The Doctor Forum II - AF & FDA Round Table Discussion

“For OA, we still need a lot — we need progress in new pharmacologic agents, we need more topical, we need injectable, we need orals, we need biologic.”⁰

- Dr Jasvinder Singh (Member of the FDA Arthritis Advisory Committee)

onight a Mozz special....I cover another amazing workshop video which covers a number of topics, some of which I feel will give us a sense of the real potential demand one day for iPPS. Yes we know OA is big and affects many, but when we go quite granular we get a sense of just what is the need and from a patient's perspective, what is going to drive them to adopt our iPPS that will most likely deliver one fine day.

Oh and the subject for this post? AF = Arthritis Foundation and the FDA we all know as the Federal Drug Administration. These two parties recently came together for a round table workshop, this post is a summary of what was covered.

This forum indeed was a bit of a marathon, I've tried to syphon the best and relevant parts to us into this post. Again I won't just be copying and pasting what I thought were the good points, I will point them out and Mozzify them, this means to draw parallels for us, how is it relevant to us and how can we benefit from this info?

I'm again splitting this post into two parts plus a third later on to make it slightly easier to digest and easier for me to edit! References can be found at the end of part 2. Part 3 will come out after about a week and will contain more notes and will center upon Questions and Answers from the forum. There was just too much material to post all at once!

As per usual, please enjoy, at least as much as I did listening, interpreting and summarising, not only for you...but for my benefit too! An educated and informed PAR investor is so much more ahead of the pack, don't you think?



INTRODUCTION

Specially earlier on I always wondered how much the FDA knew about all the possible OA solutions out there including ours. They now would have a good sense of what we are about. Sure they will apply their high safety standards to all drugs....but recently I got a good clue as to how acute their awareness actually is. This is apparent in just two segments of evidence:

• The classification of OA being labelled as a serious type of disease and
• A very recent conference held between the FDA and The Arthritis Foundation (USA) which tonight's post is based on.

If you have the time be sure to watch the forum, be warned it's quite long when you add all the parts, It's a good forum and you will learn quite a bit on the current rationale and thinking in this field. It's a fairly easy to understand presentation and mostly doesn't get too bogged down in the science. You can easily skip through parts that get boring or you don't find too captivating or relevant. The main link can be found in the reference section at the very end of Part 2.

Tonight will indeed be a journey of discovery. We will hear from some top Doc's and their thoughts on the OA scene. But not just random Doctors, this comes from some FDA staff as well as some experts in the private field. We will get a clearer sense of what the FDA look for. Later on in this Mozz special we will learn about another drug in the OA space and you will learn if there is a possible competition to us and how their efforts are going.

We will read and learn about a couple of clues that can boost the chance of clinical success by a factor of 3....(yes Paradigm has employed the strategy).We'll even cross suspension bridges and talk about some castle type defences and how all of this is even remotely connected to PAR and YOUR holding. But first, let's hear from a patient.



PART 1


A PATIENT PERSPECTIVE

A whole segment is dedicated to a patient, Bill Agee, that has had OA since 1995. He has accomplished a lot in his working life but he suffers terribly from OA. The takeaway is that sleeping at night is one of the biggest challenges. It is in this very area that the data so far published by PAR seems to be one of the highest in terms of positive results. Here is a snapshot of what Bill has endured since 1995:

• 23 knee surgeries
• 1(left) knee replacement
• Peroneal nerve decompression due to scar tissue from 23 procedures
• Lumbar spinal fusion (L3 to L5) due to severe OA
• Two surgeries of right ankle from fracture of right fibula
• Post traumatic OA due to removal of hardware from surgery of ankle procedures.

He said he was extremely lucky to not have had any infections as a result of the above.Currently he is facing the difficult decision between an ankle fusion and an ankle replacement.

If this guy isn't a perfect candidate for iPPS, to at least try it...I'll eat my hat. Multiple areas of pain...yes one could state that he has already had a lot...but he is still in pain...after all the procedures.

