Have you guys seen CSL's new Melbourne HQ? I drove past it about 2 weeks ago, very impressive. One day...could this be a PAR office. PAR staff? This is what you may move into one day...Don't scoff. $0.76 to $300...21 years... that is CSL. Do I need to remind you new readers to us...CSL addressable market size is LESS than ours.
Don't actually believe me? Here is a hint...PAIN. Don't ever rely on ONE poster no matter how enthusiastic she or he sounds...go to your local search engine and type in "How many people are in pain right now".OPPORTUNITYThe real crux of the problem, and thus the opportunity for us is:
"Overall, the effectiveness of both HSCT and ERT on the skeletal and connective tissue manifestations of MPS is limited, presenting a need for improved and/or alternative treatments".The increase in GAGS accumulation leads to an increase in a particular signalling protein called TLR-4. This in turn leads to a release of another protein called TNF-a and other inflammatory cytokines. The researchers investigated Pentosan's action on these pathways and their findings were quite a read. Lets explore.
Don't forget, you increase these inflammatory cytokines and you increase downstream tissue damage and cell death, Its more apparent in cells that have higher levels of GAG accumulation but it still affects other cells as well.
The opportunity here for us is material. Lets investigate the proof-of-principal from the researchers.
THE EVIDENCEThe bioavailability of Pentosan in the SubQ version is much greater compared to the pill format.
Let's take a look at the comparison for GAG amounts in urine as well as certain organs but we will take a look firstly a the pill (oral) version first...
In the below charts we see the oral version resulted in good improvement in terms of GAG levels but only in the urine...
What's your guess:
Where did the Sub Q formulations (1, 2 and 4 mg/kg) end up?
Any guesses, where do the three SubQ iPPS value's fall?
Lets do the reveal:
The asterisks are levels indicate P < 0.05
ALL SubQ versions resulted in improved readings against the untreated rats.
COMPARISON OF THE BONEIn a first for me, this paper went through a number of sub classifications for bone morphology comparing Normal Bones, MPS bones and then the three iPPS treatments.
Here are the results in table format :
I first checked out Normal, then went to MPS column to see which direction (increase or decrease is measured values) is bad...and then compared the SubQ versions...I like where its heading.
The same exercise was then carried out for the spine...again have a read through the table below. Compare Normal with MPS to get a sense of where the figured SHOULD be at and then take a look at the iPPS dosing measurements. Incredible. These are morphology of the actual bone. Now just imagine the restorative nature of iPPS particularly in
early stage tissue damage.
REVOLUTIONS
Ready, set...rotate...
We saw in Part 1 (see posts below) the rats and how they performed with the pill format, now we get the below chart with the iPPS format:
"All groups of treated MPS VI rats (oral and sc) remained on the rotating rod significantly longer than untreated animals (p,0.005). At the higher speeds (30, 35 and 40 RPM) MPS VI animals receiving all sc PPS doses had significantly better endurance and remained on the apparatus longer than those receiving oral PPS (p,0.05)".
"All treatment groups exhibited significantly better rotarod performance than the age-matched, untreated MPS VI rats. This was increasingly evident at faster speeds. Also, at faster speeds a significant benefit of sc. vs. oral treatment was observed. Of note, the 4 mg/kg sc dose appeared to be less effective than 2 mg/kg".Again, incredible evidence of how strong particularly the 2 mg/kg dose is. For those that are new, remember this isn't a linear relationship, its a bell curve...the best dose is around that 2mg / kg but yes it does depend on the observation. On average this seems to be around the best.
A NEW BIOMARKERThe researchers found a new biomarker that are know as calgranulins or alarmins, also known as S100A8/A9.
