round November 2019, I got excited...PAR were to have a meeting with the TGA and though it was only a preliminary meeting, I thought that that might be the start to a real path of eventual revenue at least in Australia...
Skip forward to past the middle of 2023 and we are still here waiting ...I'm not too disappointed as there has been so much added to this scenario...there is so much going on in the background, this is now just one of the potential milestones to eventually come!
Tonight, let's explore what some of the authorities are actually waiting for and what we might eventually deliver...watch out for some incredible data again in this post when we view some of the MPS results that are out there already... the evidence is compelling and its mounting... but by the end of this post, you may just get a better sense of "What do they really want?"
INTRO
We have heard Paul speak to Scott in a great interview, see Appendix A below for the said meeting, if you haven't as yet heard it. It's still relevant and you'll pick up some clues on where we are at and what some of these authorities want exactly.Here is a MES (Mozz Exec summary).
The authorities want a degree above the average, above the norm and yes above the standard of care....Yes there are indeed drugs that can facilitate pain and function...sure they may not be great drugs, they may have side effects, they may not reduce pain by a big degree, but you can argue that they do work on a fair amount of the population and while they aren't to be used long term, well they can be used to assist in these areas.
Finally, an authority is really a group of authorised people, quite like a peer review, these guys want something that's going to also put themselves on the map. If you have some sorta revolutionary never-been-seen before data, a top peer viewer is going to be more anxious to exclusively acquire it to further their readership and their standings. It works the same for the authorities to some degree. Get a safe drug with never been seen before data and function and you ultimately will have a better chance to broach the market and command a worthy deal. A win win - a win for us as the sponsor, but a win also for the great authority that approved it and got it out to the market!
Win for the Sponsor, win for the approving Authority.
So, if we just reduce pain and improve function, we aren't novel and it wont cut it. This means we have to rely on the full licence and we all know that that translates to time and money.You also have to realise that apart from oncology and viral indications, there hasn't been much else that has gotten through to a provisional...
What do we need to do then? We'll cover this next.
TASKED
So we want to try and get ahead of the slow moving clinical trials...how can we do this?
Overtaking a slow moving clinical trial? Is there a way?
Well there is a Provisional Approval by the TGA in Australia in terms of OA for example. In Brazil we know that we are trying to get an exemption for our Phase 3. Again, it's a similar situation there and tonight, we will have a look at this in a little more detail as an example.
MPS as we know is a terrible disease affecting not just one or two bodily systems but many. There are two main treatment standard of cares namely Enzyme Replacement Therapy (ERT) and Bone Marrow Replacement (BMR). Both of these indications do little to zilch in terms of addressing musculoskeletal pain. At the very best ERT and BMR go some way to some symptom management, but there is nothing out there that has shown to properly address joint pain.
Now it could be argued that if we bring down pain and improve function of the joints, this will go a long way in terms of a possible application to have a Phase 3 bypassed in a region such as Brazil. However, we want and need to go for gold. We want to not only show that we have good positive effects here in pain and function but we can do more.
MORE
What more can we aim for? Well something that potentially addresses the disease course itself. As an example, there is a marker known as Glycosaminoglycans (GAGs), its present in every mammal's tissue. If we show we can address GAGs by way of halting the increase, or one better, reducing them....we all of a sudden make it to the next grade, the next class of product. The effect of this is not only a faster potential pathway, but a higher chance of a really interested Global partner cutting a distributional deal. Get them onto our books and we become a different company. Simple.
GAGs?
So what are these GAGs and what is the disease of Mucopolysaccharidosis (MPS) anyway?
GAGs are simply long types of sugar chains. The body needs these to metabolise these (Mozz Speak: break down these long chains of sugar into usable fractions) as they can be used in a plethora of important cellular processes. It keeps the cells healthy, it keeps them functioning and it allows them to grow, divide and yes, even conquer (in a good way),
"These cells help build bone, cartilage, tendons, corneas, skin, and connective tissue. Glycosaminoglycans (formerly known as mucopolysaccharides) are also found in the fluid lubricating our joints".2
If the build up of GAGs occurs due to the lack of these enzymes then cell destruction and death can occur.
