The Doctor Forum II - AF & FDA Round Table Discussion - PART 2
STATS
The next Batter up, err the next presenter was Dr Yura Kim. Not only this speaker is employed by the FDA which is further evidence that the FDA are acutely aware of the whole situation of OA and what exactly it entails BUT this staff member is from the Biostatistics area. It's another indication that the awareness of the FDA is broad.
Dr Kim started off her presentation by clearly stating that to date the available approved drugs treat only short term symptoms of OA, primarily pain and function and DO NOT TARGET THE UNDERLYING CAUSES or LONG TERM PROGRESSION OF THE DISEASE.
As I have said before, it is one thing to address pain and function, it is another to do that safely and for a longer duration but my friends and readers....it is just quite another to do all of the above AND target the underlying causation. This will be the accelerant for us long term.It is this unmet need to address the pathophysiology of the OA disease that will put us on a global stage.
More clues can be obtained by Dr Kim as to what the FDA (and the world?) are looking for in the longer term:
Xray/MRI measures of cartilage thickness improvement
Pathological remodelling of the subchondral bone
Addressing of Synovial inflammation
Assessing function and how patients feel
Discussion of Total Knee replacement
As an example the FDA will no doubt be highly interested in knowing how iPPS could potential stave off or at least reduce the numbers of TKR over time, for this, longitudinal studies would assist and in part our extension studies may at least go some way towards addressing and answering this question. Dr Kim goes into a bit of a discussion in terms of sample sizes required for various hazard ratios over time (Err yeah I kinda phased out a little during this bit) however it did give me some insight on some factors required to come up with the right sample sizes and considerations relating to that.
BIOMARKERS
This topic almost seemed like a theme for this workshop, a number of speakers presented material in this area. Very topical for us with 008 going on.
The next speaker was Dr Nikolay Nikolov.There are three broad categories of endpoints from an FDA perspective
Feels (Pain for example)
Function
Survival (in our case, survival of the joint)
He touches upon biomarkers and summarised by saying that Biomarkers in themselves would be unlikely to be able to be used as endpoints but could be a useful adjunct or secondary endpoints. Pain and Function will definately be supported by such observations and it makes sense that a subset of biomarkers will be observed as additional endpoints and of course in our separate synovial study, 008.
In his summary he states "FDA recognises the important public health need in OA and wants to collaborate with sponsors and other stakeholders to bring safe and effective treatments for OA to market".
Continuing on in regards to biomarkers and their role in clinical OA trials, the next speaker, Dr Virginia Kraus from Duke University, stated that to be clinically relevant a given study would need to show at least 9 units decline on the WOMAC pain scale...
This is good insight for us, it's nice to see WOMAC pain drop...but it is more meaningful when we know what the benchmarks are, how much of a drop is good? How much is great...and how much do I need before I can go to a pub to celebrate (after lockdown of course).
Ok so what was our WOMAC drop? Dr Kraus talks about the WOMAC 100 scale. 6 Our results were reported in the 0 - 50 scale. Thus multiplying our results by 2, we achieved an amazing 26 point drop on average! That's some 3 times the drop mentioned by Dr Kraus.
Dr Kraus then specifically forms a link between Biomarkers and screening for patients into OA trials, a stat she quotes:'Selection biomarkers' for enrolling patients into clinical studies increase the likelihood of drug approval (from 8% to 26%).CTXII is the main contender that Dr Kraus puts forward which has been around for some time as a principle biomarker used.
I know at least some of you will remember the relevance of CTXII...here is a reminder for the rest:
I'll cover off some more on CTXII in the next section with some new material about it.
Another biomarker she mentions as an emerging biomarker is CRTAC1. I know almost nothing about it, yes I'm writing it down for future research...my research topic list is supposed to become smaller over time.
Nah all good, I love it... just wish I had a little more time...
Dr Kraus then gives us an analogy of a suspension bridge, let's take a look:
She rationalises this by saying that the biomarkers can form a link to the ultimate goal which is on the other side of the bridge, namely "Clinically relevant outcomes", examples are the worsening of pain, observation via X-ray and eventually Total Joint failure and thus requirement for replacement. She states that there are two distinct ways to connect to the other side of the bridge, one by direct connection (like the cables on a suspension bridge), (see pale blue arrow in figure above), the other way is via the suspenders (I've highlight a few by red boxes on her picture above).
This immediately reminded me of our own Dr Krishnan's diagram that adeptly explains how iPPS works through its multi action. How it DIRECTLY affects....and INDIRECTLY affects. This to me, is part of the MOA...the power of our drug. There are multiple pathways it gets to the ultimate goal.