"In the current paper we show for the first time that A100A8/A9 and IL-8 are significantly elevated in serum from MPS VI animals. We have previously also shown increased AGEs in the MPS VI rats, which may be explained, at least in part, by elevation of the S100A8/A9 complex. A100A8/A9 also is elevated in rheumatoid arthritis and the levels correlate with disease severity and joint degradation. Continued examination of the inflammatory pathways activated in MPS should identify additional biomarkers that could be used to monitor disease progression and treatment response, and further our understanding of the pathogenic mechanisms occurring in these complex disorders".REDUCTION OF SYSTEMIC INFLAMMATION"By the end of treatment (7 months of age) all groups had markedly reduced levels of TNF-a, TNFR1, IL-8, S100 calcium protein A8/A9 complex (S100A8/A9) and CRP compared to untreated MPS VI controls".Gags:
"We next examined total GAG levels in the urine and tissue homogenates of the treated MPS VI rats (Fig. 3A–D). A reduction in urine GAGs was observed in all PPS treatment groups (oral and sc), although the reductions in the sc treated animals were significantly greater".
"Total tissue GAGs (liver, spleen, kidney) also were significantly reduced in the sc treatment groups, but not in the oral group "
"...there was a clear dose dependent increase in the fracture force and ultimate flexural strength (Fig. 5C and D), indicating that whole bone mechanics were improved with treatment. No biomechanical improvements were observed from oral PPS treatment (data not shown). "
"Subcutaneous PPS treatment resulted in significant improvements in most microCT measurements, and some clear dose responses were observed. ".
"Skull microCT revealed improved dentition, tooth mineral densities and snout lengths in the sc treated MPS VI rats (data not shown), as we had shown previously with oral PPS treatment".Skull lengths:
"It is notable that the bones in the jaw and mandibular area of the skull are the least mature bones in rats at 1 month of age (the age PPS treatment was initiated), and exhibit a linear increase in growth up to 6 weeks. This, coupled with the fact that a majority of the bones in the skull form by intramembranous rather than endochondral ossification, may provide an explanation for the differences observed in femoral vs. skull lengths".SUMMARY OF BENEFITSThe researchers found the following common advantages of both SubQ and Pill format administrations over the two rat studies:
- Markedly improved mobility, improved tracheal morphology,
- Increased trabecular bone in the femurs and vertebrae,
- Improved dentition, including tooth mineral densities,
- Reduced levels of inflammatory markers in the serum
- Positive effects on skull/snout lengths with both sc and oral treatment.
Sub Q Superior Benefits over oral:
Modest improvements in growth plate organization from sc treatment
More consistent trabecular effects were observed with
Significantly increased BMD
Trabecular bone is responsible for increasing the strength of bone when force is applied, which may also explain the enhanced strength observed from the 3-point bending tests
Performance of the treated MPS VI rats on an accelerating rotarod was greater using sc treatment, particularly at the faster speeds, which could be a direct effect of the aforementioned increased trabecular bone formation and flexural strength.
One of the surprising, positive outcomes from this study was that PPS treatment led to a reduction of GAG storage in the MPS VI rats. A notable difference between the oral and sc treatments was that in the latter significant reductions in tissue GAGs were observed.
SAFETYImportant to measure these as it is not just an initial dosing...it's continuous.
"Due to the enhanced tissue uptake and potential accumulation of PPS following sc injection, it was important to assess the long term safety effects in the MPS animals. Throughout the 6-month study we monitored liver enzymes and various clotting factors weekly. There was no elevation of liver enzymes above baseline, and no abnormalities seen in clotting factor levels. No adverse effects of sc PPS treatment were observed. These results are consistent with our ongoing studies in MPS I dogs".ADJUNCT THERAPYERT and Bone Marrow replacement therapies have been around for some time. The problem here is that these therapies do very little in terms of pain relief in the musculoskeletal regions.
"However, the effectiveness of these therapies on the bone and joint manifestations of MPS is limited, and skeletal disease often continues to progress in treated patients. Similarly, HSCT also has limited effects on the bones and joints in MPS, and PPS could be a useful adjunct for transplanted patients as well".The researchers also acknowledge that there are ramifications, possibilities that iPPS will have efficacies in other areas such as neurological indications. MPS patients also suffer a number of problems in this area too.