"Over time, these glycosaminoglycans collect in the cells, blood, brain and spinal cord, and connective tissues. The result is permanent, progressive cellular damage that affects the individual's appearance, physical abilities, organ and system functioning, and, in most cases, mental development. Symptoms may be similar or vary among the different types of the disorder".3
But the diseases of MPS stops these long chins of GAGs from being broken down. In biology we call these enzymes. The enzymes are lacking if you have this disease and this you then get a whole stack of problems. One such problem is that good levels of HA are prevented from being manufactured by the cells ...this leads to lack of lubrication in the joint fibres, this leads to joint pain...we all know what can help here.
In truth, there are many ways that these long unbroken GAG chains can play havoc on these patients, here is another set of terrible chain of events involving chondrocytes and the skeletal tissues and structures:
EVIDENCE
So I am an agency (I'm actually not, I'm just using that as an example to step into their shoes for a sec).
I want to see a good drug I want to see a safe drug I want to see patient convenience (ie we don't want to have an IV drip in these patients for 4 hours per day for the rest of their lives...SubQ delivery for instance...) I also prefer a meaningful duration of drug effect, what's the point of I have to poke myself every few hours for the rest of me life...no chance I want to provide for and approve an efficacious drug because that positively reflects on me too, we finally have a good drug that has passed my onerous tests at scale and will now provide a lot of utility for the populations...
But you are in the midst of a Mozz Post. I want to not only know WHAT we need to enhance an application to an authority... I want to know what evidence we already HAVE. Are we on a good path, do we have scope, what are the chances of success? What benefits will we be supplying to a potential market/patient population and why exactly will our drug be in demand?
Paradigmers, read on for some of the most amazing charts I've seen to date in the space of MPS but specifically focusing on GAGs.
Here is a quote to start us of;
"As shown in Supplementary Fig. 2, we did observe reductions in liver or spleen GAGs in the treated mice, although we hypothesize that this is due to the remaining PPS and the fact that the drug is known to accumulate in these tissues after injection (Greenslade et al. 1983). In contrast, in the spleen where less residual PPS will be present, significant GAG reductions were observed".1
Here is Supplementary Figure 2 (see below).
Black column = Untreated MPS I Dogs White columns = Oral PPS Grey = SubQ PPS Treated dogs
Mate, this is the evidence I'm talking about, GAGs reducing in multiple organs at the same time. None of this invasive intraarticular injections...just natural stimulation of the body's own processes and devices. iPPS is non toxic and doesn't fully block cell secretion...it downregulates, it stimulates, it signals, mate it WORKS WITH THE INTERNAL BODY's OWN PROCESSES.
It is safe. Safety profile of not just a coupla years...70 years plus, 100,000,000 injections. Nothing has died at the hands of PPS...not even higher dosed rats.
GET IN _ _ _ _ _
The next paragraph from the researchers indicate what we have suspected for a while.....
You want to soar away from pain? You want to fly high knowing you are potentially addressing the ongoing destruction within? Get in early (not advice, subject to read out).
The earlier the better, I have read a number of stats about how OA manifests usually over ten years, the micro fractures occur way way before they are ever detected on MRIs and certainly long before X-rays illuminate the problems...As the Man from the West once mooted, one day we should have a proper testing kit of a grouping of wet biomarkers (Think CTXII, C2C, Args, HA, COMP etc) to determine who is susceptible from early onset and who should use iPPS as a prophylactic?
The below paragraph has ramifications for our Brazil MPS program and was no doubt one of the main reasons we started off with an older age profile and worked out way down the age stratum based on efficacy but more so on safety. This drug has the potential to certainly alleviate symptoms like joint pain but may prevent needless cell death and potentially assisting the alleviation of more structural manifestations of this terrible inherited infliction.
