In a matter of a week we potentially show the world what we have. A first time Disease Modifying OA drug? There has never been a drug that can do this, and do it safely in the OA spectre.
Tonight I think it is fitting we take a high level look at what this means and what it involves, we'll also take a quick look at the possible ramifications.
Watch out also for a most curious experiment and its ramifications for us.
Please enjoy.
WHERE WE HAVE COME FROM
It hasn't been an easy path so far...its taken time, lots more time than we thought. There have been hurdles that we have had to over come. Yes it hasn't been an easy journey and a lot of given up thinking its just taking too long. But I remain enthusiastic. Why?
Because our drug fundamentally works Because when it doesn't work, there are no real negative consequences, there is no decision to make, no opportunity cost. There are no serious AE's and this drug of ours doesn't lead to an increase chance of rapid joint failure. Because yes it has taken a lot longer than we all thought BUT there are reasons for that, good ones. We have increased our foundation. We have increased our scope. We have increased our outlook and our addressable market.
Yes we have one more major hurdle to cross, a P3 that we are in the midst of, but as I type this, there are more patients getting dosed and more people and investors finally hearing about us. Even here we still have small clues like the expansion of the clinical sites, think Canada. A drug company that is having difficulty with their current trial DOESNT EXPAND out their reach and include new jurisdictions. With Marco on board, this word will eventually spread...not in a liner fashion, an exponential one.
A GO TO EXAMPLE
One of my best experiences was with Afterpay. I could see it in the early days shop after shop...those front window stickers starting to pop up all over the place..every second window in the shopping centre had this logo appear. I knew there was a ground swell happening and the exciting thing for me is that they hadn't even hit the US market yet...they were just starting in the US and UK was next in line. All you had to do is extrapolate what market penetration and growth rates they were achieving in Aus and multiply it out into the USA...the share price at the time was $7.
This was everywhere...every second shop, billboards on freeways...
If you were patient, if you rode out the large ups and downs, if you discounted the fact that there was competition (Humm, Split It, OpenPay, Klarna..etc) and the fact that ASIC were investigating this whole Buy now pay later industry, you could've done well - the share price eventually made it to $150.
Paradigmers, we have no competition.
We haven't even started sales. Our product isn't a nice to have, its a real solution for people in PAIN. Its a product for people whose quality of life are being degraded. This, iPPS, in a lot of cases, will give back patients their lives...it will allow many to walk the stairs again, to go on longer walks, to get back into their sports and activities. Have we not seen the golfer's hiatus of some 8 full years finally being bale to play again. Have we not read the stories of the footballers that had to hang on to the corridor walks to make it back to the kitchen who are now in training mode once more and play basketball with their kids?
Our product doesn't just work positively on some small tiny fraction of the population ...a full 88% or so (SAS program), so far get SOME positive effect with a full 50% getting a 50% pain reduction so far. This isn't a band aid type product like Panadol that lasts just 6 hours. Our market size isn't some niche small sliver of society.
Like Opioids, iPPS isn't addictive.
In a week's we may just find out that we not only reduce pain and increase function, we, at least in some percentage of patients, address the underlying. This has never happened before with any other drug in the OA field.
We can positively affect ALL joints simultaneously AND we don't have to have this injection invasively, ie intraarticularly?
As if the above isn't enough, on top of that you are telling me we may be able address pain in general?
Mate, I don't know about you,..but grand final week for me happens next week! To read that announcement will be a definite unwrapping of some sort of gift, let me tell you (subject to announcement).
ITS NOT FROM LACK OF TRYING...
Mate, think about this for a sec... 41 Clinical studies 38 Interventional trials Some 13,000 patients
It resulted in the SAME efficacy as us (pain reduction) BUT one small difference, an increase of rapid joint failure...in how many patients? 2.5%. That was Tanezumab, the FDA said NO...Too dangerous.
This was worth some $1,800,000,000. That was a number of years ago.
We pass our P3, I'm telling you now, we will score a deal that's north of this. Add DMOAD to it...well...I don't need to say much more (spec comments, don't rely on one HC poster).
The OA field indeed is "disproportionate" 0.5, littered with clinical failures. This sets up the perfect conditions for us.
