Mozzarc
Emerged
DISCLAIMERS
Some general caveats first though. This is completely a speculative attempt to GUESS what the timelines are. In no way should you rely on anything presented here, it is all of my own personal work, it's a rough guide. These timelines are subject to potentially a LOT of variation. A lot of it is behind the scenes that we just aren't privy to most of it. There are also many factors that can blow out the timelines stated below and perhaps in a few rare cases my stab at the times might be conservative. Overall its probably prudent to build in a little extra buffer just in case so you, me and the bank aren't totally unprepared.
DYOR totally.
BRIEF RECAP
Rare or Orphan indications have their own challenges, "...including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints".5
Lets take a brief look at those above points that are typically lacking in many Rare disease trials:
1) LOW PATIENT NUMBERS
Well we will have MPS I and MPS VI patients, numbers seem low but are quite reflective of a powered sample size. Our Phase 3 with 30 or so patients will also be suitably powered. Some recent ERT drugs also had around this number in their clinical trials. Don't forget, with just 13,000 USA patients the numbers are low. Compare that to OA...officially (old) figures are approx 32,000,000...but in reality they could be as high as 90,000,000.
Paradigmers, that's just ONE market, USA.
2) LIMITED UNDERSTANDING OF THE DISEASE PATHOLGY
Not so in our case, we have a good early understanding of the MOA of Pentosan, we have the whole OA program in all its sub studies and a large SAS program, EAP program and of course our OA Phase 2. From a joint and musculoskeletal perspective, there is strong overlap. There are also a number of other studies conducted with the use of PPS.
3) VARIABILITY
Yes there are patients that our drug may show a lower response to, the good news is that most if not all, do have a level of pain reduction and degraded joint function improvement. We are also looking at how iPPS can positively effect other areas within the MPS space, see also 'NOT JUST PAIN' below.
4) LACK OF ESTABLISHED ENDPOINTS
Its is here where we have already done some good work. We will get to some of these endpoints in this post soon.
There are a number of incentives to overcome the resistance BioPharma companies would naturally have in spending a lot of time, effort and money developing drugs for a tiny market in terms of numbers. We stand to gain here in that we already have some decent evidence in terms of efficacy in the musculoskeletal area, pain and of course safety profile.
Mainly for you new guys, OA is our main indication that we are pursuing but as far as our secondary indication, MPS, it has been said that our solution for MPS could be a company maker in its own right. Yes it is an official Orphan indication but this by no means equates to only a small revenue potential one day. It could be fairly lucrative but of course much much less overall revenue potential than the OA program itself.
The exciting thing about MPS from our point of view is that though the timelines presented below might still seem far off, it should be somewhat quicker than the OA program. Of course no one knows exactly how these programs will play out, but that's kinda the excitement that things can strike outta left field.
NOT JUST PAIN
The focus for both the MPS I and VI strains is not JUST pain relief.
Paradigm will assess a number of key secondary and exploratory endpoints, including effect of PPS on:
• Pain and function (mobility);
• Urinary GAG levels;
• Walking-related pain;
• Quality of Life, activities of daily living, subject/parent global impression of response to therapy; and
• Pulmonary function.
DESIGN
Trial Design The phase 2, randomised, double-blind, placebo-controlled study will evaluate the safety and tolerability of PPS in treating subjects with MPS VI who exhibit pain and functional deficiency due to musculoskeletal symptoms associated with the underlying disease. Twelve (n=12) subjects will be recruited into the study and randomised 2:1, with eight (n=8) receiving PPS and four (n=4) receiving placebo. All MPS VI subjects will receive ERT throughout the study.
Subjects will receive PPS at a 1.5 mg/kg (≥9 years of age) or 1.0 mg/kg (<9 years of age)
THE TIMELINE
I'll discuss each event below the timeline to give you some of my rationale. As always, don't be shy to offer up your own thoughts, do you agree, do you think any events could be shorter or longer in duration? Do add to this thread if you have any comments or want to add to the discussion!
Single left click the above image to enlarge.
EVENTS
1) MPS I kicked off in Adelaide, Australia and aims to recruit up to ten patients. Whether they need the full 10 is contestable, more than likely they will get to some tipping point and they will have enough data to be able to link to the MPS VI program.
2) Once MPS I is completed, a couple of months would typically be required to lock the Database and then perform any required data cleaning before preparation for analysis and summary.
3) Meanwhile MPS VI in Brazil continues in the background. The clinical trial is being conducted in Brazil at the Hospital de Clinicas de Porto Alegre and the Hospital Universitário Alcides Carnerio, The Principal Investigator is Dr. Roberto Giugliani, a world renowned geneticist specialising in inherited metabolic diseases. It was Dr Giugliani that recently presented at the Annual World Symposium.. The Phase II trial we are performing comprises of 12 patients.
