GrandRhino
Founding Member
Written by @Mozzarc
ou've heard of Christmas in July...well this is Christmas in late May...
Oh this will be rich, whatever is Mozz on about now? He has lost it totally this time?
Investors, I want to start with an acknowledgment...thanks to the poster, @Denial. Apologies in advance for the dad pun but there is NO denial that I hadn't come across this presentation by Dr Mukesh and it was only cos of Denial that I saw it. But its what was in it that caught my eye...
It made me bump up this proposed post right up the scale.
Why? Well read on....
Tonight, an important post, and you will get a sense of just what the heck I mean about Christmas being somewhat earlier, in my view...
Please do now enjoy.
A CHRISTMAS BACKGROUND
Ahh Christmas was always special to me as a kid...the fact that we were on holidays, the fact of presents and the lights and decorations. Now we grew up in a pretty humble house...no silver spoons, a few wooden ones and just enough stainless steel ones.... My folks saved like crazy beans...the benefits of their hard work are now as they age, certainly not a lavish lifestyle but they can afford the basics and are happy. They lived within their means. Christmas time as a kid meant presents and though they were simple, they were great!
A Magic time...
Tonight, I received a Christmas present. In fact so great it is, I would've wanted something not unlike this at 008 interim read out!
But as usual, we first need some science...we need some background, so you can understand just what exactly the heck I'm on about ....
THE SCIENCE
CTX II - What is this precisely?
Well its a shorter name for C-telopeptide fragments of type II collagen. 1
Mozz Speak
Sometimes you will see CTX II prefixed with a little u or a little s...
Here is the key:
u = urinary
s= serum
Serum is basically a blood sample (centrifuged to removed out the clotting parts, what you have left is a liquid, this is serum).
Ok for me to explain this 'C' and 'N' terminal bit we need a basic example of something else and then we'll come back to what this CTX II is all about.Detergent is a good example here. When I wash the dishes I, like a lot of you....ok well ALL of you, use a detergent and I clean up the dishes. SIMPLE.
Yeah but what's actually happening here?
A process we take for granted, there is real chemistry in the every day task of washing up ...
The detergent molecule itself has two ends...a hydrophilic end and a hydrophobic end....(yeah I haven't looked this stuff up from Mr Google because I remember my dad teaching me this stuff in Year 12 Chem, yep, he was a teacher!). What this means is that the hydrophilic end gets attracted to water...and the hydrophobic end isn't attracted to water, it gets attracted to OIL!
(Phobic, like phobia means a non interest, repellent, opposite for philic)
So what happens is the oil loving end sticks to your dirt/grease off your plate and the water loving end gets attracted to water...so you put on the detergent, it picks up the dirt and then you rinse with water and the entire detergent molecule along with the dirt gets washed away due to the attraction of the water.
Its the same sorta concept with this CTX II thing, it has two ends, a C end and and an N end.A diagram here might help:2
Lets chat a little about collagen.
Yeah this baby is important, collagen makes up something between 25 and 30% of our entire bodies, think of it as the structural fibres that is the main component of connective tissue.Yeah you want good collagen...
Now we have the appropriate background to continue...
THE QUESTIONS
https://hotcrapper.com.au/attachments/image-png.4392766/?temp_hash=976c228fd2a89a93e3e5211ccd426af8
These are the questions we should now ask....
WHAT HAS CTX II to do with Knee OA?
CTX-II reflects cartilage degradation, it can infer cartilage breakdown. The more the CTX II you have in your urine, the greater the chance your cartilage is undergoing this breakdown.
Can CTX II be a biomarker for knee OA?
Well the answer to this is YES!
Lets take an in-depth look at some discovered relationships here.
Here is a quote from a research paper:
"...the biomarker CTX-II comes from destruction of type II collagen, exclusively in joint cartilage". 3
Another study took a control group of elderly people and compared them with groups that had OA and specifically looked at two markers, CTX II and YKL-40. Here is the researchers conclusion:
"Combined detection of serum CTX-II and YKL-40 can improve the sensitivity of early OA diagnosis, and it has an important diagnostic value for early OA patients. Therefore, it can be used as a biological indicator for early OA diagnosis, severity assessment, and evaluation of treatment effects". 4
Yet another study group had this statement in terms of results:
" uCTX-II was more strongly associated with the bone markers than with the other cartilage markers, while the other cartilage markers were not so strongly associated with the bone markers". 4.2
Ok how about some more novel science...check this out:
Here is a study that used fluorescence to effectively track and count the sCTX-II and uCTX-II microbeads tracking the CTX assays ...here is their conclusion:
"The results from the developed FMGC assay showed high correlation with those obtained in ELISA. The completion time of the FMGC assay was 24-fold and 3.5-fold shorter than the ELISA for urinary and serum CTX-II. Taken together, it enabled the simultaneous detection of both sCTX-II and uCTX-II. This FMGC-based assay would be a promising tool for monitoring of osteoarthritis". 4.5
Strength in Numbers?
