n a matter of a week or two we finally will put in an...

n a matter of a week or two we finally will put in an application to the TGA for them to determine whether we are then eligible to put in a Provisional Application.

*whew*

Tonight let's explore what this mean, whether we are a chance and perhaps any possible positive ramifications.


Please now, do enjoy.


THE PROCESS

Known as the Therapeutic Goods Administration of Australia, it's the TGA that grants us the ability to sell our drug into the Australian market. For a full license we need to complete our Phase 3. But there is a process called Provisional Application which allows sponsors like us to get a drug selling onto the Aussie market earlier.

Before we can even apply for the actual provisional application, we have to knock on the door and see if we are a chance, this is called the Determination process.

We have already had the prelim meetings and ascertained the ballpark. In fact it was in the Scott and Paul interview where we heard Paul say that unfortunately it's not just a case of having the ability to address Pain and Function, we need something a little extra. We will cover what that is in the next section.

The process graphically is like this ⁰:







ELIGIBILITY


_{What do we need to get this?}




So do we stand a chance?

Well let's take a look at what they need and how we fit into each of the TGA's 5 categories:

1. Medicine

Well yes, we are a new medicine in that our route of administration and also our effect is addressing an indication that hasn't been addressed before in terms of what our drug can do.


2. Serious Condition

It was back in June 22, 2021 that the American Arthritis Foundation partnered with the US FDA to host a workshop to determine this status:

"The fact that the workshop took place at all shows that the FDA is taking osteoarthritis seriously. In fact, it has now labeled OA a “serious disease,” said rheumatologist David Felson, MD, MPH, professor of medicine and epidemiology at Boston University, speaking after the workshop. The “serious disease” designation allows companies to use the FDA’s Accelerated Approval pathway".²

Side Note: Dr Felson is a consultant to PAR. It's quite the coup.


3. Comparison against existing therapeutic goods

This is where it starts to get interesting, comparison with the other drugs on the market...I could say, what other drugs on the market??

The key here that there shouldn't be any other drug that is doing what we do, already on the market OR if there is...then our drug that we are applying for provisional determination should have:

"...preliminary clinical data demonstrating that the medicine is likely to provide a significant improvement in the efficacy or safety of the treatment, prevention or diagnosis of the condition compared to those goods".

All we really need to do here is show connotations of structural positive morphologies along with adequate prognostic and diagnostic OA biomarkers and we should pass this test with flying colours.


4. Major therapeutic advance

You thought section three was good ...4 is better for us...because in my humble, not only we are showing SOME DM properties we are showing it with two distinct bonuses:


A) We are doing it quickly; 128 days time
B) We are doing it in a major way. To smash CTXII down by an average of 25% or so in the cohort along with regression of BMELS and increase of Cartilage vol. Well this is the evidence we have been waiting for to submit.


5. Clinical Study Plan

Well of course we need to have this in place...it needs to occur within 6 years (we should be good in say 2 years max? So we definitely will meet this condition).



SUPPORTING DOCUMENTATION

The TGA want a fairly concise summary of supporting documentation, they actually suggest it should be no more than ten pages long and include the following:


A) Justification for addressing all eligibility criteria
B) Justification of any early, or surrogate endpoint(s) used to demonstrate clinical benefit specific to the condition that is subject of the application (see Mozz Note below)
C) Overseas regulatory status



MOZZ Note:

Regarding B) Now it makes sense why way back in March 2021 Paul answered Scott by saying the TGA want something more. There are drugs out there than can cater at least to some extent for Pain and Function. Sure they may not be wonderful options and have nasty side effects with long term use...but to get something through this program, we need something special. It's not till NOW that we have the evidence.

C) the authorities like TGA want to ensure that we aren't just going to apply for this provisional licence, obtain it successfully and never continue on with trials in the background. We still need to go through all the formalities of a clinical trial before getting the full licence.



They then list additional attachments that should be included in the application:


D) Evidence of safety and efficacy and status of recruitment
E) Summaries of pivotal studies
F) Additional safety data from pre clinical and clinical settings
G) Where published papers are highly relevant for the medicine, surrogate or early endpoint, the full text of such literature
H) Other forms of literature references or unpublished reports and expert statements may also be used in addition to the pivotal study summaries but would be considered low-level evidence


While D to H is a fair bit of info, each and every point can be answered by PAR, we have all of that supplementary data and more. Finally we are in a position to supply it. Back in 2019 when the TGA application was first mooted, we wouldn't have been able to supply even half this info let alone Point 5) above ie submitting the plan to submit comprehensive clinical data on the safety and efficacy of the drug within 6 years. We finally are in that position now.