THE CHANGED LANDSCAPE
A number of years ago it was all about Radiography, yup, X-Rays. But this reliance on X-Rays has been one reason why drug development hasn't progressed in the area of OA. "It is generally believed that this emphasis on radiographs has hampered development of disease modifying OA drugs (DMOADs) due to inherent limitations of radiographs including: their lack of sensitivity to joint tissue changes". 1
In the last 10 years in particular, MRI's have added a lot of colour and our understanding of what exactly is OA has grown and developed.
MRI - a changing landscape in the world of OA.
We now know that OA is all encompassing, its the morphology of the bone and surrounding tissues and cartilage. It involves the entire structure. We also know that the pathophysiology at play isn't just prevalent at the pain stage. No, they are there, present, up to a full TEN YEARS before it ever shows up on an X-Ray!
The ultimate First line for us eventually? I would think so.In fact as my Western source once said, one day it might be that a patient at risk takes a simple test to weed out these biomarkers and what they are telling the patient and as a complete prophylactic, you'd go on a preventative style course of Pentosan. Yes perhaps more important for athletes and sports folk..but could well apply if your job/lifestyle involves a more repetitive manual style of labour or you are just at some risk, some predisposition.
REQUIREMENTS
The FDA themselves referred to the following three areas in terms of possible DMOAD connotations2:
Normalise the X-ray (reverse progression).
Improve the X-ray (halt progression).
Slow JSN by at least a pre-specified amount (slow the rate of progression).
Mozz Speak : JSN is Joint Space Narrowing, you don't want narrowing...we want a nice gap between those adjoining bones full of slippery gliding and non fragmented cartilage.
MRI in the more recent years is adding much valuable and and important observations to the assessment of OA. The thinking here is that an addressing of JSN eventuates in the delay or perhaps even a lowering of chance of surgery, a possible staving off of TKA or THA. With some 3.5 million estimated surgeries just in the USA being required in 2030, well its a big problem that's just growing. Surgery is really seen to be the ultimate solution but its a decision that's not taken lightly. Post op pain, dissatisfaction and a replacement of natural tissue with artificial plastic/steel has its own problems and issues.
The awarding of a DMOAD is the ultimate prize.
But the observation of JSN alone does not cut it. Its just too late when you get to that sort of stage. It tells you very little about the micro structures of the cartilage and surrounding tissues. Enter the biomarkers. the early detectors of what's going on. Whether it be C2C, CTX or COMP...these little guys give us the warning that destruction is already at play.
Here is yet another cross section of the key OA Biomarkers (see figure below)3, a lot of which we are currently studying and about to report on at the Day 56 point. I'm not sure how much detail we will get but I'm also very much looking forward to the 6 month and then 12 month read out. Yes the 56 day will be the first clue for us, for the world...but the 6 month will tell us how the active group fares compared to the placebo group over a longer period of time, a real potential DMOAD and durational story.
OARSI 2021 depiction of OA Phenotypes, endotypes and molecular endotypes.
The science has progressed, we now know we need to observe not just individual tissues but we need the observation of the "...interrelationship between tissue pathologies".3
In essence we need three parts to come together:
PGIC is also an area that the FDA want data on. Its one thing to address pain and function, but are the patient's lives being positively impacted overall? In terms of daily activities? The FDA are wary of patient's lives having a positive effect to a new (well, repurposed) drug.
We studied this PGIC in our SAS program7 and these observations have also been included in our main P3 trial:
So, yes 008 is important, I think it will be quite pivotal, but we also need to tie and link these observations in with the clinical endpoints. We need to check these observations against placebo. We know that the placebo effect can be strong and it is particular pervasive in pain related indications. Yes it can also effect more objective structural phenotypes too.
"New evidence continues to suggest that placebo effects influence physiological mechanisms and outcomes of pain. Placebo effects have been documented across different diseases, including symptoms ranging from itching to cancer-related fatigue, from Parkinson’s disease to attention deficit hyperactivity disorder (ADHD), from anxiety to social phobia, from depression to addiction, and from asthma to immune diseases".4
COMPARISON TO PLACEBO
Placebo plays a strong effect in many trials but it is a particular strong force in pain indications. "New evidence continues to suggest that placebo effects influence physiological mechanisms and outcomes of pain".4
But how have we compared to Placebo/Control so far when placebo has such a strong effect??? Do we stand a chance?