How about a paper that compared some thirteen studies spanning some 2856 patients and check out that p value below...!
"Thirteen studies involved a total of 2856 participants were included. Pooled SMD showed that urinary CTX-II levels were significantly elevated in knee OA group compared to controls (SMD 0.82; 95% CI 0.41-1.24; P < 0.0001). For KL 3 to 4 versus KL 2, higher urinary CTX-II levels were found in severe knee OA patients". 5
...Read their subsequent conclusion:...
"Conclusion: This is the largest scale meta-analysis assessing the diagnostic performance of urinary CTX-II levels as biomarker for knee OA. According to our findings, urinary CTX-II levels have a potential to distinguish knee OA patients from healthy controls which can serve as biomarker for knee OA".
Ok one more (there are a few more but I think I'm getting my point across here)....this one was a study conducted in Rotterdam, this gives us specific fold increases and was based on a mean follow up of some 6.6 years, as our mate @Eire2011 recently stated, you get a sense of just why it takes so long for some of these drugs to come online, you need longer durational studies to form such amazing and comprehensively thorough conclusions.... have a read, it's mind blowing:
"Subjects with a CTX-II level in the highest quartile had a 4.2-fold increased risk of having radiographic OA of the knee (95% confidence interval [95% CI] 2.5–7.0) and of the hip (95% CI 2.2–7.8) compared with subjects with a CTX-II level in the lowest quartile. We observed a substantially stronger association between CTX-II levels and radiographic OA for subjects with hip pain (odds ratio [OR] 20.4, 95% CI 2.3–185.2) than for those without hip pain (OR 3.0, 95% CI 1.5–6.0). Subjects with a CTX-II level in the highest quartile had a 6.0-fold increased risk for progression of radiographic OA at the knee (95% CI 1.2–30.8) and an 8.4-fold increased risk for progression of radiographic OA at the hip (95% CI 1.0–72.9). All of these associations were found to be independent of known risk factors for OA, such as age, sex, and body mass index". 6.5
Mate, the executive summary from that paragraph above is a 6 and 8 fold increase of Knee and Hip OA in the highest quartile of CTX-II measures. This eludes to a powerful link.
Ok so you get the picture, there is some hard core evidence of the relationship between OA and CTX II.
Recap time - Why do we care, so what if they are correlated?
Because this can be used as a predictor for OA, this can be used potentially as a marker...how is your OA progressing, are you at risk...? If there is a STRONG correlation, our drug bringing these levels down safely will become all the more important, all the more relevant and all the more CHANCE of getting a possible earlier approval and/or being in the race of a much larger tie up. At the end of the day, this, as shareholders, is what we want.
Yes I understand Mozz that there is some quantitive research here but what about qualitative?
Well in truth all of the above are peer reviewed, but how about something that's even more recognised by the authorities....
I'm now talking consortium, none other than a specially set up group to look at biomarkers, their predicative nature in the OA space and this to be conducted over a longer period of time involving a number of Key Opinion Leaders.
I present to you the FNIH (Foundation of National Institute of Health Consortium).7 The FNIH is located in North Bethesda, Maryland.
For this research, these guys were led by Dr Hunter (Sydney) and presented their data back in 2015 to OARSI.
What indeed did they find?
Mate, the slide deck is like 119 slides long 8, but I've filtered it down to just one that has the most relevance to us:
In more detailed words, they stated:
"The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXIα both significantly predicted case status (OR 1.29 and 1.20, respectively)".9
OR means Outcome Rating Scale, see reference 10 for more details on what this is and how reliable such a scale is in the setting of patient outcomes analysis.
The above conclusions coming from these guys caries weight. The 119 page slide deck is actually worth flipping through (see reference 8), how they came up with these biomarkers and some of the charts are quite interesting. The long and the short of it is that this is the sort of predictive data the FDA want...It is a requirement for a faster pathway for us if there is any possibility of that occurring.
The thing I love is that we aren't just pursuing ONE Biomarker from ONE single sub group, we are investigating a number that spans not only biochemical markers, but importantly, the structural ones as well (think Joint Width Space, the all important effect on physical BMLS, MRI analysis etc)...
PAR will be presenting our data at some point in the future to the FDA, it will be pivotal. (My views).
But for me, that's still not enough.
Huh?