PRELIM DATA

The determination stage which we are about to apply for comes before the provisional application. If we are eligible then we are allowed to apply. It will take 30 days from the time of submitting to hear either a YAY or a NAY....If it is a YAY...we then work the PAR staff even harder to get this application in ... Do me a favour, if you ever meet the PAR staff, do please let them know how happy you are that they are working so hard for us. It is because of their efforts they are progressing this beast. It seems quiet on the surface....we do not see what's happening under the water line. I get small bites and samples and I'm impressed.




_{Yeah that clock pic above is apt...One example...a particular staff member woke up at 5am, was in at work by 6:45am...worked all day, had dinner at 6:30pm to 8pm...went back to the office for two more meetings and finished finally at just past midnight. I don't believe you Mozz, no one has meetings in Australia after 8pm....true...these were zoom liaisons with the US staff and some fundies. Their hard work is NOT lost on me...I will thank each and every one one day...personally...irrespective of whether we make it and are a raging success one day.}




The TGA understand that the clinical data available at this stage might be limited to a smaller patient cohort or even a non validated surrogate endpoint. It's in this area where PAR now has some good evidence across A BROAD RANGE of possible surrogate endpoints. Our application will only be strengthened by this wider range of observations PAR has made.

There is some flexibility the TGA provides in that the surrogate endpoint used doesn't have to have masses of supporting data in tow, they state it by saying: "... the clinical data available may be limited", and "... results may be based on surrogate endpoints that are reasonably likely to predict clinical benefit. The scientific evidence may therefore be less comprehensive than would typically be required, but needs to be adequate and convincing evidence based on clinical trials (usually randomised controlled trials)".


" A surrogate endpoint does not need to be validated (i.e. be an endpoint that is known to predict clinical benefit and could be used for standard approval), but needs empirical evidence to support that it is reasonably likely to predict direct clinical benefit".


As a summary of requirements:

1. the ability to predict benefit based on evidence
2. the strength of the evidence
3. the certainty of the prediction
4. why remaining uncertainties are considered acceptable

We could take each point above and take maybe just one marker from each of the two groups, biochemical and structural and apply the logic. Let's do that as an example.

BIOCHEMICAL CTXII

1) Highly prognostic, get these levels to halt or even reduce and you have this covered.
2) Not just a small decrease, a large one and SS
3) It's not PAR saying it, it's the KOL's, the Biomarker Consortium. The certainty of the prediction is the simple fact that CTX-II is THE most prognostic of all OA biomarkers.
4) None that I know of


STRUCTURAL - BMEL Regression


1) You can't get better evidence, reduce the BML, Reduce the inflammation, potentially increase the JSW and as an added benefit of all that? Reduce pain and increase function of the overall joint!
2) Nothing like an MRI...here are some lovely data from our 005 program⁴:


Mozz Notes from Secondary Data Release in 2019:
Red Underlines = iPPS had positive effects, BUT Placebo went the other way and continued to degrade! Compare the iPPS result with the Placebo...
Orange underline = Par legally cannot use the world 'large' offhandedly
Blue underlines = Take a look at the PGIC p values - despite such a low n = 56 (active). This is the data the agencies have considered and thus granting us a Fast Track already.




3) Highly correlated evidence exists of the existence and persistence of BMLS and the linked progressing of OA⁵:


So if your BML proportions continue unabated...your pain and OA progresses...reduce this and the opposite is true.

4) Well none that I know of




_{Structural mods observed just 128 days after iPPS. MRI's gave us empirical data.}

As part of the application justifications must be given for the first 5 points as seen above. One such Justification is the significant improvement in safety of efficacy:

You must demonstrate, based on preliminary clinical evidence, that the medicine provides a clinical benefit over existing therapeutic goods for the indication that is the subject of the determination application (for either treatment, prevention or diagnosis of the condition) by addressing either of the following:

• improved efficacy for the entire population relevant to the therapeutic indication OR
• a better safety profile for the entire population relevant to the therapeutic indication

I believe we would tick both of those boxes above. Improved efficacy for sure, but also a much better safety profile. There is a fair bit of evidence to show the not so safety profile of long term NSAIDS usage and certainly the corticosteroids usage.