He recounts a typical shopping trip to Costco...he can only go if he is accompanied by someone as it is just too painful to lift anything and after the trip he is in so much pain he is "done for the day".

Bill has not been able to go on vacation since 2015. He just can't walk that far without the onset of pain or sit in a plane for so long, ironic as he has some two million frequent flier points built up from his prior days of travelling.

"There is nothing that seems to work consistently"

At the same time he refuses to take opioids as he is aware of what they can do. He has tried all of the NSAIDS and is takes Tylenol for pain. He wakes up on average 14 times a night. Paradigmers, it's at this stage I want to remind you that Sleep at night was the single best category that we have seen in the data so far in terms of positive effects on pain categories by iPPS:



_{iPPS's recent results. Sleep at night was a stand-out.}


"If I think about pain management goals, I would love to have no pain." Bill went on to state, "I think ideally my utopia would be the release or approval of some new drugs to eliminate the pain".

He finally pays tribute to three docs that have managed to put the workshop together (some Docs were from the FDA) and he has one wish to continue to hold these such workshops.Paradigmers, I will push for us to one day be featured in such future workshops. I want us to be a truly possible candidate to provide at least some relief to such suffering patients. I want to see our slides at a forum like this showing the great results we have.

Now I understand that this is just one patient case...but my point is PGIC. Thats Patient Global Impression of Change.....There would be many in this guy's situation, there would be many more that are leading up to at least some part of his experience....the numbers that are in pain are vast....

The other point I want to make here is that this guy's testimony was brought forward into such a conference by some of the leads within FDA and one of the staff members commented that FDA management were also listening into the forum. I have no doubt at all the focus the FDA has...

I'm pretty convinced that they are going to work hand in hand with us to get us over the line. They are not just some distant body that are trying to make our lives difficult. Quite the contrary, I believe that despite their workload and their focus being on other global events at the moment, we have a real good shot ...a real good chance of getting over that line...the opening of the IND.

Now like any disclaimer I must state that there is still some sort of chance that we could get further questions, some more delay, I can't rule that out, but I believe the chance of an opening of an IND soon is increased. (My views). My fingers are crossed.


DAAP

No DAAP wasn't a typo...DAAP is a division of the FDA and it's full form is Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP).

The next segment is based on a speaker from the FDA division known as CDER. They stated that traditionally the end points used in OA drugs included:


WOMAC PAIN

WOMAC FUNCTION

PATIENT GLOBAL ASSESSMENT


However, there seems to be a shift and they are more considering the intensity or pain of OA as a possibility (improvement from baseline).

Paradigmers, how good it will be for us to blast away all of those criteria ...and importantly, to do this safely.The below slide was presented and the two criteria bolded below are considered to be the most clinically relevant efficacy outcome measures for the relief of OA.






WHAT DOES THE FDA LOOK FOR IN TERMS OF SAFETY?

Some of the highlights were covered by the next FDA speaker and included:

Short Term- Inflammatory and immunogenic reactions, contamination/infections
Long Term- Ectopic tissue formation, acceleration of cartilage degradation, tumorigenicity


Let's tackle some of these:

Inflammatory reactions? Quite the contrary, iPPS has shown to REDUCE this.

Infections - this is stated as a number of RA solutions that are classed as immunosuppressants can lead to an increase in infections as the immune system is effectively dulled. Does not apply to our molecule. We don't suppress or block the immune response, we downregulate it, big difference.

Acceleration of cartilage degradation - this has been observed at higher frequencies with the use of NSAIDS. Again we may have the opposite effect...(subject to trial observations).

To be further evidenced via our important Synovium study, 008, we should be able to go the other way...IMPROVED cartilage retention and even some enhancements in certain subjects. (My views).

Tumorigenicity, a lot of drugs out there will have good efficacy against the target indication, but it kinda defeats the purpose if it results in an increase in cancer or some other nasty, right? Again there is evidence that iPPS can be used to decrease the chance of tumours!