"SubQ Administration Immunohistochemical assessments of various brain regions were carried out for both groups of subQ treated animals. Overall, the impact of PPS on the CNS was much more evident in the group 1 animals who started treatment at 1 week of age and were treated for 31 weeks. Although double the dose was used in the group 2 animals (50 vs. 25 mg/kg), little or no evidence of CNS effects was found. This could be due to the fact that treatment was started at 5 months of age, and/or the fact that the duration of treatment was only 12 weeks".
One day a prophylactic?
"These findings are in agreement with the potent antiinflammatory effects of PPS we have observed in the other MPS models (Frohbergh et al. 2014; Simonaro et al. 2016). Further, they suggest that the age at which treatment is initiated is more important than the dose, since group 1 animals were treated with half the dose of group 2 (25 vs. 50 mg/kg), but treatment was started at 1 week of age (as compared to 5 months). This suggests that for optimal clinical effects in patients, treatment should be initiated as early as possible to prevent irreversible damage. It is also important to note that group 1 animals were treated for a longer period of time (31 weeks), as compared to 12 weeks for group 2 animals".
Crossing the great barrier?
The BBB made visible by staining techniques. The blood vessel is the black channels, the tightly packed cells are the endothelial cells. This image taken of a mouse brain..6
"Importantly, subQ PPS administration also had an impact on the brains of the MPS IIIA mice, suggesting that the administered PPS may cross the BBB".
Impacts on the brain?
"Although it is well known that PPS is a potent anti-inflammatory drug that impacts peripheral organs (Wu et al. 2011; Herrero et al. 2015; Simonaro et al. 2016), this is the first clear evidence that systemic administration of the drug also has an impact on the brain".
Less squigglies.
It was Dr Simonro that first mentioned this squiggly term, I remember the HC Poster @Robbie1 first posting the wonderful MPS seminar they had a few years ago, See APPENDIX B.
I thought I was almost out there alone thinking about Parkinson's and Alzheimer's, both of which are highly inflammatory conditions of the brain...turns out that these top researchers have also thought along the same lines:
"Subcutaneous PPS administration also resulted in a reduction of the neurodegenerative marker, P-taus262, in the MPS IIIA mice (Fig. 3). The presence of hyperphosphorylated tau protein and tau aggregates in patients with Niemann–Pick disease type C (Love et al. 1995), and in mouse models of MPS IIIA (Bhaumik et al. 1999), IIIB (Ohmi et al. 2009), and IIIC (Martins et al. 2015), has been previously shown, and it has even been suggested that the MPS III diseases should be considered “tauopathies,” a diverse group of diseases associated with dementia, including Alzheimer’s disease. The current finding that PPS attenuated the abnormal accumulation of P-taus262 in MPS IIIA mice therefore suggests that PPS might have neuroprotective effects in other neurodegenerative diseases, in line with an earlier report that PPS exerted neuroprotective actions in a rodent model of ischemia (Sakurai Yamashita et al. 2006)."
"For example, intracerebral administration of PPS increased the survival of mice in a dose-dependent manner after prion infection (Farquhar et al. 1999; Bone et al. 2008; Honda et al. 2012), and continuous intraventricular infusion of PPS in seven CJD patients was well tolerated over a large dose range (11–110 mg/kg/day). Survival in all seven exceeded the mean survival of untreated patients".
"Although we did not perform GFAP staining on these mice, we did observe a marked reduced of IL-B4, another marker of neuroinflammation that indicates microglial activation".
"Group 1 PPS treated animals exhibited significantly reduced latency, consistent with improved learning behaviour. Overall, these behavioural improvements were consistent with the neuropathological improvements we observed in this group of PPS treated mice".
Mate the above is pretty good evidence...but take a look at these charts..iPPS is literally crushing inflammatory markers.
The dashed lines below or normal levels. P values?
