In Part 1 we got some good overview by way of background from the Ghosh paper. We also had a high overview of what is required for a DMOAD and we had a taste of some 008 data that backs up what is required for a DM determination and the possible labelling of such.
It's in part 2 that we will explore some of the results the researchers uncovered and you know what, it occurred in a study arm that consisted of greater than n=50.
Were the results any good, were they significant? What clues does this hold for us once we start our Phase three in earnest. I'm hoping we are literally weeks away?Once we get that first dosing announcement, I know the PAR plane will finally be on cruise mode!
PAR Airlines on cruise mode.
POWER UP
When I read this statement below, I got Goosebumps. It's kinda like Deja-Vous in reverse.
Rather than paraphrase it, let me reproduce it in full:
"A power analysis determined that to achieve 80% power at an alpha level of 5%, we would need 180 patients (90 per group) to show a 20% improvement in VAS scores for the primary end points. However, in an interim analysis, the response was sufficiently strong in the NaPPS group to suggest that statistical significance could be achieved with".
Such is the power of iPPS, they got better results at interim and so could reduce n to just 114.
But I got a bonus for you...114 isn't 114.
That was in both arms combined!
Can you imagine our results at n= 233?
Granted though, we are taking a reading off the top of the peak of the bell curve, so we need to compensate for that, also there might be drop outs etc The 233 number in our P3 are all in the active cohort though.
RESULTS
The first result was PGIC.
It was nothing short of incredible...
Ready for this?
"Patient global assessment of treatment effectiveness was significantly higher in the NaPPS group compared with the control group at all time points after the fourth injection (all, P < 0.006)".
. .
Let's take a look at this graphically:
I love the separation between the two cohorts, and the consistent p values.
Why do I give a lot of credence and attention to PGIC?
Because the Authorities do.
Remember the FDA values the Patient-Centred perspective. They have an entire document covering Patient reported Outcomes (PRO), here it is9:
There are FDA guides on the Definition of Meaningful change and while the numbers of course are important, the PGIC represents a holistic assessment of patient change which incorporates not only pain intensity, function improvement but an overall sense of patient wellness.
Scoring well here is going to matter. It's firmly a measure in our P3.
ADDITIONAL RESULTS
This is actually the first time I am seeing this in detail.
Take a look at the charts:
There were 4 areas within ADL measures where the Active significantly beat the Placebo group, one example was the Getting out of Bed score:
The mean score for ability to get into and out of bed was significantly higher in the NaPPS group compared with the control group at all time points (all, P 0.006) (Figure 4A).
Here is Figure 4A
Even after week 24 there is nice separation.
There was also some discussion in the Ghosh paper in regards to the Active group deriving good efficacy and thus loading up their joints by taking on more physical activity which also then lead to increased pain levels.
Another telling point that Ghosh makes is the following observation:
"Because NaPPS is not an analgesic and is cleared from the plasma within 12 hours and from body tissues within a few weeks of administration, we can suggest that the symptom relief reported by patients for up to 20 weeks after the end of administration might have been related to NaPPS modification of some aspects of OA pathobiology associated with clinical symptoms ".
Ghosh having studied Pentosan so thoroughly offers this as rationale:
"This suggestion is consistent with those from laboratory and animal model studies that found that NaPPS was associated with reduced joint inflammation, improved blood flow in subchondral bone and soft tissues, and preserved proteoglycan and hyaluronan concentrations in articular cartilage and synovial fluid".
SYNOVIAL OBSERVATIONS
A very exciting and illuminating paragraph from the Ghosh work was a reference to a couple of other studies discussed findings of 50 mg injections of PPS directly into the joints of some 14 patients that had rheumatoid arthritis.along with 28 patients that had OA. Ghosh went on to report that associations of "...a clinically significant increase in synovial fluid hyaluronan MW of 70% to 83%, probably resulting from a direct stimulatory effect on synovial fibroblasts".
This is particularly important as we know the level and consistent of hyaluronan is compromised with the onset of OA but it is PPS that these 'parameters' are normalised. Dr Ghosh also tantislises us with this line:
"Cartilage hyaluronan and proteoglycans have also been found to be preserved in the joints of animal models of OA after IM administration of NaPPS."