LOT MORE INVOLVED

The next speaker, Dr Tim McAlindon, gave a good background on how the thinking of OA has progressed over the years.

We are now at the stage where it is agreed that OA is a disease that involves the whole joint, "A lot more tissues are involved in OA than just cartilage".Indeed this Doc highlighted a separate study which would be an entire separate Mozz post to cover, some quotes to highlight the point:

"... findings indicate that structural changes in the collateral ligaments of the interphalangeal joints were uniformly present even when the articular cartilage appeared normal." ...and..." the aetiology and progression of osteoarthritis should not be thought of as being invariably attributable to a single tissue, such as articular cartilage." ¹

The FDA themselves are quoted as saying that OA comprises of "multifactorial and complex etiopathogenesis".

What are some examples of 'Whole joint' and what is relevant to us?Ah this is the exciting part...Let's first list them:

1. Cartilage
2. Osteophytes
3. Subchondral
4. Mechanical
5. Neuromuscular

Err Mozz? Why should I be excited by the above? Ah that's an easy question....because we are mutilactionary!...Paradigmers, it is not just one aspect that iPPS tackles. It is not just the cartilage for instance that we address, we are in effect addressing all of the above at least to some extent and at least in the majority of patient cases. This is the beauty within.As I have said in the past, all that is great...but you add:

DURABILITY

SAFETY


into the mix, and In my accounting books, it's a cocktail of winning attributes. Sure there is still risk (though small, my views), sure it's not going to be overnight...but its getting slowly closer.



WHAT IS THE PATHWAY TO SUCCESS?

Well of course there is some use in a simple band aid....but there is a much greater demand to not only address pain and functionality in the short term, but there is a vast and plentiful demand for a longer term fix and in fact a regression. Dr McAlindon, the next speaker, summarises it beautifully:

"[There is] Need for an encompassing conceptual model that integrates the numerous pathophysiological pathways to OA with the plethora of clinical manifestations in a way that yields treatment targets to achieve disease modification".

I can obtain a number of key statements from that one line:

A) No point in having a drug that addresses just one simple aspect...perhaps such as a small degree of pain in one joint for a limited time.
B) This OA disease concept is all encompassing of the joint, the target needs to be all encompassing.
C) We ain't dealing with just one symptom, there are many manifestations.
D) Ultimate goal? Ahhhh.... Disease Modification! Indeed the Holy Grail:



_{Indiana chose wisely....not the most sparkling gem encrusted cup....a simple down to earth, natural based, reused solution. That's what I'm talking about.}


DMOAD doesn't necessarily mean an overnight cure....it can be the slowing...it can be the halting...and in some cases, we may see not only regression, but the body's regeneration. This again may not present itself even in a majority of cases, but if it does (eg if you possible treat it early enough, Mozz view) attract even a smaller fraction of the total number of arthritis sufferers, we are dealing with a very, very large market and a very lucrative one sometime down the track.



MORE THAN MEETS THE EYE

Hmm I think I should re-title this sub topic as more than meets the PAIN RECEPTOR. What do I mean? Dr McAlindon goes on to state that not only is there a weak relationship between Structural manifestations of OA and pain, but this relationship can be inverse.

Eg Lower the pain, the more the structural progression. This can be terribly misleading, imagine you manage to suppress the pain with one of those NSAIDS or worse, OPIOIDS and you are under the delusion that all is going along swimmingly...after some time you find that things under the hood are deteriorating...the next thing is you are sitting in a surgeon's office discussing the next step - not good.

Paradigmers, for true disease modification we need to address BOTH....Pain and structure. It is this potential evidence at a P3 level that is on my radar....we have seen snippets of it in our Phase 2B....reduced pain outcomes coupled with the very exciting empirical evidence of- Lowering of Size, Grade and Volume of BMLS- Positive reduction of Biomarkers such as COMP, ADAMTS-5, markers of the disease pathology.

