they'd be selling at these prices (not advice, personally opinion only).

So PAR didn't pick Day 112 randomly, there is a body of evidence at this time point. I was very concerned when I first learnt that PAR are changing their look through from Day 56 to 112. But they aren't just doing that for commercial reasons, they are doing it because they know they still have a great chance to actually make it by Interim. If not, then they will certainly make it, based on probabilities and chances of success by day 404. But as I said, PAR are very mindful,very careful when it comes to statistical powering and what they hope to achieve. In order to further increase the chances of the trial overall (day 404) but also specifically, at Interim. PAR have done one important thing.

They have bumped up n to something, I believe, is greater than what they need. We heard it from Donna, she said that the powering of the trial is set at 0.3 drug effect size, but look at 008, look at the learnings and look at the new measure like ADP. It's great they are going conservative, it gives them room for error, it allows for the usual few drop outs and people that said they could initially commit to Day 112 and Day 404 but have exceptional circumstances and end up aborting.

Now, let's just take a closer look at this evidence.


EVIDENCE

So the first chart I want to show you is to do with Pain. Pain is citicial. It's the number one key phenotype of OA². It's also our Primary in the Phase III.




What I want to point out in the above chart from our 005 trial is that yes, there was a drop off in pain...ie pain reduction isn't as great at Day 112 compared to Day 56 but the drop off ain't bad. It's relatively flat, the gradient isn't too steep. This is what we want, we want that durational effect to last, we want the pain drop off to be relatively flat.

But remember, there are two aspects that govern a successful trial. Statistical Significance against what you are up against (placebo in our case) BUT very importantly, we also what clinical meaningfulness. There is little point if you do get strong confidence your drug WORKS, but it's of little use if it only works to a teeny tiny fraction. We need Clinically meaningfulness in our result set...the next chart demonstrates this:




Now this chat above excites me for four separate reasons.

1) Good separation Active versus Placebo
2) Mate, what are we measuring here? Greater than 50% pain reduction, that is highly clinically meaningful. That's a very high bar/hurdle PAR have set.
3) Look at the (lack thereof) drop offs from day 56 to 112. It's not much of a drop off! The curve is relatively flat; a gentle descend...when we land a plane, we don't want a steep uncomfortable oxygen mask supply falling from the roof descent yeah? We want gentle glide path down and a smooth landing.


This is not what we ever want to see yeah?


4) Helllloooo p values... Day 53 is incredible. But even Day 109 (see chart above) would've been also amazing based on such small n.


But that was 005. How about something much more recent in terms of what is the minimum hurdles we need to show with regards to the minimal Clinical Important Improvement (MCII)?

The minimum hurdle for us is some 12% pain reduction and some 17% function improvement.


Yeah Paradigners, we had to achieve minimum values in the teens on both, we achieved circa 45% on both:


Guys, we have the minimal hurdle in the teens (17 and 12% respectively), what did we achieve in 008? Circa 45% on both. This is the power of YOUR drug.


Paul and team have built this P3 study accordingly. They have used one of the best statisticians on the planet to help us navigate and construct an awesome P3 plan. (I wonder if I will ever meet John B one day, now that will be quite a meeting). They have utilised the top KOLs and we know the absolute quality and credentials of the PI's and Program Directors. I've said it before, I say it again, Thank you PAR staff for your enormous efforts to get us to this point. Now let the next phase begin.


So we know we have a case to beat the Meaningful thresholds...what of the duration and the prevention of rapid decay of curves in terms of how iPPS performs after peak effect?

To make it more obvious, have a look at my green line below to make it more obvious:




And again here at day 109 (close enough to 112) in terms of Function:



Again, look at that separation, and that was only n = 56 or so. We will have 117 (active) mid next year.


One more chart highlighting the iPPS duration of effect in terms of pain over time, that middle reading below is at day 168...





When I saw the below chart for the first time two things happened. I actually gasped and my eyes lit up.

This was one of the most telling charts for me. (Possibly the only one that ever bet it in terms of Mozz positive reactions was the CTXII chart - I've posted it three times already in HC over the last few years...I'll post it for a fourth time but it will need to be an Appendix otherwise some of the older folks here will start getting upset! LOL).




Yeah Mozz, we have seen this already...Ahh but wait...



Yeah Mozz, we have seen this already....

Ahh but wait...

Let's just zoom into that same chart above ...




Helllloooo, Hot Copper readers, can you see my little introduced burgundy arrow there? Thats showing the material separation between 2x2 and placebo at day 112.Thats with n ONLY at a crazy nutty unbelievable 15 !? Hello is anyone understanding this and just how this will translate for you at Interim and day 404?




Day 112 ?? (See what I did there in the above graphic).

Mark your calendars. PAR have spent lots of time, lots of money, lots of effort...but while it has been a really tough ride so far...the future isn't just potentially bright for us, it's a whole heap brighter. They have showed us that, in the Prob of Success Webinar and the data demonstrated on the slides. The FDA agreed and have incorporated and approved the revised protocols. This is one of the biggest silent achievements PAR has had and let me tell you, this has gone predominantly completely understated thus far. This will not always be the case. We will genuinely have massive green days in the future (Spec statement yes, but quite very possible).

Most (non HC!) holders are clueless and do not understand the ramifications of the science, the stats and the potential commercialisation. Our day of reckoning, Day 112 draws closer...





....Bring it on!





- Mozz









POST SCRIPT

I've been planning this post for a few weeks now but it was only earlier tonight just before posting that I realised there is a whole chunk of pertinent additional information. I couldn't wait any longer to get this Part one out though. Wait for Part two, even more great evidence on why PAR is confident in what's coming up. I hope to post Part 2 within the next week or so, stay tuned!





APPENDIX A

Most of you have seen this one, but this one chart still makes me go a little more nutty than I was already measured at baseline:



CTX-II is one of THE MOST PROGNOSTIC of all biomarkers for OA. If your CTXII levels are going up over time from baseline, you certainly have OA.

Simple.

So it turns out that iPPS REVERSES the course of CTX-II levels. I'm not aware of ANY other drug that does this consistently, that does this safely.

Look at the above chart, see what placebo did, their CTX II levels worsened. COMP and ADMATS-5 were also same, There is no clearer evidence. This drug, W O R K S.

If I ever get to present in front of an Insto in the future, that's willing to listen, I will start with this chart.


If YOU find a drug that leads to a result of reversing CTX II levels as proficiently and as safely as what is demonstrated on the above chart, you need to post it, you need to tag @Mozzarc into to this. We need to know.






REFERENCES

1] https://academic.oup.com/rheumatology/article-abstract/51/8/1440/1842109?redirectedFrom=fulltext&login=false
2] https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-024-07286-4#:~:text=Although%20the%20precise%20biological%20mechanisms,may%20change%20in%20the%20future
3] https://webservices.weblink.com.au/article.aspx?articleID=5Fk+bnXgXYyLgsUCh+26gw==