I WANT THIS TO BE PERSONAL
Paradimgers, I love independent data, I want lots of it from different and wide sources. I want it from top researchers, I want it from the KOL's, I want it from independent teams that derive great results of Pentosan (Injectable version!) from animal studies and of course human studies. I don't just want one class of animal, ie. mice and rats...I want to know what we can do for donkeys..for horses, for dogs and the odd camel too... I want the biology, I want the Chemistry and very importantly I want to here it from human patients....their personal accounts...
But, and this is the CHRISTMAS PRESENT like bit....we can see, for the very first time EVER...our own data on a particular biomarker (CTX-II) that I have had on my radar for some time now.
Gee I'm not wanting much...
What did WE ourselves observe in our Phase 2 B ?? NOT only I want to see IF our own levels of CTX II came down, I want to see by what %....for the first time I am seeing this:
Wait...hold everything, is that a 25% reduction in CTX II levels ???? 25 % ??
Super....exciting yes...but I want a little more...I want the comparison...how much did PLACEBO fall ?? If placebo fell by more than the super impressive 25% that iPPS CTX II falls then our data is invalidated, well its not meaningful right? It will be rejected....
Lets take a look! (unwrap this baby):
Investors...now that's what I call a result.......Placebo CTX-II went the OPPOSITE way... and not just marginally, look at those percentages!
How many patients, how many investors, how many people know this?
This is our raw data. This is why our current SP disconnect means nothing.
Indeed - Merry Early Christmas/Happy Holidays to you all.
DYOR
REFERENCES
1) https://bmcmusculoskeletdisord.biom...t=Background,as a biomarker of osteoarthritis.
2 https://www.sciencedirect.com/topics/neuroscience/telopeptide
3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519574/
4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307395/
4.2) https://pubmed.ncbi.nlm.nih.gov/22689318/
4.5 https://pubmed.ncbi.nlm.nih.gov/25172026/
5) https://journals.sagepub.com/doi/full/10.1177/1947603518798884
6) https://www.oarsijournal.com/articl...,bone turnover - Osteoarthritis and Cartilage
6.5 ) https://onlinelibrary.wiley.com/doi/abs/10.1002/art.20332
7) https://fnih.org/our-programs/bioma...s Project,OA progression and symptomatic pain.
8) https://oarsi.org/sites/default/files/library/2015/pdf/fnih_2015_pre_congress_workshop_final.pdf
9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851287/
10) https://www.myoutcomes.com/outcome-rating-scale
Oh this will be rich, whatever is Mozz on about now? He has lost it totally this time?
Investors, I want to start with an acknowledgment...thanks to the poster, @Denial. Apologies in advance for the dad pun but there is NO denial that I hadn't come across this presentation by Dr Mukesh and it was only cos of Denial that I saw it. But its what was in it that caught my eye...
It made me bump up this proposed post right up the scale.
Why? Well read on....
Tonight, an important post, and you will get a sense of just what the heck I mean about Christmas being somewhat earlier, in my view...
Please do now enjoy.
A CHRISTMAS BACKGROUND
Ahh Christmas was always special to me as a kid...the fact that we were on holidays, the fact of presents and the lights and decorations. Now we grew up in a pretty humble house...no silver spoons, a few wooden ones and just enough stainless steel ones.... My folks saved like crazy beans...the benefits of their hard work are now as they age, certainly not a lavish lifestyle but they can afford the basics and are happy. They lived within their means. Christmas time as a kid meant presents and though they were simple, they were great!
A Magic time...
Tonight, I received a Christmas present. In fact so great it is, I would've wanted something not unlike this at 008 interim read out!
But as usual, we first need some science...we need some background, so you can understand just what exactly the heck I'm on about ....
THE SCIENCE
CTX II - What is this precisely?
Well its a shorter name for C-telopeptide fragments of type II collagen. 1
Mozz Speak
Sometimes you will see CTX II prefixed with a little u or a little s...
Here is the key:
u = urinary
s= serum
Serum is basically a blood sample (centrifuged to removed out the clotting parts, what you have left is a liquid, this is serum).
Ok for me to explain this 'C' and 'N' terminal bit we need a basic example of something else and then we'll come back to what this CTX II is all about.Detergent is a good example here. When I wash the dishes I, like a lot of you....ok well ALL of you, use a detergent and I clean up the dishes. SIMPLE.
Yeah but what's actually happening here?
A process we take for granted, there is real chemistry in the every day task of washing up ...
The detergent molecule itself has two ends...a hydrophilic end and a hydrophobic end....(yeah I haven't looked this stuff up from Mr Google because I remember my dad teaching me this stuff in Year 12 Chem, yep, he was a teacher!). What this means is that the hydrophilic end gets attracted to water...and the hydrophobic end isn't attracted to water, it gets attracted to OIL!