"PPS has been administered into the CNS of patients with Creutzfeldt-Jakob disease, resulting in the reduction of neuroinflammation. Since some MPS patients are currently receiving intrathecal enzyme infusions, and neurological MPS disease is characterized in part by neuroinflammation, these patients could similarly benefit from PPS treatment at the time of intrathecal enzyme administration".PREDICTIONSThe researchers further postulate:
"When considering the clinical utility of PPS in MPS patients, we predict that it may be used alone or in combination with other therapies, including ERT or HSCT. When used alone we anticipate that it will reduce inflammation systemically, as well as locally in joint tissues including the synovium and articular cartilage. This could result in reduced pain, increased mobility, and/or increased joint range of motion. Over time we also predict that it may slow the progression of tracheal deformities, enhance trabecular bone and bone strength, and perhaps result in reduced pulmonary infections and/or enhance lung function"."Recent data obtained in MPS I dogs treated with sc PPS for 12 months also revealed markedly improved coronary artery disease compared to untreated MPS I animals (unpublished results)".OUR LATEST RESULTSIn the second great announcement in as many weeks (First Canine results., then MPS I) we got some great top line indications on our data and what it is saying. I derived a number of good reads from this announcement but some highlights for me would have to be:
N was incredibly low. Just 4 patients. Now usually you would expect maybe at least 1 or 2 of these to be lacking in some observable or where their results weren't quite up to well, par. But what did we get? (My emphasis added in red below)
- Aggregate (paediatric and adult) PROMIS T scores for pain behaviour, pain interference, and fatigue improved in all subjects evaluated at all timepoints (Weeks 49 and 73).
- Improved outcomes in physical tests (e.g., 2-minute and 6-minute walk tests, gait/stairs/Gower's/chair test, 9-hole peg test) demonstrating improved mobility and dexterity.
- Improvements in patient reported outcomes (PRO) of pain, function, fatigue, and quality of life.
The above three points are not only good from a clinical point of view, they play an important role in PGIC. The authorities want to see a tangible benefit to the patient's well being and their life. These PGIC's add value to a sponsor's application. Achieve this in a safe manner and you are already ticking the most important boxes.
"Changes in the profile of biomarkers after 48 and 72 weeks of iPPS treatment suggest that PPS has the potential to modulate bone and cartilage degradation biomarkers that are associated with cartilage loss and arthralgia in MPS I patients".When I hear 'modulation' of bone and cartilage and fibres, my ears picks up. Its one thing to have symptomatic benefit in a safe way, quite another to positively modify the structure. That's gold....
Keep uncovering the milestones...we know there is gold there...I've come across a number of interesting papers and research over the last few years in dealing with Pentosan's wonderful action.. but I always love it when the researchers comment they were
surprised to find some benefit or additional modality they weren't expecting...
Love it when the lab coats find surprises in the research....how many holders know this data and what it means...many investors are going to be surprised with upcoming data...upcoming milestones...and finally upcoming share price (spec personal views expressed).Their comments were:
"The enhanced effects of sc PPS included a surprising and significant reduction in urine and tissue GAGs".and further:
"One of the surprising, positive outcomes from this study was that PPS treatment led to a reduction of GAG storage in the MPS VI rats. A notable difference between the oral and sc treatments was that in the latter significant reductions in tissue GAGs were observed".THE HEART OF THE MATTERIf one really reads deep into these progressive announcements, we start to begin to understand where we may actually end up one day. A number of holders don't rate the MPS future revenue as all that lucrative. (see back of envelope section)....this is wrong in my opinion. Not only is there amazing scientific data translation as an overlap into other conditions, but I suspect there will be meaningful revenue in our future tie up in the lysosomal and rare disease space.
What are the clues for this?
A paragraph from PAR's latest announcement triggered my memory:
Here was the paragraph:
MPS I is a rare disease caused by reduced levels, or the complete lack of an enzyme
responsible for the catabolism (break down) of glycosaminoglycans (GAGs). This
disruption of normal cellular processes results in the progressive accumulation of
GAGs in bodily tissues. The disorder causes problems with neurological, skeletal, and
cardiovascular development.
