FDA delay for ph 3 trial approval, page-31

I was going to start a new thread but this thread heading sums it up well.


onight a different sort of Post, kinda covering some of my thoughts on the delay.


Personal opinions expressed below.



Well here we are and we are still waiting. Will we get some news next week? I should hope so, but there is a also a chance we will still be waiting for news even after next week *brrraaahhh*. No one really knows. We just know it is close, really close. 'Close' might be a definition depending on the eye of the beholder. From our point of view, it should be really close, from the FDA's definition of 'close', maybe it is still a week or two a way as it has been close for quite some time now!





Yes it is frustrating. Just because we know something of the science, it doesn't make it any easier. Well it does a bit. If you know this thing works and how it works that actually does help me personally. I'm more convinced of the product if I know HOW it works. If my pal on a phone call recounts to me how he went from a 8 to a 1 in terms of pain and how he can sleep restfully at night, this is good. If I know how and the causation of his great sleep nowadays post iPPS via mechanisms such as NGF reduction (not via mere blockage) it makes for a more convincing case.

We've been through the science a number of times but for those that aren't really all that familiar, here is a quick recap

1) It's a mild blood thinner, bit not so strong like Heparin where you have to be very careful
2) It is Chondroprotective
3) It helps in cell signalling
4) It directly results in increased production of higher weighted HA
5) It forms special bonds between proteins which assist in reducing inflammation
6) It helps the chondrocytes to increase the quality of the cellular matrix pool.


Ok so we get that it works, the above list isn't a definitive list, there is more, but we need more than just a good product.

We need commercialisation.

One of the single biggest steps AFTER we begin the last stage of our clinical trials (Phase 3) is to get manufacturing sorted. It can't just be any old back yard manufacturing, we need a few things:

A) We need it to comply to GMP standards. This in itself is quite a task to get registered through the FDA with a GMP stamp in lace. Again, it's not just enough to meet the std, you need to pass the audits. And yes, the FDA and Europe have their own audits to ensure you are complicit and can continue to hold what is required in terms of GMP manufacturing.


B) If you pass through A)..you then need to be able to scale.

This is going to be quite a job in itself as despite us only needing perhaps 12 doses x 70 kgs x 2.5 m/kg which is only about 2.1 grams per patient per year (or at least the initial dosing), but if you multiply that out by how many people may end up using it, we are going to need not kilograms of it, but potentially tonnes of it.

C) Ok if by some very good luck you manage your way through B)...you then need some exclusivity. No point in having a manufacturer that can do A and B but they are happy to distribute the product to any ol' Tom, DIck and of course Harry.


D) As if the above three points aren't onerous enough, you then have the very real and usual possibility that some other renegade manufacturer somewhere out there will attempt to copy us! Some drugs and substances are not so difficult to copy. Yes they will take a risk to try and distribute it to whatever markets that aren't all that regulated to make a buck off all the hard work we have done.

The good news in this area is that all 4 points above are addressed and shouldn't really be a problem.

We have GMP
We can scale, like you wouldn't believe
We have 25 years from licensing in terms of exclusivity
The molecule is extremely complex, it has been off patent for more than a decade, how many manufacturers have copied it perfectly in all that time? How many generics are out there right now?


None.





_{State of the art manufacturing facilities in Germany, producing the product for over 7 decades. Fully FDA GMP certified.}




There has been no successful generic copies so far. Even if you get one soon in the next few years, they will have to go through clinical trials and we all know how many years that would be to get themselves registered in Western Markets.



THE GREEN LIGHT

I doubt there are many that are reading this that dont know what we are waiting for and what is the next step, but humour me anyway.

IF we get a green light from the FDA we can progress, simple. But what does that actually mean?

Well of course before we can chat about what the next step actually is, we need to define what a Green light actually is!

I break it down into three real possibilities and a fourth that I don't rate:


1) FULL GREEN LIGHT


_{Let's go!}

This in my world, means that the FDA come back to us soon and say that our plan looks good, there might be a few comments and bits of advice they have but on the whole we can progress.


2) GREEN LIGHT BUT IT'S NOT AS GREEN AS 1)

What this means is that we are pretty good to go, we just need to answer a couple of questions, fix a few paragraphs and add in a little more monitoring than we thought (that's just an example).


3) GREEN LIGHT BUT IS THAT A SPOT OF AMBER?

This could involve us having to spend a bit more time to resolve some matter(s), it could be an additional test, it could be a question the authority has, it could be some extra work that's required for us to do firstly.


4) THE OPTION I DON'T RATE

There is always a chance that we need some major re-work. I'm trying not to be that ostridge that buries his head in the sand, I know it's not impossible, but I don't rate it based on all the data, on all the dialogue we have had up to this point.


_{I don't want this to be me.}


THE NEXT STEP

Once we have either 1, 2 or 3) from above, the next step triggers a number of good steps.

