Well this is quite a question to ask for sure.The Mozz issue to date has been the BBB, this stands for Brain Blood Barrier and its a membrane that the body has to protect the brain. Only molecules under a certain weight (around 4000 Dalton) can pass through. Generally the average weight of a PPS molecule is approx 5000 dalton. So in theory it can't get through.
The next question you could ask is in the case of Jonathan Simms (Read this link of you don't know about this story and how it related directly to us----> You did WHAT with Pentosan?)....how did they manage to get PPS into his brain? That was done with the aid of a catheter...
However, the researchers at Mt Sinai came across some surprising data.
A tiny bit of background first.
Cerebrospinal Fluid (CSF) is a clear, colourless body fluid that surrounds the brain and spinal cord of all vertebrates. How much do we typically have? About two thirds of a cup, around 150 ml. Its function is to add a cushioning to the brain and spinal cord, aid in delivering nutrients and assist in removal of waste. 2
It's through this fluid that samples can be taken to see what's happening on the inside....I give you two biomarkers...IL-8 and TNF-Alpha.
IL8 is not a biomarker you want to lose control over, "...its major pathophysiological role lies in affecting neutrophils".3 Neutrophils make up between 40 and 70% of vital white blood cells which make up your immune system.
TNF-Alpha - it's these guys that assist in cell signalling, they are the ones responsible for increasing an inflammatory response when the body detects there is a need.
So what then is iPPS's effect on both of these cytokines? But not just anywhere in the body, I mean from this cerebral fluid, ie WITHIN the brain?Well let's take a look at a pic:
Marvelous. Just look at the significant statistical change due to PPS in white and then further the injectable SUBQ in purple on these two inflammatory biomarkers.
Paradigmers...this is the science and these are the results so far.Now the best news is that this is not some theory in a book, some observation in a non connected unrelated lab....I say this for two reasons:
1) Paradigm have a licensing agreement with this lab. The advantage is that data from this lab can be used in the FDA submission.
2) Ahh the old 008. Yes in this synovium study which is ongoing as we speak....it will look at such biomarkers as TNF-Alpha.
PAR's Agreement with Mt Sinai.
Now I love these bar charts being positively affected as much as the next Par investor...but want I really want is an X-ray of the brain before and after to SEE the action of iPPS...actually forget X-rays, they are too dark and unless it is something really apparent like a broken bone...well you get me, I want something a bit more clearer....how about a snapshot of the brain?
You keep forgetting this is a Mozz Post™ - In fact lets go one more, lets get three snapshots of three DIFFERENT areas of the brain...
Mate, this is the clear and raw evidence of what your iPPS can do and it's being demonstrated for the first time...the treated sections all show a marked reduction of the GFAP inflammatory marker, it's so much more sparse in the treated brains in the three pics on the bottom row...less in the number and the pronouncement of those grey/black marks the healthier your brain fluid is!....this is the power of your drug.
You know what, thinking on the fly here, I reckon there is merit in performing a cognitive test on these patients before and after the iPPS treatment, I think the patients would be able to think more clearly. This is one I will certainly raise at the next forum we get such as the R&D Investor day.Paradigmers... iPPS is getting through to the brain.....this is revolutionary...no catheters required.
HOW?
How is this possible? What about the BBB? Well this question was raised by the MC in the seminar and asked of the two scientists that presented. After a bit of silence they suggested that they didn't really know but suspected it could be one of the following scenarios or indeed something else:
The long chains of PPS were breaking down to some extent to get through the BBB?
There was some sort of leakage across the BBB in some area?
Some other method?
I have read research material in the past that suggests a Trojan Horse like effect could be possible...where the PPS molecule is hidden in another molecule, this molecule has certain features that latch onto the receptor of cells and gets absorbed over the barrier..,..then on the other side the soldiers (PPS) are released. By the way, the analogy of a (Trojan) horse is not lost on me, we all know the use of pentosan in horses.
The Trojan horse example....pertinent soldiers/molecule hidden in the midst of a horse, is let through and when on the other side, the contents are released!
The Mozz way to think about it is that I want in to a dance club (err... think about 20 years ago)...I'm not getting in on my own that easily...so I call up a cute friend and she agrees to come along with me...we send her first and the bouncer is smitten and knows her from previous occasions...she holds my hand and we're in!
Scientifically? The below graphic 4 explains it quite well....D is the Drug, think PPS molecule in our case....it cannot get through the BBB by itself, indicated at the bottom of the pic where it gets rejected primarily due to the weight/size.
So what is a molecule to do? Latch on to the TH (Therapeutic peptide) who already has the ability to get through as it has they 'key' to use on R1 (also known as a receptor). The TH is admitted as usual and carries the PPS molecule with it past the BBB and into the club (Brain).
Viola!
SO this is all theory and is subject to clinical trial blah blah....but I think its a real possibility. Remember, I'm no scientist.
In addition the researchers also found that GAGs in the brain also reduced due to iPPS's effect. So again we are seeing evidence before the trial. Sure we have at least some small amount of data conducted so far but imagine the read out for our current MPS sets. Imagine how excited the future patients are going to be with finally a real viable solution to help alleviate at least some symptoms and to do so safely.