The link for me is what the researchers also mentioned in their introduction.:
"Cardiac, pulmonary and neurological abnormalities also may occur".In fact a separate group of researchers including Dr Simonaro who has been doing a lot of work with Pentosan and the Lysosomal diseases stated this:
"Several secondary endpoints also were studied, including effects on GAG storage, inflammation markers, and improvement in the arterial phenotype. The latter was chosen as a clinical endpoint due to its consistent presentation in affected animals and the documented influence of inflammation on the cardiac lesions".3The same researchers found a large 9 fold increase in terms of NF-kB (see Mozz new to PAR note below in Appendix A) signalling and a linked protein being over expressed in MPS patients....relevance? It has cardio vascular disease ramifications:
"Lyons et al. also have demonstrated activation of the NFKB signalling pathway in the
MPS I plaques. Khalid et al. have found that clusterin (CLU, also known as apolipoprotein was 9-fold overexpressed in treatment-naive MPS I canine aorta compared to normal canine aorta. The clusterin protein is of particular interest as a potential biomarker of MPS I cardiovascular disease because it is involved in morphologic transformation of vascular smooth muscle cells [29] and present in human atherosclerotic plaques, but not in healthy normal aortas".Oh wouldn't it be good to observe Pentosan's direct affect here?
Well how about this:
"Therefore, we examined clusterin in both the carotids and aortas of the PPS-treated animals using immunohistochemistry and immunoblots. The areas surrounding the plaques and the outer edges of the intima showed increased clusterin expression in the untreated vessels, while PPS-treated animals exhibited reduced staining similar to normal. Reduced expression of clusterin following PPS treatment also was confirmed by Western blot analysis, with almost complete normalization observed in the subQ treated group".Ok Mozz, nice to get choice words from researchers...how about some pics....anything out there to SHOW me the positive ramifications here?
Mate, this is as clear as one could ever see....Untreated Aorta's of MPS dogs....clogged, getting harder for those vital blood cells to get through delivering vital oxygen and nutrients....
Oral PPS, yeah, helps,,,.but can we do better?
Crikey, look at Subcutaneous Injectable Pentosan Polysulphate Sodum's action...widening those essential arteries... incredible. What does this safely? Who does this safely?
Just give me an audience with a new fund manager, I'd love to show them this. I don't care if they are all about figures and balance sheets...the science trumps. The figures will come.
Some of you work better with percentages, figures and certainly graphs....lets see the data in this format:
I somehow love that SubQ PPS
smashes down those bar columns...heading more towards normality. So so many will benefit. The world just doesn't know it yet!
...and one more measure...the normalisation of the size of the lumen. The lumen is the channels within the arteries that regulate the flow and pressure of the blood.
Normalised! (up from 66.7 in the case of untreated MPS dogs bac to a normalised 141)
BACK OF ENEVELOPE?I don't really like posting up projected figures as they are all a bit pie in the sky and there can be a number of hurdles and delays...when I do, take my figures with a ...
Pinch of salt!At the end of the day I can be wrong...I can be too early...I can be over enthusiastic and not as aware of the negatives or the hurdles! Watch out!
I do know the science. I do talk to the patients...I like what I'm seeing...the story only gets stronger. I know for a fact that a lot of the US guys (think fund managers and Pharma potentials) love the data....let me say that again...
They love the data...and guess what...they are (in my views) going to get a stack more of it....
Ok Here is the Mozz stab at projected MPS revenue..
Let me explain my rough rationale.
Price, I'm using $20,000 USD per annum per patient.
Mozz, are you mad? We will never get these prices.
Really? I'm actually possibly being fairly conservative...
We know how expensive ERT treatments are...crazy expensive!
4,5
...and...
So there is some sorta precedence here...granted our workings (MOA) are different but you gotta realise, there is competition in the ERT space but we have no competition when it comes to joint pain. There is no drug that can address muscleklosketal pain here. See also conclusion below.