(Phobic, like phobia means a non interest, repellent, opposite for philic)
So what happens is the oil loving end sticks to your dirt/grease off your plate and the water loving end gets attracted to water...so you put on the detergent, it picks up the dirt and then you rinse with water and the entire detergent molecule along with the dirt gets washed away due to the attraction of the water.
Its the same sorta concept with this CTX II thing, it has two ends, a C end and and an N end.A diagram here might help:2
Lets chat a little about collagen.
Yeah this baby is important, collagen makes up something between 25 and 30% of our entire bodies, think of it as the structural fibres that is the main component of connective tissue.Yeah you want good collagen...
Now we have the appropriate background to continue...
THE QUESTIONS
https://hotcrapper.com.au/attachments/image-png.4392766/?temp_hash=976c228fd2a89a93e3e5211ccd426af8
These are the questions we should now ask....
CTX-II reflects cartilage degradation, it can infer cartilage breakdown. The more the CTX II you have in your urine, the greater the chance your cartilage is undergoing this breakdown.
Well the answer to this is YES!
Lets take an in-depth look at some discovered relationships here.
Here is a quote from a research paper:
"...the biomarker CTX-II comes from destruction of type II collagen, exclusively in joint cartilage". 3
Another study took a control group of elderly people and compared them with groups that had OA and specifically looked at two markers, CTX II and YKL-40. Here is the researchers conclusion:
"Combined detection of serum CTX-II and YKL-40 can improve the sensitivity of early OA diagnosis, and it has an important diagnostic value for early OA patients. Therefore, it can be used as a biological indicator for early OA diagnosis, severity assessment, and evaluation of treatment effects". 4
Yet another study group had this statement in terms of results:
" uCTX-II was more strongly associated with the bone markers than with the other cartilage markers, while the other cartilage markers were not so strongly associated with the bone markers". 4.2
Ok how about some more novel science...check this out:
Here is a study that used fluorescence to effectively track and count the sCTX-II and uCTX-II microbeads tracking the CTX assays ...here is their conclusion:
"The results from the developed FMGC assay showed high correlation with those obtained in ELISA. The completion time of the FMGC assay was 24-fold and 3.5-fold shorter than the ELISA for urinary and serum CTX-II. Taken together, it enabled the simultaneous detection of both sCTX-II and uCTX-II. This FMGC-based assay would be a promising tool for monitoring of osteoarthritis". 4.5
Strength in Numbers?
How about a paper that compared some thirteen studies spanning some 2856 patients and check out that p value below...!
"Thirteen studies involved a total of 2856 participants were included. Pooled SMD showed that urinary CTX-II levels were significantly elevated in knee OA group compared to controls (SMD 0.82; 95% CI 0.41-1.24; P < 0.0001). For KL 3 to 4 versus KL 2, higher urinary CTX-II levels were found in severe knee OA patients". 5
...Read their subsequent conclusion:...
"Conclusion: This is the largest scale meta-analysis assessing the diagnostic performance of urinary CTX-II levels as biomarker for knee OA. According to our findings, urinary CTX-II levels have a potential to distinguish knee OA patients from healthy controls which can serve as biomarker for knee OA".
Ok one more (there are a few more but I think I'm getting my point across here)....this one was a study conducted in Rotterdam, this gives us specific fold increases and was based on a mean follow up of some 6.6 years, as our mate @Eire2011 recently stated, you get a sense of just why it takes so long for some of these drugs to come online, you need longer durational studies to form such amazing and comprehensively thorough conclusions.... have a read, it's mind blowing:
"Subjects with a CTX-II level in the highest quartile had a 4.2-fold increased risk of having radiographic OA of the knee (95% confidence interval [95% CI] 2.5–7.0) and of the hip (95% CI 2.2–7.8) compared with subjects with a CTX-II level in the lowest quartile. We observed a substantially stronger association between CTX-II levels and radiographic OA for subjects with hip pain (odds ratio [OR] 20.4, 95% CI 2.3–185.2) than for those without hip pain (OR 3.0, 95% CI 1.5–6.0). Subjects with a CTX-II level in the highest quartile had a 6.0-fold increased risk for progression of radiographic OA at the knee (95% CI 1.2–30.8) and an 8.4-fold increased risk for progression of radiographic OA at the hip (95% CI 1.0–72.9). All of these associations were found to be independent of known risk factors for OA, such as age, sex, and body mass index". 6.5
Mate, the executive summary from that paragraph above is a 6 and 8 fold increase of Knee and Hip OA in the highest quartile of CTX-II measures. This eludes to a powerful link.