More to come? You bet...008 around the corner...possibly early next year I'm thinking....not long to wait....7 months...maybe a fraction more....let's go 9...in the time it takes to have a baby...I reckon we might just have a powerful new born of our own...interim 008 results showing DMOAD capabilities. (My views only).

So Dr McAlindon then surmises that finally he believes though the two aspects are required for true Disease Modification, from the patient's point of view, they care less about what the x-ray's show, they are more concerned about the pain. In fact the FDA concurs that it is all about the pain. No wonder our Primary endpoint was set to Pain (and function). Yes durability and DMOAD will boost us like you wouldn't believe (my views) but tackling pain safely will be enough for Blockbuster status if we prove we are safe in a P3.


LOOMING COMPETITION?

The next speaker to present ws Dr Marc Hochberg. He presented the findings of a drug called Sprifermin. It's basically a synthesised DNA formulation. So a longitudinal study was performed over 5 years utilising two dosing groups (30 µg and 100 µg). The good news for them is that it was deemed to be safe and it actually resulted in a slowing of cartilage loss against placebo.² They are about to go into Phase 3. Looming competition for us?

Nah, not quite.

They failed the primary endpoint which was effect on WOMAC score compared to Placebo.³ Remember at the end of the day, it's firstly about pain, then it's about the structural remedies, ideally you want both for Blockbuster status (sales of over $1 Billion USD), that would come with statistical significant pain reduction that's safe and that at least has some worthwhile durability - think more than Panadol for instance.

SO while there was some benefit in terms of cartilage thickness compared to placebo for their drug, there was also no effect observed on BML's and no pain reduction compared to the placebo group.I believe they are going through to a Phase 3 but certainly compared to The Magic Juice...I think we will out-shine.As I always say, look out for competition, but there is none to date that I can find that comes close to comparison.


PHILIP CONAGHAN

Another prominent leader in the space of OA research has to be Dr Philip Conaghan. He also featured in my original post about the Good Doctor Forum and I get a feeling it won't be the last time I post about him and his work.

He presented his hypothesis that a cytokine known as IL-1 plays an integral role in the inflammatory response linked to such conditions as OA. Lots of relevance for us here.....how? It's one of the biomarkers specifically mentioned in our 008 trial:





Dr Conaghan then presented a table on the main studies in the past that had tried to specifically target IL-1. We know that there is not much success in this area as our own Paul Rennie has mentioned on several occasions the little success in targeting just one biomarker:




It's interesting to compare that last row of data from the table above to our own WOMAC results (P2B), for example with the AMG108 trial, they achieved a 63 absolute reduction in Womac score, this represents close to a 22% drop, not bad?

What was ours?

30% would be good, 40% better, ours was a wonderful 49.6% drop.⁴
Amazing:






AN OUTSTANDING OBSERVATION FOR US

Dr Conaghan then focused on the CANTOS trial. This was a trial setup for Heart Failure. It was a massive trial, some 10,000 patients studied over a duration of around 3.7 years!So this drug, canakinumab, while it did result in better heart results, it also resulted in a "higher incidence of fatal infection" compared to placebo.⁵ However, A fascinating observation after the trial was completed the researchers went back and noticed an interesting observation involving OA!

It was found that there were an astounding 40% less incidences of TKA in the treatment group. Paradigmers, this has repercussions for us. Canakinumab is a drug that results in lowering of inflammation as well as interleukin-1B. What I now want to see is how this will compare with what we observe in 008. I'm not sure if we will be privy to how each biomarker goes in terms of % reduction but if we don't get to see it, it will be a Mozz question at a future R and D day.

Outstanding.


This concludes part 1.

As the poster @88aaj commented about intel...in Part 2 I bring you more intel...how about this one, we will not only hear of an actual biomarker that is slated for observation in our very own 008 study that is progressing as I type...we will see HOW good a predictor it might actually be? We'll take a look at a few different graphics including one that actually compares radiologically the Kelly Lawrence levels of OA and we will hear more of what exactly the FDA looks for in a typical OA trial.