Picking up on a number of good points and questions (apologies...

Picking up on a number of good points and questions (apologies for not tagging every one as there are quite a few points). Just throwing my understanding out there (which could be wrong of course!).

To me, a therapeutic for the disease is ALL about pain and function (NOT biomarkers per se). Who cares if there is a shadow on an MRI if you are still in pain? Importantly, pain/function and structural biomarkers aren't perfectly correlated. We have heard Paul talk about people with no BML and still in pain, and vice versa (BMLs showing, but no pain). Hence the primary endpoints for the P3 (and all other P3 OA) trials are pain and function.

So I suspect the variation in BML responses in different compartments is real and not a typo (shown on the graph as well). I would add another point here - just as rescue mediation is a confounding (or maybe compensating) factor on pain scoring, the amount of exercise/activity could be a confounding factor for structural markers. PAR have touched on this in one of their announcements. PPS mediates pain, you do more excercise, you get a bit of inflammation which counteracts the anti-inflammatory effects of PPS etc.. so its a delicate balance (I think Mozz did a see-saw analogy once before). Perhaps the tibial compartment is slower to resolve so the balance is tilted towards BMLs at that timepoint. Maybe the tibial BML disappears at a longer timepoint?. But do you care either way if your pain is resolved for 12 months (which has been shown statistically)!

The point of doing the biomarker work (in my mind) is to support an Accelerated Approval and DMOAD. We have seen the famous Virginia Kraus slide which has been posted many times ---

The underlined words are the key to her work on recommending an AA pathway for OA. If biomarkers are "reasonably likely to predict important benefits to patients" they can be used as a surrogate endpoint for an early approval.

So a couple of things here. Firstly, the great pain results at 12 months and structural results at 6 months will each show different degrees of scatter, significance, p value etc. over placebo which is well and good (esp if below the magic 0.05). But one of the other key outcomes from the 008 trial will be - how does the long term pain outcome correlate with a short term biomarker response?? You can imagine a scenario of 2 variables, each with its own bell curve, where a) a score in one of them correlates perfectly with a score in another or b) a score in one has no correlation to a score in another (ie they are independent variables). What is the regression/correlation of an early signal, with a long term benefit?

Secondly, the words "reasonably likely". The correlation does not need to be perfect. Ultimately, for the label you need to show efficacy in pain/function over placebo to a high degree of certainty, but the biomarker correlation to support early approval just needs to be "reasonably likely". So I'm not looking at this data in isolation, although the structural changes are fantastic (and support DMOAD or course)! I imagine there would be work going on in the background to look at which biomarker changes give the closest prediction of a 12 month pain outcome, and propose for those to be included in the P3 protocol to help with AA. Ideally these same biomarkers (or different markers?) are used to define DMOAD so the label can be expanded, but I'm less clear on the whole DMOAD definition/pathway/negotiation. But clearly we are changing things and Paul made clear what PAR think of the disease modifying capabilities of PPS (courtesy of youtube translate).

Many Physicians refer to the Holy Grail of osteoarthritis is a therapeutic product that can in tandem with the symptomatic Improvement of pain and Joint function Improvement also provide structural Improvement to the Joint in other words restore cartilage volume restore cartilage thickness reduce bone marrow lesions and reduce sinovitis. Doing all of that at the same time that is the Holy Grail that is what the market is looking for so please keep that in mind today as we go through the presentation. Are we addressing a very significant unmet medical need with these data I hope you agree with us the answer is a resounding yes.