Ok so you get the picture, there is some hard core evidence of the relationship between OA and CTX II.
Recap time - Why do we care, so what if they are correlated?
Because this can be used as a predictor for OA, this can be used potentially as a marker...how is your OA progressing, are you at risk...? If there is a STRONG correlation, our drug bringing these levels down safely will become all the more important, all the more relevant and all the more CHANCE of getting a possible earlier approval and/or being in the race of a much larger tie up. At the end of the day, this, as shareholders, is what we want.
Yes I understand Mozz that there is some quantitive research here but what about qualitative?
Well in truth all of the above are peer reviewed, but how about something that's even more recognised by the authorities....
I'm now talking consortium, none other than a specially set up group to look at biomarkers, their predicative nature in the OA space and this to be conducted over a longer period of time involving a number of Key Opinion Leaders.
I present to you the FNIH (Foundation of National Institute of Health Consortium).7 The FNIH is located in North Bethesda, Maryland.
For this research, these guys were led by Dr Hunter (Sydney) and presented their data back in 2015 to OARSI.
What indeed did they find?
Mate, the slide deck is like 119 slides long 8, but I've filtered it down to just one that has the most relevance to us:
In more detailed words, they stated:
"The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXIα both significantly predicted case status (OR 1.29 and 1.20, respectively)".9
OR means Outcome Rating Scale, see reference 10 for more details on what this is and how reliable such a scale is in the setting of patient outcomes analysis.
The above conclusions coming from these guys caries weight. The 119 page slide deck is actually worth flipping through (see reference 8), how they came up with these biomarkers and some of the charts are quite interesting. The long and the short of it is that this is the sort of predictive data the FDA want...It is a requirement for a faster pathway for us if there is any possibility of that occurring.
The thing I love is that we aren't just pursuing ONE Biomarker from ONE single sub group, we are investigating a number that spans not only biochemical markers, but importantly, the structural ones as well (think Joint Width Space, the all important effect on physical BMLS, MRI analysis etc)...
PAR will be presenting our data at some point in the future to the FDA, it will be pivotal. (My views).
But for me, that's still not enough.
Huh?
I WANT THIS TO BE PERSONAL
Paradimgers, I love independent data, I want lots of it from different and wide sources. I want it from top researchers, I want it from the KOL's, I want it from independent teams that derive great results of Pentosan (Injectable version!) from animal studies and of course human studies. I don't just want one class of animal, ie. mice and rats...I want to know what we can do for donkeys..for horses, for dogs and the odd camel too... I want the biology, I want the Chemistry and very importantly I want to here it from human patients....their personal accounts...
But, and this is the CHRISTMAS PRESENT like bit....we can see, for the very first time EVER...our own data on a particular biomarker (CTX-II) that I have had on my radar for some time now.
Gee I'm not wanting much...
What did WE ourselves observe in our Phase 2 B ?? NOT only I want to see IF our own levels of CTX II came down, I want to see by what %....for the first time I am seeing this:
Wait...hold everything, is that a 25% reduction in CTX II levels ???? 25 % ??
Super....exciting yes...but I want a little more...I want the comparison...how much did PLACEBO fall ?? If placebo fell by more than the super impressive 25% that iPPS CTX II falls then our data is invalidated, well its not meaningful right? It will be rejected....
Lets take a look! (unwrap this baby):
Investors...now that's what I call a result.......Placebo CTX-II went the OPPOSITE way... and not just marginally, look at those percentages!
How many patients, how many investors, how many people know this?
This is our raw data. This is why our current SP disconnect means nothing.
Indeed - Merry Early Christmas/Happy Holidays to you all.
DYOR
REFERENCES
1) https://bmcmusculoskeletdisord.biom...t=Background,as a biomarker of osteoarthritis.
2 https://www.sciencedirect.com/topics/neuroscience/telopeptide
3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519574/
4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307395/
4.2) https://pubmed.ncbi.nlm.nih.gov/22689318/
4.5 https://pubmed.ncbi.nlm.nih.gov/25172026/
5) https://journals.sagepub.com/doi/full/10.1177/1947603518798884
6) https://www.oarsijournal.com/articl...,bone turnover - Osteoarthritis and Cartilage
6.5 ) https://onlinelibrary.wiley.com/doi/abs/10.1002/art.20332
7) https://fnih.org/our-programs/bioma...s Project,OA progression and symptomatic pain.
8) https://oarsi.org/sites/default/files/library/2015/pdf/fnih_2015_pre_congress_workshop_final.pdf
9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851287/
10) https://www.myoutcomes.com/outcome-rating-scale