The Heartfelt addressing...

ne thing I just love about iPPS is the multilayering. It's starting to happen...as I type this, we don't just have one cooking pot back there on the commercial stove, we have a few.

1. OA Dosing component stage 1 - P3
2. MPS VI Brazil
3. MPS I - Adelaide, Australia
4. Various Pre clinical models in the works
5. Some indications set for Phase 2 (Eg RRV/CHIK-V)

Yes there is also the multi pathophysiological ways it works its magic...but I actually mean the number of different indications we one day may address.

Yes we are firmly focused on the big OA program as well as the rare diseases called MPS. But tonight I look much more into the future....How iPPS addresses a heartfelt topic, that is, Heart failure.



PRE INTRO

I have covered an initial study of Injectable Pentosan, the Wonder drug, before in terms of efficacy on the heart and how it assists in bringing down ADAMTS-4, here are the references:


iPPS - Heart of the matter Part 1

iPPS - Heart of the matter Part 2



But tonight we take a different angle. This post is going to get technical, I will try and make it as easy as possible to understand, we do need a fair bit of background for you to get my points.It's worth sticking with it as the final points I eventually make I think will be well worth the read...certainly it has some potentially stellar repercussions later on in our journey.

In actuality we would need a whole group of posts to cover Heart failure, how it manifests, what are the conditions and solutions. This post merely scratches a very specific surface. There is just a whole stack to investigate but the good news for you and I is that PAR have started this journey in earnest.

That's what I want to see...the small seeds are planted, the Redwood (err Beech tree?) is growing...small and humble for now...give it 10 years and then lets see where we all are at. Our OA (and MPS) program is first and foremost, but in this post I'm talking Heart Failure...



_{When will our company grow from seedling to one of these Beechwood beasties?}



INTRO

If you are a Cardiologist you will know the term HFpEF. I'm not a cardiologist, I had to look it up.

HFpEF stands for Heart Failure with Preserved Ejection Fraction.

Yeah initially to me without doing ANY research or reading I would've guessed it was some kinda piece that is emitted but doesn't make it all the way out?

Not quite, actually nowhere near it....

Think we need a better definition.

There are essentially two types of Heart Failure here, one is with a change in pressure and one is without. So the 'p' stands for With Preserved Ejection Fraction.

The Fraction part isn't actually referring to a piece of the heart/muscle/fibres/valves etc...it is a mathematical concept they are talking about...ie a fraction like 2/4 eg 50%.The (maths) fraction bit refers to how much the oxygen rich blood is pumped from the heart.If you want more technical info the equation involved is ¹:





Now those that need the diagram, here is one ²:





So preserved ejection fraction is basically getting heart failure BUT there is NO real change in the % of ejection pressure, ie the Diastolic pressure.
Its a measure of how the heart isn't preforming despite the left ventricle (See diagram above) recording usual or normalised pressure readings.


“Physicians are busy people, and like it or not they often focus on a single number,” Guichard said. “Systolic blood pressure is the focus, and diastolic pressure is almost completely ignored.” That is a mistake, he argues. “The majority of your arteries feed your organs during systole. But your coronary arteries are different; they are surrounding the aortic valve, so they get blood only when the aortic valve closes — and that happens in diastole.” ⁴


So what is normal fraction, well it varies a bit but here is a rough guide ³:





DIAGNOSIS

The problem here is that it isn't that easy to diagnose:

"Unlike impaired ejection fraction, which reliably defines heart failure with reduced ejection fraction (HFrEF), the diagnosis of HFpEF can be challenging as there is no single abnormal echocardiographic parameter that defines its presence. A diagnosis relies on thorough interpretation of the entire echocardiogram, including left ventricular mass, left atrial volume and assessment of diastolic function". ⁵


Take a look at this diagram for the interplay and how it's all connected:





One note here, hypertension has been linked to a very high 80 to 90% of all HFpEF cases, remember, Hypertension is increased blood pressure. ⁶

Girls and guys, what's the common link to most of these conditions? Clue, It starts with a capital 'I'...

Don't make me do a Mozz Quiz^® just to find out its Inflammation with a capital I.



COMPARISON

Lets compare the two types, HFpEF and HFrEF (R = reduced), and get a better sense of what they involve.

So the Heart failure where the fraction isn't preserved simply means that the left ventricle is not pumping out blood at normal levels, lets call it under 50%.In the case where the ejection fraction is preserved, this means that the heart looks to be pumping out normal levels of blood ( greater than 50%) but something is still wrong, there are signs of heart failure.