Graphically, how do these Mozz proposed revenue figs look?
CONCLUSIONThere is more and more compelling evidence building in the MPS read out. I sure am looking forward to the final read out in the Brazil MPS VI program which should happen by the end of the year. Don't be fooled, we not only can garner a meaningful revenue here BUT the science will be exemplarily on what iPPS can actually do. This could be an early example of what to expect in other inflammatory indications. Not only that, but it involves the pathophysiology of other tissues like the heart, the lungs and even the brain.
You and I do not know how this will exactly play out, don't forget, as the researchers also suggest...iPPS could actually potentially stand up on its own if administered early enough. Take a read:
"Overall, we conclude that PPS should continue to be investigated for the treatment of MPS,
particularly as a subQ formulation that may be given biweekly or perhaps less frequently.
There are several ways to envision PPS use for MPS; either as an adjunct together with ERTs or
as a stand-alone therapy. The latter may be particularly amenable in the context of newborn
screening to treat MPS children prior to the initiation of ERTs, or used in patients who cannot
receive ERT either because it is not available or because of immune responses".To be honest, I thought that MPS is an Orphan Indication.
I thought we were initially a Phase 2/3 study...
But now I hear a P3 may not be required for ALL jurisdictions. This creates a wind in my sail. I know now I was always initially right...there is a chance that we may not need a P3 in all geographic regions...
This saves us time.
This saves us money.
This will result in a faster route to revenue.
Yes the main game may be OA for now....but MPS will also play a most definitive part.
-Mozz
Yes, of course DYOR
APPENDIX ANew holder to PAR? Wondering what NF-kB is?
"
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases".6I view it as the grand-daddy of the inflammatory signalling process. One of the seminars in the past drew an analogy to a cascading waterfall..
Nice waterfall...but not so nice cascading increase of inflammatory cytokines...
Help! The above shows us just what mayhem, what destruction a chronic inflammatory environment can do to one's bodily processes. Don't forget new guys, we need SOME inflammatory response, that keeps us very much alive. The problems subsists when it becomes chronic - never ending. SAFE circuit Breaker? You bet...we call it iPPS. Yeah, it's what
you own.
Most of the over expression of inflammation and signalling is triggered from NF-kB. Our own CSO Dr R Krishnan has talked to us about it on a number of prior occasions presenting the below graphic as an example.
The take away is the fact that our iPPS molecule interrupts this never ending chronic inflammatory process by not only addressing the processed
indirectly, but
directly.Yes, it is this multi modular action that is key to success. Not unlike a debate, you don't use just one key argument to convince the other side...you use MANY and VARIED! The key to winning a debate...the key to addressing a serious unmet problem...the key to ensuring one day we will achieve some wonderful revenue in not just a local scale, a global one.
(My views of course)
REFERENCES
MAIN1]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071040/pdf/pone.0100882.pdfOTHER2]
https://app.sharelinktechnologies.com/announcement/asx/688f748aa01acf61b43751f21543df923] https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0153136&type=printable
4] https://www.drugs.com/price-guide/vimizim#:~:text=The%20cost%20for%20Vimizim%20intravenous,not%20valid%20with%20insurance%20plans.
5] https://www.fiercepharma.com/sales-and-marketing/biomarin-s-380k-price-tag-on-vimizim-high-but-far-from-highest#:~:text=BioMarin%20(%24BMRN)%20has%20slapped,the%20world's%20most%20expensive%20drugs.
6]
https://www.nature.com/articles/sigtrans2017237] https://www.ncbi.nlm.nih.gov/books/NBK470401/#:~:text=The%20arteriolar%20lumen%20regulates%20the%20flow%20of%20blood%20through%20the%20capillaries.&text=Venules%20are%20the%20smallest%20veins,and%20nutrients%20for%20water%20products.
8]
https://pdg.com.au/project/elizabeth-north-stage-2/#
ell it was back in May 2021 that I presented possibly one of the most amazing papers I've come across to date on our molecule.
(20min delay)