* = p < 0.03 ** = p < 0.005 A. = Serum B. = CSF
The researchers then performed a mass spectrometric analysis of urinary GAGs in normal, untreated and finally treated MPS I dogs...take a look at these charts:
I got one more chart for you and this one comes from a different research group, in fact one of the first to apply iPPS to just 4 MPS human patients...
Remember, the authorities want to see biomarker reduction, function improvement and pain coming down all with a safety profile to match. All very good, but show me meaningful amounts of biomarkers falling such as GAGs then we can talk applications to potentially bring forward revenues? (My views)
That's early signs of GAGs reducing in just n = 4. What will Brazil's n=13 show?
We will know this by the end of the year or so. The end of the year is 13 weeks away.
A PICTURE IS WORTH....
Ok so we saw some pretty impressive charts back above...but what about an actual biological snapshot? Some basic background first...
Now lysosomal storage diseases like MPS I result in vascular lesions. In fact the researchers frame it this way:
"Vascular lesions are one the most consistent and clinically relevant features of the MPS I dog model".
The problem here is that this causes vessels like arteries to become thickened...and this presents a problem for blood flow.
As a chart we see this:
p value for the above was outstanding, p = 0.0041
But can you just imagine what effect our drug would have on these artery walls?
Ohh wouldn't it be totally awesome to be able to, one day in the distant future...have the ability to SEE what iPPS does to these patient's artery walls? Like in terms of thickness...
Mozz can only dream...
I dream of flying....well the SP flying...green pastures where are you?
Mate...miraculous is a word I could use...but let's go one better...let me SHOW you what they saw!
The above crazy-good dream-like picture shows the difference between untreated artery walls, Oral PPS...and SubQ...we can clearly see the nice thinner walls of the SubQ treated specimens. This is not the future...this is the PAST! It's the researchers own images of the literal effects of iPPS. See Reference 1 to read and see it for yourself.
This is the absolute miracle of iPPS.
CONCLUSION
I refer to the researcher's own conclusions, it's such a nice wrap:
In conclusion, the current study shows for the first time that subQ PPS treatment reduced neuroinflammatory and neurodegenerative markers in the brains of MPS IIIA mice and that neurobehavioral deficits were attenuated as well.
The impact of starting the treatment early (1 week of age vs. 5 months) appeared to be greater than doubling the dose in older animals (25 vs. 50 mg/kg) .
Overall, the data supports the conclusion that subQ PPS administration could be beneficial in MPS IIIA and perhaps other neurological LSDs, particularly if the treatment is started early in life, and should be evaluated further.
I'm telling you, when the authorities get a sense for this data, for these images that PAR will present and will show the contrast between the placebo group....mate, they ain't going to know themselves.
What I would just give to be able to hand over that dossier to them later this year...and then to hear and see their expressions when they have the follow up meeting to discuss the path forward...
Dear PAR, when you eventually get those minutes back..if they are indeed stellar, please drop us a couple of lines in an ASX announcement or a webinar...for we would all like to hear that.
...Gold.
- Mozz
APPENDIX A
Interview with Scott Williams and Paul Rennie
At the 1hr, 3 min and 20 second mark, Scott asks Paul about the TGA application, Paul alludes to the fact that the authorities don't just want pain drop and function improvement which some drugs can currently do, they want more than the std of care. Provisional approval will allow us to market the product and distribute it while an application for a full licence (that's subject to, and as a result of, a successful P3 trial) is ongoing (within 6 years). Yes this Provisional Application will take a number of months to process but if successful, will bring revenue forward for us.
APPENDIX B
A superb meeting with lots of great data...as a teaser, these guys present data of iL-8, an inflammatory biomarker in the brain. Yes iPPS reduced it...
Not by 15% Not by 30% Nope, not even by 37%
It was 90% reduction. I can't tell you what that could mean for so many diseases involving the brain - neuroinflammatory conditions.
round November 2019, I got excited...PAR were to have a meeting with the TGA and though it was only a preliminary meeting, I thought that that might be the start to a real path of eventual revenue at least in Australia...
(20min delay)