Also under the Justification sub headings it is interesting to note that the TGA request Comparator studies against registered therapeutic goods. This provides further evidence to demonstrate significant improvement in safety or efficacy of the medicine. This is also another reason in my view that PAR would need time to conduct and formulate such documentation.

At HC it's often easy, very easy to grumble and moan and say things are taking too long. Do we know what's involved? How many staff do we have to complete all this work AND what if they get even one step wrong. Remember this is the TGA...if it's rejected, there is no second chance, there is no going back, we must then wait all the way till a full registration in USA/Europe.

Like a teacher at school trying to assist the student on how to complete an assignment and get a good mark, the TGA suggest that they are the ones that "will evaluate whether there is a high probability that patients will experience a clinically relevant benefit on the basis of preliminary clinical data".




_{Like a Teacher helping a student? TGA helping Paradigm?}

I used to always wonder how much help they actually will give us? A pal and I asked this once of a guy who has worked many years for agencies (particularly the TGA and FDA) and he said that they do actually want to help us to succeed and bring successful and safe drugs onto the market.


Furthermore, theTGA suggest that the sponsor should consider the evidence in light of such characteristics like:

• Life expectancy
• Symptoms
• Pivotal study surrogate endpoints
• Existing medicine for the treatment , prevention or diagnosis of the proposed therapeutic indication.

As a further justification for Point 4 above, A major therapeutic advance, it looks like the TGA really do want something fascinating and never seen before data! To be honest, I wasn't aware of the standard they needed. I suppose in hindsight it makes sense as we are really asking to be able to jump the queue in terms of sales...see also Section below "What does it give us".




The TGA guide eludes to the word MAGNITUDE.

They realise that we might have a drug that shows SOME benefit...but they are after some degree of confidence around the SIZE of this good effect. If it is barely material, we ain't going to have a case to proceed further:

• the magnitude of the demonstrated improvement in safety and/or efficacy
• the likelihood of the early data or surrogate endpoints to predict clinical benefit
• the impact on patient outcomes taking into account both safety and efficacy
• the magnitude of the advance in relation to other therapeutic goods registered for the indicated population. Where no product is registered on the ARTG, the comparison should occur against the accepted standard of care
• the strength of the preliminary evidence, characterising the uncertainty

Yeah it's fairly full on, a bit like an end of school exam!

To give you a sense of the higher hurdles involved, take a read of this:


"The demonstration of a medicine's clinically significant benefit based on improved safety and/or efficacy is not sufficient. Rather, there should be demonstration of a major benefit, i.e. beyond the level that could be described as clinically significant".


"The medicine should provide a therapeutic advance, in comparison with other registered therapeutic goods, where possible, by addressing a major or urgent unmet need for Australian patients in a substantial way".


So the hurdle is high...but you know what, our evidence is of that calibre or greater.


It puts us in good stead as we have some really good data, albeit in low numbers, which is entirely acceptable AND we are showing good signs of DM....surrogates (yes plural) that are showing meaningful and in some cases statistical, significance.



WHAT DOES IT GIVE US?

_{If we make it through, what can we expect? Anything positive?}

Ahhh now this is an important topic for us. What do we get by all this effort? What I ask you, do we get by all this time? Remember, we have effectively been contemplating the chances of a TGA application since 2019...it's now 2024 and we aren't there quite yet!!!


Is it worth it?

In a word...



Yes



We get a chance at revenue in advance...this is always going to be good because remember...yes it is for OA...but once it turns up on the Aussie Doc's PC's in their clinics and surgeries...well they are going to be able to prescribe it...but word of mouth is strong...word of mouth will spread and people that are in pain...acute and chronic alike...well, they will have a chance to be able to take it.


Let me be the first to assure you that I for one, am going to assist spreading that word if I can...I reckon you should too once we are green lighted...but thats for a future day and a future post!I have heard back of the envelope figures of some 10,000 patients in the first full year after we are provisionally approved.Maybe that's a bit too optimistic but maybe it isn't..


Mozz quizzes are special events, there is demand for them, it's surely time for one now...sit back and enjoy and try your best to get the right answer yeah?




HOW MANY AUSTRALIAN ARE CURRENTLY IN CHRONIC PAIN, RIGHT NOW?



A) Well didn't you just give us the rough answer, you said 10,000 might take it up...so I guess around 30,000, a third?