ARDS
At Day 81, 61.5% of participants in the iPPS group showed near remission in comparison to 14.3% in the placebo group.5
PHASE 2B OA 6
The good news here is consistency. Our results from each of the SAS batches, from other indications and our own Phase 2 OA have shown some good consistent performance of our drug against the placebo cohorts. The data from 008 is also against placebo, its going to be really interesting to see what the data is telling us between the two cohorts...
A MOST CURIOUS EXPERIMENT
Listen to this one. In 2010 a group of researchers wanted to see what some of these biomarkers do when health individuals exercised8. One of the most well studied biomarkers in the OA field is COMP. They conducted two experiments with healthy individuals under the age of 40 that had no OA and had no past injuries.
Experiment 1 - The took blood samples before Jumping exercises and again took blood samples after the exercise.
Experiment 2 - They took blood samples before a running on treadmill exercise regime and then took another sample after.
Experiment 2 resulted in Increased COMP levels after exercise.
Experiment 1 had little to no effect on COMP levels. The conclusion from this was that "This suggests that the acute serum COMP response depends on loading characteristics".
We know that patients with OA have higher levels of COMP.
In our case we work from the opposite side. We have taken patients that have OA. We checked their COMP levels before iPPS and then after. We did this in a clinical double blinded placebo based setting, here were our amazing results:
Our effect on COMP, the biomarker that predicts subsequent cartilage loss by MRI, fell while the patients in the placebo INCREASED.
Paradigmers, this is evidence from the SERUM. We will be soon getting info in the Synovium.
Yeah so what Mozz, they are all body parts, its all the same, right?? No, wrong - the ramifications for the synovium are different for two DISTINCT reasons:
1) The concentrations in the synovium are greater compared to serum
2) The sample - I have my answer.
What is the meaning of 2) Let me give you some background.
MY QUESTION
I posed a question a number of months ago...I asked many Geriatric specialists, I asked a number of GP's...I asked some pals in the know.
My question was this:
Does the fact that OA biomarkers being more concentrated in the synovium mean that the action of a drug (like iPPS) mean that we could expect any different effect/observations in this area compared to a sample of serum (bloods)?
I recently kinda got some colour on it...
The way it works is that the readings in the serum are like the way in which blood sugar levels are reordered over a longer period of time, like a historic reading. This is known as a HbA1c, its the average reading over the past couple of months. Think of this as our serum readings. But the synovium is different. It is a real live point in time measurement. Yes some fragments and increase in biomarkers such as COMP will increase immediately in the serum too. But this aspiration of the Synovium is the big difference in an OA sense. And this is another reason why this study could just be quite telling.
WHERE TO FROM HERE?
Well we have to check out the top line results of course. If they are good, we wait for the 6 month read out. But it will create some headlines in the meantime. It will be very exciting and it will allow us to begin work on discussions and start to build this in when we are on stage. Yes, we will be on some stages in the next 12 months. There will be conferences and seminars, there will be many private closed door discussions too. One of the main conferences I look forward to is the OARSI Conference in Denver in March.
By then we will have our 6 month data and we can well, really shake it up at the club. Pool_Lord, Cucumber and salmon sandwiches please, might have a Crownie too, haven't had one of those for some time.
The top line result of a most pivotal study is almost upon us. In itself it may not be enough to get a DM badge on our label single headedly, but if the data is decent it will lead to meaningful future discussions. It will make headlines and new investors to us will be alerted.
I personally think the 6 month data release will be highly pertinent. But this 56 day result will give us a real insight on what's happening in the synovium and form a link with the serum and will serve to show whether we have something completely super stellar. I've been asked what happens if the results are so-so or if they don't really show a massive change leading to a DMOAD. All is not lost in this case either. We know that Pentosan has a real positive action against inflammation in a majority of patients so far, we know the symptomatic relief patients are getting and we have the trump card of SAFETY. This in itself is enough to put us in the class of the most highly profile of drugs in a disease area that has had no real solution, ever.
he countdown is on!
Normalise the X-ray (reverse progression).
Improve the X-ray (halt progression).
Slow JSN by at least a pre-specified amount (slow the rate of progression).
(20min delay)