Think of these multi pathways as a backup...a multi pronged attack. Not only are we firing arrows at the enemy from the pulpit and watchtowers...but we are also employing other techniques be it cannon balls, boiling oil and forces underground travelling underneath the enemy to attack them from behind. Vivid imagination? Who, me?
Ready for more insights on these biomarkers?
Ok a study was performed to actually check how good CTXII is a predictor for knee OA progression within 24 to 48 months. The odds ratio worked out to be 1.29, in percentage terms it's a 60.8% hit rate. This means that it predicts about 2/3 of knee OA progression, it's quite high and is deemed to be a good biomarker....Paradigmers, what I'm saying to you is that if iPPS is shown to bring this biomarker down in our 008 study (like we saw in COMP levels, another biomarker in our Phase 2), it will add lots to our story. Yes sure it's frustrating when our SP does not move...when things get delayed, but once we hit real traction, I too will be smiling back at these slower days. (My opinions).
Two further studies, (titled CALCITONIN and OFELY studies) from France also formed this strong link between presence of CTXII and eventual Knee or Hip Joint failure and thus replacement:
As further proof of how these biomarkers work, it was found in another study that levels of the biomarker CRTAC1 dropped after surgery (Total Joint Replacement). This indicates the joint breakdown finally stops....now of course we don't want to have a surgery just to slow and stop this biomarker!....if iPPS can do this pre surgery and in fact in some cases avoid surgery or at the very least delay it by years....well join the dots.
Dr Kraus then went on to state there are a number of trials to further test the biomarkers to establish a connection between the biomarkers and the progression of radiographic observable OA, the FDA are in the midst of considering granting Dr Kraus and team formal qualification for the set of biomarkers. Interestingly Dr Kraus also mentioned that one of their own trial submissions had been held up due to "the overworked FDA staff who have been dealing with the very necessary Covid trials and approvals".
CONTINUING THE BIOMARKER DISCUSSION
The next speaker was Dr Jeffrey Siegel who is the Office Director of Drug Evaluation Sciences for OND/CDER/FDA.On one of his slides he presented a number of Classifications of biomarkers, namely:
Susceptibility/Risk Biomarkers
Diagnostic Biomarkers
Prognostic Biomarkers
Monitoring Biomarkers
Predictive Biomarkers
Pharmacodynamic/Response Biomarkers
Safety Biomarkers
*whew* Quite a few there, the first 4 of them above are more for measuring the disease and status, the others are more of a response type tool.
The FDA have a viewpoint in this area that there is some potential scope for biomarkers to "Support regulatory acceptability of a surrogate endpoint for accelerated or traditional approval".
I find this area to be relevant to us.
Imagine the scenario where 008 data comes back and it is examplorary, this could then enhance what is being observed in the parallel main trial (002) and lend support to a faster pathway or at least an enhanced read of the data set.Indeed the FDA has some legislation in place (also known as BEST - Biomarkers, EndpointS and other Tools) to support the use of biomarkers that deliver a strong and diverse level of evidence to support meaningful clinical outcomes (eg how a patient feels, functions or survives (joint survival in our case)). An example could be again great data being observed and a classification like accelerated approval being sought after some time after trial commencement as the data comes back.
The next speaker was amazing to hear, Dr Sharmila Majumdar, spoke so at ease with all OA concepts, it was amazing to hear her depth of knowledge flow so easily. Some good points I managed to glean:
Cartilage degradation and morphology is really the end stage. Sure I knew this but her articulation of it was poinginet. What I'm trying to say is that the start of OA is so early on, there are absolutely no visible symptoms at that early stage. Many a poster here at HC have stated that there is a real argument of getting a course of iPPS when you know there has been an injury or you know something is up...long before the real OA progression sets in.
Sure I'm no Doc, we will all need to wait for some years before such theories and hypotheses are tested at scale, but this is the early evidence we have to date.
As Dr Majumdar states, its happening at cellular level...levels of Proteoglycan for instance is just another marker, another tool in determining what is going on.Some more takeaways from her excellent presentation:
1) The Meniscus plays a major role in whole Joint Function
2) A study was conducted by looking at ACL tears and dividing up the cartilage into 5 distinct regions. Cartilage is being affected in a very short time after an ACL injury, just 2 years on. More than me attempting to summarise her presentation, take a look at this graphic:
Jeepers Mozz, what's all this?