B) Those seasoned Mozz Quiz© attempters always know it's never answer A...let's double this, my answer is 60,000




C) Double again, 120,000?




D) Surely it can't be north of 180,000 ??? Like right now that are in pain today...ie pain that lasts for over three months...






The answer?


Wait for it.....






3.4....


Huh? 3.4 Hundred thousand?


No I mean 3.4 MILLION !!

Don't believe me?See ref 3 in the reference section at the end of this post.


Check out this infographic


:

So 10,000 doesn't seem that out of the realm of possibilities, specially after a full year of it being out there, it will take some time for word to spread and I don't think PAR are allowed to advertise and market a provisional drug...that must wait for a full licence and even then there are conditions and rules especially in Australia.

(Wait for the day we see full sized Billboard ads in the USA on the freeways and in the sporting stadiums...mate)


^{Yeah not terribly sure I should ever be made Head of any Marketing division...More Scientific Research please Mr Mozz, less Billboard material ? Yes that lady really is ditching her crutches as her edema has resolved quicker than normal (Subject to clinical data, not advice).}


Ok So getting back to the numbers, I've heard it could be as many as 10,000 in the first year...what does this mean for us?

Well the average cost for the patient is around $4000 AUD, this includes the clinic's fees. I would guess our take would be around the $2500 mark.

Now I'm going to be plucking figures outta the air a bit here but let's say we need a distributions parter, call them a logistics partner to help us locally warehouse and distribute into the Aussie Doc network.They are going to take a cut for this, it won't be small..so maybe let's cut off 60% of it...that leaves us with $1000 even. From this we will have overheads and Royalties to our dear suppliers, bene.Let's stick to revenue and not worry about profit for now.

At $1000 per patient, the maths is straightforward with circa 10,000 in the first year.

A cool $10 million.

But the SP will eventually reflect this via a P/E ratio. Growing companies attract really good PE ratios....

NVIDIA's P/E ratio is currently 78! I will use a conservative 25. We should really be using 50 plus, specially after a few quarters of increasing numbers for only the Australian market.

$10 Mil at P/e 25 gives a valuation of $250 million

This equates to 71 cents per share.

Ho hum?Maybe ...but look at year 2...

Year 2 I would estimate that our patient numbers would increase, a fair bit as word spreads...

Im guessing around 25,000. I think it's a fairly conservative number but using the same calc as above...we now get

$1.78

Starting to get interesting...at the same time we should have a readout from the US/Europe. That's when things start to layer.Get a Global Deal in between somewhere there and all these little calcs go out the window as if it's anything close to Tanezumab deal from 11 years ago....Well let's quickly do THAT calc out of interest.

$1.8 Billion USD indexed to today's figures give me about $2.39 Billion USD...In AUD that's about $3.62 Bil. AUD.

That's for a drug that shows no DM...we show DM !

How much do I ascribe for this?

50%? Prob not enough...to not only genuinely alleviate symptoms but to halt and reverse the course of the disease... now that's worth something..

Divide this into 350 million shares and we get $16 odd.


Now we are talking...




PURPOSE

The purpose of this post was to give you guys a sense that while it seems it's all boring above the water line, underneath there is a flurry of activity. There is much proof to be gathered not to DO the application, but to get the application in to see if we are even ELIGIBLE to put an application!

Very easy and rational to get frustrated with weeks and weeks of waiting...but when we are armed with the knowledge of WHY it is taking so long to get work done, it gets a little easier. When we understand what's at stake and what are the positive possibilities, well for me it is easier to wait....not saying that I love waiting...not saying that it's easy to be patient...but it's a little more digestible when I know those guys, the PAR team, are very busy and very diligent, they have to be, we only have ONE crack at this!





- Mozz






DYOR required and is a generally good idea.
Not good to rely on any one poster no matter how enthusiastic they sound.






REFERENCES

0] https://www.tga.gov.au/provisional-approval-pathway-prescription-medicines
1] https://www.tga.gov.au/resources/resource/guidance/provisional-determination-eligibility-criteria
2] https://www.arthritis.org/science/impact/drugs-for-oa
3] https://treasury.gov.au/sites/default/files/2021-05/171663_painaustralia_0.pdf
4] https://app.sharelinktechnologies.com/announcement/asx/9fe3dc76fd51b4a6345f9b4542e23c82
5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816469/