Mate, what about a diagram to really make sense of this ⁷:



As an example of complexity, don't just think there are a distinct mutually exclusive groups here, indeed a diastolic HF and systolic HF can and do overlap. There might be "subtle abnormalities" ⁸ in systolic performance in the case of a diastolic (HFpEF) case. These abnormalities can be more pronounced during exercise (Hint: I'm sure you guys have heard of cases where people suffer heart attacks while exercising, that's when the heart is loaded).



PREVALANCE

So of the two types, what is the percentage occurrence? It works out to be around 50%. Half of all Heart Failures involve a HFpEF. "Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). " ⁹


So is Heart Failure common?



*Closes eyes* That's like you asking me do I think IPPS is any good???



Almost six million Americans have heart failure, and more than 870,000 people are diagnosed with heart failure each year.¹⁰



Yeah, its common.

Heart failure is associated with high morbidity and mortality. These two words become key as far as the FDA is concerned, later on when we eventually get to the clinical trial part. A few years away for sure but you and I both will still be holding some shares at that later point right? (Not advice, must formulate your own opinions).

But Par folk, I wont just leave it at that, with some quote off the internet. What about the TREND....

Take a look at this chart ¹¹:





The blue line above is the HFpEF...its trending up, as the researchers summarised:

Given the high prevalence of HF overall, the increasing frequency of HFpEF, and the lack of therapeutic options for HFpEF, the need to better understand the emerging epidemic of HFpEF is critical.


But I'm not here just to state the fact, I'm here to ask questions AND I'm here to make it relevant to us.


Why is HFpEF Increasing in Prevalence?


Several factors are likely contributing to both the increasing overall prevalence of HFpEF and the increasing proportion of HF that is due to HFpEF. These factors include:


Increased life expectancy and aging of the population


The epidemic of cardiac and non-cardiac comorbidities; and


Increased clinical recognition of HFpEF.


The link for us as PAR shareholders is contained in the above statement. There are at least two main connections here1) Its connected with OA, this lack of movement leads to increased HF and 2) iPPS is showing to have efficacy in not only OA but also in the Heart, lets explore.



RELEVANCE

Yeah yeah all great Mozz, We can all become budding cardiologists now (yeah right)....but please tell me what this has to do with an investment in PAR even if it is a number of years away?

Par folks...how many drugs are there to treat HF?

Ok let me be a touch more specific, how many drugs are there that treat HFrEF?

A few...here they are the main classes. ¹²

• ACE inhibitors.
• angiotensin-2 receptor blockers (ARBs or AIIRAs)
• beta blockers.
• mineralocorticoid receptor antagonists.
• diuretics.
• ivabradine.
• sacubitril valsartan.
• hydralazine with nitrate.
• digoxin

Not a single one above is devoid of side effects.

Next question and we will get a sense of the relevance here to us now....How many drugs are there that treat HFpEF?





There are none.



Huh?

Not one.



Yeah they have tried to use some of the HFrEF remedies like ACE inhibitors, here is a quote:

"The clinical efficacy of an ACE inhibitor in patients with HFpEF was assessed in the PEP-CHF trial, which included 850 patients ≥70 years of age with an LVEF >40 percent and echocardiographic evidence of diastolic dysfunction [28]. The patients were randomly assigned to an ACE inhibitor (perindopril) or placebo. Overall, there was no impact of ACE inhibitor on the primary endpoint ". ¹³



Beta Blockers?

"An individual patient-level meta-analysis of 11 randomized controlled trials of beta blockers that included patients with HFpEF found no evidence of benefit in the small subgroup of patients in sinus rhythm with LVEF ≥50 percent ".¹³


Shunt devices? Nope, in fact they can be harmful:

"However, we do not routinely perform this procedure in patients with HFpEF; a trial that studied the long-term effects of this procedure did not show a benefit and suggested possible harm".¹⁴



ENTER iPPS

So what's the story with iPPS, is there some efficacy in this area?

I'm glad you asked:


_{Source: Our own PAR announcement: Preclinical Heart Model https://app.sharelinktechnologies.com/announcement/asx/1356774292e1726eaafc26e34d472ef5}


As our own Dr Ravi stated, "We are very pleased that the pilot study conducted in the laboratory of Dr Maria Vistnes has provided cutting edge data to further clarify the mechanism of action of PPS in HFpEF".




THE LAYERING APPROACH

We often hear that the most successful long term Pharmas are the ones that don't just rely on one indication, one path to revenue, they look for many. We indeed have seen this clearly play out with my go to example, Humira (New to us? Do check Appendix A below).