Again, I could dedicate a full Mozz post to just this one question, to save time (I have very little of it after coming across such workshops)....here is a more detailed analysis for those that are curious. If you can't be bothered ploughing through the science, my version follows just underneath:
Results: In the posterolateral tibial cartilage, T1ρ values were significantly higher in ACL-injured knees than control knees at baseline and were not fully recovered 2 after ACL reconstruction. T1ρ values of medial tibiofemoral cartilage in ACL-injured knees increased over the 2-year study and were significantly elevated compared to that of the control knees. T2 values in cartilage of the central aspect of the medial femoral condyle at the 2-year follow-up were significantly elevated compared with control knees. Cartilage in the posterior regions of the lateral tibia was significantly thinner, while cartilage in the central aspect of the medial femur was significantly thicker than that of controls. Patients with lesions in the posterior horn of the medial meniscus exhibited significantly higher T1ρ values in weight-bearing regions of the tibiofemoral cartilage than that of control subjects over the 2-year period, whereas patients without medial meniscal tears did not.7
Mozz view of above: ACL injuries result in changes to bone and cartilage morphology within a short time (yes, 2 years is short when we are talking about the average OA onset and subsequent progression). It appears that if you split up the cartilage layer into 5 parts, some parts degrade at different rates compared to others, as Dr Majumdar states, it's all about the "early biochemical changes". ('Biomarkers in Mozz speak). The difference between someone that has no ACL injury and a person that does have an injury is generally stark. Err... Chalk and cheese...
Another slide Dr Majumdar then presents depicts the difference between an injured and uninjured tibia bone. I've placed Black Mozz arrows to highlight the difference of these localised changes in the figure below. Her point here is that you can't just take a reading across the entire bone and average it out. Its localised consistency that's the key. Look at the inconsistencies as indicated by the variation of colours in the left side compared to the right side pic. Paradigmers, remember this is just 2 years after such injuries...OA may not symptomatically present itself for years later to the patient. This is what's happening at a granular level...this is what we will we be addressing and this is also why iPPS could be so important also as a preventative measure.
The next point was that pain is highly subjective and varies not only across bones involved but patient to patient. Through machine learning this data was disseminated and while it could be determined to some extent in terms of a predictive model, it certainly varies for each patient.
A final insight by this presenter stated that when they used Artificial Intelligence modelling, many of the subjects that had to have total knee replacements after 5 years were actually classed as KL grade 0 at baseline. This has some ramifications in the fact that at least in some cases when biomarkers present themselves earlier diagnosis can be very important. I would also add again just how important it might be in the future to get it checked out earlier rather than later and then at least consider a course of iPPS if you are deemed to be at a higher risk?
MRI -v- XRAY
The next speaker was Dr Frank Roemer who took us through the differences between X Rays and MRI. Don't forget X Rays are a much older form of tech, but it is not redundant!He first started off the presentation by a good easy to understand comparison between KL grades, notice the decrease in joint space as the disease progresses.
He then presented the usual info in terms of Radiological definition of OA by the way of the following highlighted slide:
The eligibility for most trials being KL 2 and greater, with the yellow box above indicating an early to moderate classification of the disease. He then goes on to say that there is a very big BUT....he alludes to a study called 'MOST' whereby they observed that some 21% of KL 2 graded knees have in fact NO cartilage damage and some 41% in the lateral tibiofemoral joint. In addition a quarter of patients that had this lower level of OA (KL grade 2) actually had severe and widespread full thickness damage.
Paradigmers, his point here is that there is a lot more to OA than we can simply grade and that KL2/3 is NOT a homogeneous sample of early to moderate OA. Mozz speak? Just because you are officially or even radiologically classified as Grade 2 OA, this does not necessarily mean you have a long way to go before you hit the end in terms of joint stability or some sort of surgical remedial procedure.
But as Dr Roemer then gives an example of X Rays -v- MRI and in the below image you can see what he is talking about. BL is Baseline....In the top right image there is very little difference observed compared to the top left pic. But the bottom two pics tell a different story as the cartilage 'line' is thinner on the right pic compared to the left, the bottom two images are MRI images, the top two were X Rays:
Another good slide he presented was a colour coding of the various parts of the joint:
Finally Dr Roemer presented a summary on the differences between X Rays and MRI's:
Ok thats what they call a wrap....well not quite, there is a Third part to follow in about a week...this will summarise the Q & A section of the Doc II forum.
It was a really insightful forum and each speaker had just 10 minutes to go through their presentations. I think they will conduct more of these such forums and one day, maybe in a year, maybe more, I hope we get a mention!
As always, remember my views expressed throughout, there is science involved and while it is usually exact, it can be subject to interpretation. Best policy is always to DYOR.
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Xray/MRI measures of cartilage thickness improvement
Pathological remodelling of the subchondral bone
Addressing of Synovial inflammation
Assessing function and how patients feel
Discussion of Total Knee replacement
(20min delay)