IPPS IN THE BRAIN
I got even more information from this study into the very first origins of the anti inflammatory sighting offered by Pentosan:
"The anti-inflammatory activity of NaPPS was first reported by Kalbhen using a rat model. Based on the findings, this investigator suggested that the anti-inflammatory activity of NaPPS was largely mediated by its ability to restabilize "leaky" peripheral vasculature and improve microcirculation in the tissues of affected joints".
I have never come across this statement before and it no doubt is the research puzzle piece before Ghosh's eventual further work on PPS.
A few of you would remember the MPS Society's 35th conference. I will include the video as an Appendix A, the word "leaky" above, triggered my memory about PPS infiltrating thru the Blood Brain Barrier.
Paradigmers, the levels of this inflammatory marker fell by a lot.
20%?
More
50%?
Even more.
Here is a chart that was presented in the conference.
Yes, thats a 90% reduction in IL=8 levels.
I bring this up here because Ghosh et al reports the following:
"The reduced levels of LOX metabolites produced by the leukocytes in patients treated with NaPPS could be associated with diminished production of leukotrienes, such as 5HETE, diHETEs, and LTB 4. LTB 4 is a particularly potent proinflammatory mediator stimulating neutrophil adhesion, chemotaxis, and degranulation. 31 In addition, LTB 4 can induce the synthesis of interleukin-8 and platelet-activating factor, 566 P. Ghosh et aL which can also perpetuate the inflammatory process. "
The takeaway here is that LTB4 is a particularly potent inflammatory mediator. It also in turn stimulates production of IL8. IL8 is heavily involved in brain inflammation and that itself has been associated with a number of brain related disorders. See also Appendix A where I will elaborate a little more on this concept.
There were a number of other sightings and observations however, I am deferring these for another separate Mozz post later this year. I believe this particular study has been presented by PAR in a number of key meetings as also indicated by the recent presentation by Dr Donna Skerrett.
Another classic from Dr Ghosh and team. It was indeed quite an insight to say the least.
Mozz
DYOR is prudent
ACKNOWLEDGEMENT
If....ok WHEN, we really make it, I will definitely be attributing our success to the PAR team, but that certainly includes the late P Ghosh. Without his work and the collaboration of Paul, we never would have had such detailed insights into the workings of Pentosan and the progression of human clinical trials. The Co Author, Margaret Smith, has also done some great work, some of which I will be featuring either later this year or next year. It will no doubt be the largest single body of research, interpretation and publishing I will have ever undertaken and possibly will ever do in connection to iPPS.
APPENDIX A
I had the good fortune to briefly meet Dr Simonaro from the Icahn School of Medicine, Mount Sinai, NYC at the 2023 Oarsi Conference in Vienna. She also is waiting patiently for PAR to progress so that she can one day give real and meaningful relief to her patients in the MPS field.
The video below goes through a number of great concepts covering the role of inflammation in such diseases as MPS. So great is the destructive role of MPS, the researchers bred a normal mouse that had a defect that causes it to never develop inflammation and bred it with a mouse that had MPS VII. This resulted in a mouse that had MPS VII but NO inflammation. Scientifically this is called a Double Knock Out (DKO) mouse.
Take a look at the red arrow below which I have added. This mouse is the DKO, it's snout is not as elongated as the normal mouse BUT it is not as short as the MPS VII Mouse. The same with the Green and Black Arrows depicting the equivalence in femur bone length. You can then compare the two mice (Normal and DKO) with the MPS VII that has the disease BUT also has roaring high levels of inflammation. It is the evil combination of chronic inflammation coupled with the MPS disease that results in marked disease phenotypes.
Guys, my point? IPPS materially addresses inflammation.
Dr Simonaro also observed Pentosan acting in the Cerebral Spinal Fluid, thus eliciting a reduction of inflammation in the brain. Here are the "squigglies" she mentions in the below video:
What you are observing in the above figure is the top three panels depict that Inflammatory marker known as GFAP, but in the iPPS treated panels at the bottom, there is less of this inflammation as indicated by less quantities of GFAP.
A truly amazing insight for us, for MPS sufferers in the future but excitingly (although very, very early days still) potentially, for various conditions of the brain.
The below video contains some excellent material, I commend it to you if you have never seen it. After a number of years, I still remember the poster @Robbie1 posting this originally.
MAIN REFERENCE https://www.sciencedirect.com/science/article/pii/S0011393X05001311?via%3Dihub
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(20min delay)