Multiple indications layers on each other to super size the overall revenue picture. Fellow serious PAR investors...I will be happy once we start moving on upwards properly...once we re-crack the $3 mark...the $4 mark and go beyond. It will happen one day (my thoughts).But its not the mere low single digits that enthrals me...this is just a small example of what I'm imagining:



_{Now let's not get too carried away, the above is just some figs I've plucked off the top of me head...but seriously, tell me there isn't a real chance of something like the above one day playing out. I know it, YOU know it...but they (Rest of market) don't quite get it yeah. Our little secret for now.}


The possible future addition of heart failure indeed is a massive one.

There are NO drugs that even work for HFpEF. We could really be the first and look at our safety profile.

Are you guys getting a sense of what we might be wroth one day. I understand we all want massive increases and now. I'm talking years here, at least as far as HF goes. But I'm also talking multiples of just a 100% increase from our current dilapidated share price.


Multilayering massive streams of future revenue with a heart felt addressing of a serious indication like Heart failure??




Yeah - It's those promising days in the future that I'm here for.





Best to DYOR







APPENDIX A


The multi-layered sweet elixir of Humira: Look, they had to wait for a number of years...clinical trials, acceptance....first revenue (zero to an outstanding 280 million USD in just 12 months....hitting some 22 countries in just ONE year). Yes acceleration like you wouldn't understand.,.but while year 1 was super charged at $280 million USD...skip forward to year 13...I give you (well Humira gives you) Fourteen Billion USD...that's per annum...year in...year out. It went higher than that...2019 they hit $20 Billion USD...at today's rate that's a feint worthy $28 Billion AUD.

How tiny does a crazy $280 million in the first year look compared to the surpassing of $3,500 million mark in the year 2008 (see chart below). Can you imagine this COULD be us one day. The thing to remember is, you need to hold at least some shares for that long. (My views, not advice, there are risks for any stock).







APPENDIX B

Ladies in particular, this one affects you girls more than us boys...please be aware of the symptoms and signs:




Heart disease is the nation's leading killer of women. "Women in mid-life are definitely at the highest risk. It's a volatile time for women, as the menopause transition is marked by changes in body composition, fat distribution and an increase in cholesterol levels". ¹³






REFERENCES

1] Juan Pablo Arroyo, Adam J. Schweickert, in Back to Basics in Physiology, 2013.
2] https://www.momjunction.com/articles/heart-circulatory-system-diagram-parts-functions-for-kids_00648438/
3] https://www.healthline.com/health/ejection-fraction#ejection-fraction-results
4] https://www.uab.edu/news/research/item/10393-diastolic-blood-pressure-how-low-is-too-low#:~:text=Blood%20pressure%20consists%20of%20two,in%20more%20ways%20than%20one.
5] https://www1.racgp.org.au/ajgp/2019/july/heart-failure-with-preserved-ejection-fraction#:~:text=Heart%20failure%20with%20preserved%20ejection%20fraction%20(HFpEF)%20is%20a%20clinical,fraction%20at%2050%25%20or%20above.
6] https://www.mayoclinic.org/medical-professionals/cardiovascular-diseases/news/heart-failure-with-preserved-ejection-fraction-hfpef-more-than-diastolic-dysfunction/mac-20430055#:~:text=system%20is%20stressed.-,Pathophysiology,capillary%20density%20that%20may%20contribute.
7] https://www.labmedica.com/clinical-chemistry/articles/294773150/cv-biomarkers-associated-with-incident-heart-failure.html
8] https://www.mayoclinic.org/medical-professionals/cardiovascular-diseases/news/heart-failure-with-preserved-ejection-fraction-hfpef-more-than-diastolic-dysfunction/mac-20430055#:~:text=system%20is%20stressed.-,Pathophysiology,capillary%20density%20that%20may%20contribute.
9] https://www.uptodate.com/contents/treatment-and-prognosis-of-heart-failure-with-preserved-ejection-fraction/abstract/3
10] https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure#:~:text=How%20common%20is%20heart%20failure,in%20people%20older%20than%2065.
11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870014/
12] https://www.nhs.uk/conditions/heart-failure/treatment/
13] https://medicalxpress.com/news/2019-10-woman-heart-health.html
14] A ) https://www.uptodate.com/contents/treatment-and-prognosis-of-heart-failure-with-preserved-ejection-fraction/print#:~:text=INTRODUCTION%20Heart%20failure%20with%20preserved,)%20%5B1%2D5%5D.