Remember that paragraph I mentioned above in regards to asking about a cognitive test before and after? Well the researchers covered a sample of this too. It makes sense right? Cognition and motor skills improving as this brain fog caused by swollen GAG cells start to be alleviated due to the action of PPS....This in theory could result in an improvement in reduced hyperactivity and an increase in motor skills...
Evidence? Let's take a look at what the researchers observed:
Hyper activity on the left, motor skills on the right...This is not the last time I'm going to look at this chart...I will print it off and stick it on my study wall (right along next to my Doctorate that Mr @edski1 USA correspondent bestowed upon me).
Amazing. Look at those latency (think of it as delay in reactions) lines (Purple triangles) on the graph that BEND and fall away back to a more normal level ....what drug that you know of that can do this?
CLINICAL STUDIES
The seminar then went on to discuss and present two trials that had been performed, one we are familiar with is the Hennerman trial 5. Paradigm have mentioned this in the past on several occasions and they even met the scientist at one of the world symposiums on MPS a few years ago in Orlando, USA. The other was a more recent study conducted in Japan involving three patients. It should be noted that these patients were not selected on the basis of pain necessarily, it was more the observation of iPPS on them as MPS patients.
Here is a summary of their results. It's quite a read. I'm loving all those red arrows pointing down in terms of GAGs and up arrows in terms of increase in range of motion. PGIC sure...It's also MGIC...Mozz Global impression of change...change one day in our share price trajectory and level (my views) when more of the world finds out about us and we find a suitable and adequate global partner.
MECHANICS
In question time the researchers were asked, how? What is the theory behind PPS's effect on a reduction of GAGs? Dr Simonaro suggested that despite it just being a hypothesis at this early stage, it could be PPS's effect on the lysosomes, she stated it works by,
"...helping the integrity of the lysosomes",
"it's making healthier lysosomes".
If you have healthier lysosomes, then the machinery will work better.
This is an entire branch of study here involving lysosomes, degradation of material required in cells (otherwise wastes can build up) and as the researchers alluded to, the study of autophagy. Might be a whole new chapter of research during quieter times, we will no doubt have some of these quieter moments coming up and into the future. However, as our indications start to overlap and indications move from phase to phase, I have a suspicion we are going to have a lot to keep us entertained going forward.
BIO AVAILABILITY
It was also in question time that we heard a little more about the bioavailability comparison between our two forms of PPS that they had observed in the research to date, Pill format -v- SubQ. Dr Simonaro stated that in regards to the pill format it appeared that only 2% was retained however the SubQ was a lot more, up to 25% was retained by the body. A vast difference.
SPEAKING OF GLOBAL PARTNER
So where do we stand with an ERT provider? What is our benefit? What do we come to the party with?
Well the current ERT has little to no effect on joint pain.
"One of the major complaints of patients affected by MPS I, II, and VI is joint stiffness which hampers the easy execution of normal activities of daily life (combing, bathing, dressing, putting a hat on the head)." 6 iPPS we know has a very good effect on range of motion, function and of course pain relief.
In reference to other studies conducted on ERT solutions, a paper in 2018 stated that "Although the majority of the authors agree that ERT has an effect, albeit limited, on joint stiffness, other papers report no effect of ERT on joint limitations ". It is in this field where we will excel and be complimentary for a procedure such as ERT. A symbiotic relationship.
NEXT RESEARCH STEP
One of the researchers went on from stating that the effects also seem to be noticeable in the nervous system by pointing out observations from a Dog MPS study. The next step involves Bene working with the researchers on a possible fluorescent staining trace to gather info if its possible to track PPS into the brain. A new study the researchers mentioned is to involve the combination of the PPS treatment with Gene therapy with funding from the National MPS society. Watch this space!
We all look forward in the realm of OA to be awarded with a accelerated label like Fast Track or something else, but we have already in effect been granted such a label by getting both of our MPS indications utilising iPPS by the FDA as Orphan designations. This automatically entitles us to a closer working relationship with the FDA, a dedicated manager and a more timely response throughout the process. I'm getting the impression that after these two current trial data is out, PAR will also actively seek to partner to take us to the exciting point of registration. Yes, the stars do seem to be slowly aligning and I can see a brighter future not too far away.
CONCLUSION
Some breakthrough data here involving the brain and the nervous system. In question time it was asked if these wonderful effects are a direct result of PPS outside the nervous system and brain or whether they suspected it was actually PPS getting in, they seem to err towards it getting in but more research needs to be done here. At the end of the day, for us shareholders, it is the positive effect it has that is important. This has many ramifications into the future for us.
Great video. I very much enjoyed the participants great reaction to the data, specially when the MC said with enthusiasm that the observation of the positive effect on GAGS "rocked my world". Despite us having delays...despite it being a long pathway ahead of us ...I think my world is about to be rocked somewhat too...in a good way.
IL8 is not a biomarker you want to lose control over, "...its major pathophysiological role lies in affecting neutrophils".3 Neutrophils make up between 40 and 70% of vital white blood cells which make up your immune system.
TNF-Alpha - it's these guys that assist in cell signalling, they are the ones responsible for increasing an inflammatory response when the body detects there is a need.
(20min delay)