I'd say the first major task is then to work on the actual IND submission. It will of course depend on the which of those above points transpires. If it is pretty smooth sailing then it could be a few weeks. If it's more onerous then it's prob a number of weeks or even a couple of months to submit the application for the IND.

Once it is submitted, the FDA have a statutory 30 days to respond. That's in writing, so that part in theory, is less likely to simply drag on.

Now according to me, once the Min. Effective Dosing is determined (as part of the FDA feedback we are waiting on) also known as the MED. and once the FDA gives us feedback that we are good to go in terms of putting in our IND for our P3, the next trigger that might happen is the Determination of the TGA Provisional Application, that's for the ability to apply for a temp (provisional) license in Australia while we wait out our P3.

I think it is hinged/linked to the FDA decision but that's completely my own opinion. Normally a determination is like 20 business days, we are well north of this, so north I reckon we are up in the tropics somewhere.

I don't know how it can take this long. I would understand if it took this long if we were in the actual application phase itself, but we aren't. This shouldn't really take that long but here are a few Mozz type thoughts as to why it might be:


A) It's a very broad acting drug, we aren't a single receptor targeting wonder drug...we are a SYSTEMIC acting drug, this involves a lot more pathophysiological interplays, this will result in the TGA asking more questions than perhaps the typical application.


B) We are claiming a lot. We aren't just claiming a little pain drop, a fraction more ROM in someone's leg/knee and less stomach cramping from the drug as a side effect.

Man, we are claiming MORE drop in pain than the stronger opioids

I need to interrupt myself here to give you a sense of how important just this one category of pain actually is.

Have a read of this, my emphasis added in bold:

"Pain is a common medical problem, and relief of pain is an important therapeutic goal. Although nonpharmacologic approaches to treating pain (e.g., behavioral techniques) show promise for certain conditions, pain is most commonly treated with analgesics. Over the past decade, there have been growing concerns about the harm — abuse and addiction, as well as serious injury and death — caused by the use of prescription and over-the-counter analgesics".


But the above is not just from a random study, below is an extract from the same article written by the FDA:


"We at the Food and Drug Administration (FDA) have been engaging physicians, pharmacy groups, patients, and other stakeholders in an ongoing effort to strike the right balance between two important goals: on the one hand, providing access to pain medications for those who need them, and on the other hand, managing the variety of risks posed by analgesic drugs. Recent FDA advisory committee meetings and actions reflect this effort".


Pain relief is big.

Acetaminophen is one of the most commonly used analgesics.

Right time for a Mozz Quiz©, it's been a number of weeks:



HOW MANY DOSES OF ACETAMINOPHEN WERE PRESCRIBED JUST IN THE USA IN 2008?



A) 2008 was a while ago, we are only talking USA, I'd go 750,000



B) Are you kidding, it would be well into the millions, 9 Million ?



C) 145 million?





ANSWER:

"In 2008, approximately 25 billion doses were sold in the United States.1 Acetaminophen is marketed as a single-ingredient drug but can also be found in a multitude of over-the-counter combination products, such as cough and cold medicines, as well as in prescription opioid–acetaminophen combination products (e.g., Vicodin [Abbott], Percocet [Endo Pharmaceuticals], and Darvocet [AAIPharma]). Although acetaminophen, when used as labeled, is generally safe, the ubiquity of the drug and its relatively narrow therapeutic index create the potential for serious harm from both inadvertent and intentional overdoses". ¹


Yeah it's a massive problem, here is a very recent paper on it's usage:



"Acetaminophen toxicity is the second most common cause of liver transplantation worldwide and the most common cause of liver transplantation in the US. It is responsible for 56,000 emergency department visits, 2,600 hospitalizations, and 500 deaths per year in the United States. Fifty percent of these are unintentional overdoses. More than 60 million Americans consume acetaminophen on a weekly basis, and many are unaware that it is contained in combined products ":²



Now I'm not inferring that iPPS is the new panadol! But there are many people out there that would be taking panadol for chronic pain, ie they would be taking it for months on end! It will affect a number of people in different ways by treating the underlying issues in many cases as we have seen for a good number already in the varying programs such as SAS and clinical trials to date.

In other words the FDA are very aware and are across pain and how important it is to have safe drugs to address it, This isn't an easy feat that can be just ticked off in a day.


Ok back to my points:

We are claiming super duration of effect
We are claiming a 5 times improvement in rescue medication adoption and an immaculate safety profile to boot.

The above points are fairly incredulous and lovely....on top of that we are are claiming structural medication in terms of morphology and even inflammation....not over years and years...but within just 6 months.

That's borderline miraculous. Actually it is miraculous.


Nothing in the world can grow our cartilage volume back like iPPS can (subject to further data and testing).

Nothing on this planet can safely reduce inflammation and produce my second favourite molecule from within the cells in anyone older than kids, HWHA.

