AAAA - An Accelerated Application Analysis

ne of the most important and pivotal moments would be a filing of an accelerated application, if such an event were to take place. Tonight lets take a more detailed look at this program, what it means and if we are all a chance of being awarded such a designation.





Remember these are just my personal thoughts, they are built from what clues we have had in the past and how we may progress but at the end of the day, its only personal speculation Our actual pathway may not at all be like what is begin discussed below. If I sound enthusiastic then you should also consider the negatives and hurdles we may face.

Remember none of this is advice, this all just simply may not work out due to some intrinsic or extrinsic reason, factor this in if you decide to invest.

Always ask the question, "What if I'm wrong?".






Tonight's post is a bit of a marathon so I'm breaking it up into not two, but four parts ( ! ). A lot to be said about AA and I have a number of personal opinions and ideas as to how and where this could go. At the end of the day, its an exciting proposition for us. Its also a bit tantalising as we don't know when PAR will be able to start thinking more seriously about this pathway. A lot will of course depend on milestones to be achieved and discussions to be had.

In truth I've been planning this post for not weeks, but months, gathering bits and pieces along the way...bahh, when the clouds are the darkest and it all looks like the share price is having one of it's bigger tanties...it's time for a little enthusiasm and a glimpse into what exactly we are all holding.



_{Tantrum time? Yes but real food is coming? Food for thought...}



In Part 1 we tackle what is this AA, what does it consist of and are we at all a possible fit for this AA program?
In Part 2 we tackle a major part of an AA, the Surrogate. What is that and again, are we a chance here?
Its in Part 3 that we cover more supporting evidence, we cover another jurisdiction and we start to chat about timing.
Finally in Part 4 its slide time, we check out some ones that I hadn't seen before, we will hear from a certain KOL and we dare to dream for a sec...




Lets begin - Please sit back, get comfortable and do enjoy this Mozz Marathon tonight.








Conceived around 1992 primarily to tackle the HIV epidemic at the time, the entire light of the FDA's Accelerated program is to simply get good drugs that show promise out to the market quicker and earlier than otherwise might have been possible compared to the standard approach. It doesn't mean that companies don't have to prove efficacy, it doesn't equate to a full and immediate licence to sell and be covered under insurance. It means while they can sell into the USA, they still must continue their designated confirmatory trials to show efficacy and demonstrate the safety profile.

The Accelerated program has been a success bringing in a many new drugs into the market earlier, reducing the overall time patients have had to wait for drugs when there were little to no current and viable solutions.

"Conclusions and Relevance The study showed that use of the FDA’s expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue".^1.5






To be eligible for such a mighty program, we need a number of criteria to be met:


A) We need to be tackling and potentially addressing a Serious Disease

B) We need to be addressing a condition that is unmet

C) We need the drug to be fairly safe

D) There shouldn't be a current decent std of care already out there and we are merely mimicking some part of that product that's already out there.

E) There is a general assumption that Patients and Doctors would be willing to accept a slightly higher risk and side effects from a treatment of life threatening and severely debilitating disease.

F) The sponsor (that's us!) should be able to demonstrate that a surrogate biomarker (we will cover this later) is reasonably likely to depict the positive effect of the drug, ie leading to an improvement in the patient's condition.






So in summary, what are the specific major keys for an AA?


A drug that treats a serious condition AND...



Generally provides a meaningful advantage over available therapies AND ...



Demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint).







The simple way to determine this is to go back through the key points in the Requirements section and simply apply them.

Well, lets do that:

A) We need to be tackling and potentially addressing a Serious Disease

Yes, OA has had this determination, first criteria is met!



B) We need to be addressing a condition that is unmet

Yes, again we are addressing the market of OA that has no solution. A patient typically progresses though the (Kellgren and Lawrence) grades of progression and finally reaches end stage where the only solution is a joint replacement, not ideal. There are no drugs that are DMOAD (Disease Modifying OA drugs). There is nothing that slows down the course of OA, that halts the disease and there is certainly nothing that reverses the course of the disease. Only iPPS has shown to do this so far with any degree of consistency.

The drugs that are out there are purely symptomatic and are tagged with side effects, some quite pronounced over the longer period of time in which the disease usually manifests over the years.


C) We need to be fairly safe

An immaculate safety profile so far. Don't forget, there have not only been numerous animal models and studies over time, but it has been used in humans for not years but decades. There has never been any recorded fatality or major and debilitating AE. We now also have a bank of human clinical studies and data that we are building ourselves.



D) There shouldn't be a current decent std of care already out there and we are merely mimicking some part or totally of that product that's already out there.

We covered this in B). What is out there is merely symptomatic and does nothing to address the underlying pathology of the disease.



E) There is a general assumption that Patients and Doctors would be willing to accept a slightly higher risk and side effects from a treatment of life threatening and severely debilitating disease.

In our case this won't be relevant, there is LESS risk compared to the symptomatic solutions out there. We will INCREASE the likelihood at least in some fraction of the patient cohort of avoiding ultimate surgery. The best cases I can refer to are the numerous cases of footballers that have managed to avoid surgery altogether. Paul Rennie himself has also managed to delay the inevitable . These test cases are real and are hard evidence of the DMOAD effects.


F) The sponsor should be able to demonstrate that a surrogate biomarker is reasonably likely to depict the positive effect of the drug, ie leading to an improvement in the patient's condition.


Now realise that there wasn't a great chance of us achieving positive results in just 6 months, specially structurally....we did achieve this in just 6 months. We even got decent p values when n was incredibly low. That wasn't supposed to really happen., We were never intentionally powered for that.


This means the drug effect size was off the charts.


The FDA also guides us with what are some examples of what they are looking for:

A diagnostic product intended to improve diagnosis or detection of a serious condition in a way that would lead to improved outcomes.


A product intended to mitigate or prevent a serious treatment-related side effect (e.g., serious infections in patients receiving immunosuppressive therapy).



A product intended to avoid or diminish a serious adverse event associated with available therapy for a serious condition (e.g., product that is less cardiotoxic than available cancer therapy).


A product intended to prevent a serious condition or reduce the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease.



In my opinion:

We do lead to improved outcomes.
We have a product that mitigates a serious treatment side effect (opioids!)
We do result in the avoidance of potential serious adverse effects, look at our pivotal rescue medication...resulting in a much less dependence and usage of the poor standard of care as observed recently in our 6 month 008 rescue medication data.

...And possibly the biggest one, the fact that we finally have a drug that can address the progression of OA to a bending of the potential course away from a more advanced stage of the disease or at least delaying this time. This is key for an AA.. It actually comes down to a measure referred to as Quality of Life Years. The insurers and payers look at this together with the actuaries, those real statistical boffins that churn the numbers to find out the cost of risk and what is worth insuring and to what extent.





The FDA look at either of two concepts, a drug under investigation where it could address an unmet condition to which there is no current drug providing the benefit of our drug AND/OR they look for a drug that would mitigate the safety concerns of currently available therapies.

What if we do both?
What if our drug provides much higher and meaningful pain relief and material function improvement but, even more extraordinarily, it results in first time ever seen DMOAD AND it has an immaculate safety basis?



In part 2 we learn of a very pivotal observation required that can make all the difference in the Accelerated chances arena. We won't just learn about this in theory, we will see how it applies to us and what, if any, evidence is out there that might just support us. Yeah, I like to make things personal. I like to think we have a fighting chance of really knocking out the authorities with raw and never seen before exemplarily evidence for an amazing accelerated application one day!