We have been told by Dr Micahel Imperiale that this program was on track to conclude by approximately end of Q1 2023, I have no information to suggest otherwise and we shroud be on track to meet this time frame.
4) Again, once this program concludes at the end of 24 weeks for each patient, the same steps as Event 2) takes place. The only additional step here is to most likely merge it with the findings of MPS I to form a full dossier ready for submission into the next exciting phase, phase III.
5) There is a slight overlap here with the previous step in terms of kicking off the trial design. The PAR sub teams (think Clinical, Reg etc) wont just be standing around in the hallways waiting for these trials to conclude. They will be already busy planning and preparing for what a Phase 3 trial design might look like based on the data that's coming back. How do you merge the good data being seen in the two programs to set up a well thought out Phase III? What should be the endpoints and protocols? How many sites would we need, what should the statistics be like, how do we power such a trial?
It's these questions that will form a basis in order to tackle the next event.
6) Its highly recommended to have a Pre IND, even for an Orphan indication. It is here where PAR can ask questions and garner information on what the FDA are looking for. We learnt a lot in our first EVER pre IND in terms of OA. Not all of it was good news, it was at this meeting we found that we could not automatically bridge to a lot of past data and studies.
Well worth the extra time and effort, its at this meeting the sponsor can get a clearer picture of what needs to be done to achieve the ultimate goal, product registration after a successful P3!
Its at this time though that useful information can be gained to know what the FDA are focused on, what they want to see and what needs to be done to increase our chance of success. It is at THIS time we learn if we are on the right track or what other tasks need to be completed before we can start in earnest.
7) If any fat needs to be built in, its probably between steps 6) and 8). Clearly in terms of our OA pathway it was a lot longer than we anticipated. You will notice I haven't built a whole heap of time between these steps. I've done that deliberately as this is an Orphan disease. This means the communication between FDA and sponsor is at a heightened level. We have our own dedicated team. I don't anticipate the 30 day rule being implemented here.
It should be a case where Dr Skerret and Dr Imperiale can simply conference call in our dedicated FDA rep and chat about any questions they have. Thus In my mind 3 months between Pre IND and start of P3 should be ok? Possibly we need to add a month or two here as a buffer?
8) Mate, another indication done and filed? When our IND here is open I think it will be again something to celebrate. It will then be a case of taking its own course, its own time and bubbling away in the background. It's a little hard to say exactly how long a P3 here may take. It also depends on whether we have partnered up and how much cash we have on the books. This will have an impact on how many sites we have and what we can do in parallel. It also depends a bit on trial design and how many sites we have for recruitment spread across what regions.
All a bit pie in the sky but I've allocated almost a full year ...again quit conceivable with 30 odd patients that it may take around a year and a bit to finish. The good news here will be if the P3 Protocols are roughly the same as P2 in that it will be a study of the patient over 24 weeks.
9) A couple of months for data compilation cleaning and analysing here I think is a fair allocation.
10) MPS results read out, an exciting time potentially.
11) Ordinarily for Labelling and Marketing up to 6 months to 10 months is not out of the question, however with Rare disease this time is usually shortened considerably. I've allocated 3 months, again in reality it might be a fraction more.
12) Registration by August 2025 seems plausible to me. Perhaps If I had to have money on the line (wait a sec, I do!) I might say its more towards the later part of 2025, BUT I also think that we are addressing something that affects children, there is NO other drug that works like ours in terms of offering genuine pain relief, better Quality of life, addressing a serious condition and can do all of the above safely. This will count for SOMETHING towards a possible expedition. This means those ordinarily long timelines can POSSIBLY be bent and be shortened?
I personally don't take the smaller chance of Breakthrough or a trial being declared open, much into consideration, its more at the back of my mind, I love the concept of UPOD (Under promise, over deliver)....so I deliberately say 2026 instead of 2025 in my own mind, but I'm also not selling myself short. I know we have a shot at more aggressive time lines specially if our data comes back as positive as it has been, but at scale.
We could really have a game changer here one day fellow shareholders.
- Mozz
REFERENCES
1]
2] https://webcast1.boardroom.media/watch_broadcast.php?id=61f1c2733d2b4
3] https://app.sharelinktechnologies.com/announcement/asx/b336d5fe79d9b7a2518fe56dcc22a9e6
4] https://repository.upenn.edu/cgi/viewcontent.cgi?article=1037&context=ace
5] https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1017-5