Mate


C) Why would the TGA commit when big brother FDA is about to get back to us. I don't mean that in a flippant way, according to their criteria 5, maybe we do need a solid plan in place (P3) and dose to be determined before the TGA will allow us to apply and deem our determination to be 'eligible' ?



HOLD UP

So what's the hold up? I have many theories here, In actuality it is probably a case of 'All of the above". So what's some of my own thoughts on this one?

1) We aren't single targeting

This makes it very broad and complex. The authorities can't just look at the end result, they need to check all the pharmacodynamics; how does it affect the major systems of the body. Yes we are re-purposed but the route of admin is different and the knock on effects have to be determined and checked.


2) We are claiming a lot. Pain and function improvement with less reliance on rescue medication coupled with a duration of effect is certainly one heck of a claim set, but to be sighting actual morphology changes, increased cartilage volume coupled with a faster regression of BMELS and indeed Osteophytes is going to warrant some investigation. It's quite a claim to get SS in such a low cohort in such a quick time. Then couple that with the observations of synovial inflammation coming down along with the wet biomarkers, we have quite a case here. No wonder this will take some time to review in my opinion.


3) Because of the above two points each department in the FDA must do their own due diligence and there would be a number of departments involved. Everything from Pain to Haematology. Everything from Toxicology to approving varying degrees of monitoring for safety.


4) The FDA would know that once they have their guidance/feedback ready, the sponsor (that's us) will put in an application for an IND and this would get accepted if we comply. They know that a drug like ours is going to be tried by a lot of patients, a real lot of patients. Not just some small segment of the OA population, it will be potentially tried by anyone that has ongoing pain. It could be very widely adopted by other inflammatory related indications. This is vast.


.


RISKS

An independent review on a drug or a stock should always cover risks. No matter how well this product claims to work, no matter what the patients say, there are still going to be risks. Yes it looks bad when there is delay after delay from an authority. However, I do believe with the body of data and evidence that has been submitted, it seems to me (I could be biassed, take that into consideration), that it would be hard to outright refuse us. Yes they could add wads of extra monitoring because we are not only not decreasing our dosing, we are not keeping it the same as 002 Stage 1 but we are increasing it to what we suggest is the MED.

Yes there could be some caveats or hurdles the authorities place but I don't think it will be a show stopper.


The other main risk of course is funding. We have enough funds to get us through the next few months but definitely we will need a package after that. Again here I think this could resolve once we get that green light, it all hinges on that.

There could be other risks you and I can't see. One needs to take this into consideration regarding their investment decision.

Some often say this is a binary play, it will either work or it won't,. I tend to see it with a few more options than that. For example, a specific other-than-FDA controlled region. This wouldn't be an easy path, the market would spit the dummy and it would potentially be a much longer process. Indeed the USA is the ultimate market for us, there are other big markets too, but once we get the go in the USA, the rest is really quite academic, Australia included,


_{Hey hey, don't worry USA-baby, we are persevering and being patient with you!}



NEXT?

Well I'm telling you here and how, the market is gunna love if we get good feedback from the FDA that's relatively smooth and we are finally in a position to put that revised protocol through officially, but let me just say, we get a TGA eligibility that's really going to make our potential future partners sit up and pay attention to what exactly they are about to partner up with!

In case some of you are a bit lost and need me to boil this spinach down for you... I'm talking potential revenue earlier than 2027. No, that doesn't mean the last day of 2026...I'm talking somewhere in 2025.

How?

Aussie revenue. It's possible.

You know that also means a partnership/deal in Aussie Land. From Pitt St we know that's not a trivial market and will actually equate to some decent revenue, then multiply it out by a decent PE ratio and all of a sudden we wont be $0.25 a share any more.

The knock on effects of the FDA are profound. We could finally get a number of calls on the PAR red phone from new parties that were on the sidelines. It will add to a potential auction style situation to try and get a deal or even multiple regional deals going.

I don't know how this will play out, but I do know there will be more excitement in the background once we get that FDA go.

The other thing that helps me sleep at night is the fact that we don't have a lot of shares on issue, anything sub 500 million odd is still quite low. I agree there might be a little more dilution to come but it may be very carefully and deliberately surgically instilled into our register via a small strategic placement and will not cost us a lot more new shares, this will be particularly true if these milestones are set and our share price starts ascending.



_{No Pool_Mission_Commander, it's not a R****T, it's a plane, when will our SP take off like this, perhaps slow at first but then adding altitude steadily.}




I still believe we are very very close now, we can not only potentially pivot from here but our movement up can be quite stepped up from a genuine turnaround, we just need that feedback!







DYOR, spec statements contained in this post









REFERENCES

1] https://www.nejm.org/doi/full/10.1056/NEJMp0908913
2] https://www.ncbi.nlm.nih.gov/books/NBK441917/
3] https://en.wikipedia.org/wiki/Food_and_Drug_Administration