In a matter of weeks, hopefully not months, the PAR team will submit their revised final IND application into the FDA, harmonised with EMA as well as Canada, UK and Australia.
I know there are a few newer readers to PAR @ HC that are indeed wondering what does this involve and indeed what does this infer?
Let's have a quick high level peek!
PAST
Without going into all the (gory?) details, PAR already had a Phase 3 submitted and approved known also as PARA_002. This was to consist of Two stages, a dosing study to determine the Min Effective Dose (MED) and then stage 2 would then utilise this MED in the Phase 3.
It was all supposed to be relatively straight forward. However, while the doses from Stage 1 may have had some signals, they were nothing in comparison to the 2mg/kg twice weekly dose (2x2) ! To me at least this was a tad surprising, I didn't think a slight deviation off the 'peak' dosing curve would result in such a drop in efficacy signal for the cohort.
Now the Stage 1 dosing program wasn't a total loss, it showed PAR that the best dose in fact was the one used in both the 005 and 008 programs. It also contributed valued and required safety info.
So this meant that we would then have to check with the FDA that they were happy for us to utilise the 2x2 dosing in the Phase 3.
It turns out that while all that was going on, the 008 study, a study focused more on the synovium, had a read out. This read out also proved surprising, but this time in a good way. It showed us signs we weren't really powered to see! In just 15 patients utilising this 2x2 dose we attained a lot. In the case of many observables, we attained close to, or better than, a statistical significance. These weren't off-hand nice to have observations, they were not only material, they were first time seen.
Nah, not first time seen for PAR, first time seen ever for any OA drug.
There has never been a drug for OA that shows all three aspects: 1) Pain reduction better than opioids 2) Positive Structural morphologies 3) 1 and 2 above in a safe manner without ANY Serious AE's
We also showed the above over not just 6 months, but we saw the great results continuing out to 12 months without any boosters. From a commercial sense, this added to the game changing nature of iPPS.
However, this meant that the excellent observations were too good just to stand around and enjoy, we needed to incorporate them into our proposed P3.
Anything to do with Clinical Trials is a longer proposition. It took a while to compile these excellent results of 008 but also all the pre clinical and non clinical observations the FDA requested earlier this year. We needed to do all of this to be able to effectively take the stellar results of 008 and to be able to modify our P3 protocols. The good thing that PAR did is that they not only sought feedback on the dosing and monitoring but they submitted a draft protocol simultaneously. I reckon this would have saved us at least 3 months, probably more.
Yes it took forever and a day to get the FDA feedback...but this finally came a few weeks ago. It was relief, they effectively said that the 2x2 shouldn't be an issue. The FDA also gave PAR detailed feedback and commentaries which I believe will assist us in moving forward into an effective P3.
Yes it has been a long slog to get here...but I think it will be certainly worth it. To incorporate some degree of duration and to have those excellent MRI's and X-Rays documenting the structural improvements in a harmonised multi regional Phase 3, that will be quite the headline when it comes out.
PRESENT
So now PAR are busy bees once more. They are no doubt having multiple meetings with their KOLs and consultants, they are discussing and implementing the suggestions and comments from the FDA. I believe it will still take some days or weeks but once done, they can officially submit the final copy. The FDA then have 30 calendar days to respond. It certainly doesn't mean we are a 100% go, it means we have a good chance of it requiring only one 30 day cycle, but there still is a chance that the FDA will have some further questions. I hope this chance is very very low.
The new protocol is an exciting one as it incorporates a number of observables we have seen to date. The big one for me is the Durational increase to 12 months. Par would have put this in from a commercial sense to show the future payers just how long this drug is effective for without the use of retreatment for a longer period of time. This becomes much more commercially lucrative.
As shareholders we want the highest chance of success. This clue was attained back at 005 as well as in 008. It comes in the form of stats. To achieve the Drug Effect Sizes we did and observed consistently with such few patients (n was 56 in 005 and 15 in 008), this means hat when we do our P3 the associated p values can only fall IF we keep the drug effect size constant.
As a very rudimentary exercise I plugged some numbers into a simple clinical trial number generator, this is what I got:
What the above depicts, albeit in a crude fashion, if we attain some 88% of the cohort receiving a positive effect (we saw this in the SAS program), we are powered to 90% and Im looking for p value certainly under 0.05 but I've chosen even lower, 0.002 (prob of rejecting the null hypothesis, Mozz Speak = obtaining good results and having the confidence it is because of our drug's effect, not some random chance) , the n should be around 108. We suspect our n will be around the mid 400's, what I'm saying is that we would have a high probability of attaining decent p values with the expected drug effect sizes we have already consistently observed. In other words, with an n of circa 450 we really can expect the 2x2 dosing to be a success. Obviously don't rely on the above, it's just a rough guide, it will all be subject to the rigorous stats applied in our actual trial.
PAR have expertise in recruitment and will select and refine the best clinics they have used so far. The Phase three numbers are usually in the thousands, to have anything under 500 is amazing and also documents the power and effectiveness of the drug we hold.
At the end of the day if the FDA do have some questions, it will mean another 30 day cycle after we get back to them, it isn't the end of the world, but it would be nice to get this thing sorted once and for all.
FUTURE
I suggest that after the revised IND is open and we are allowed to start a Phase 3 (will be known as Clinical Study PARA_012) we will be in a different class. I think it is at this point and beyond that we will genuinely be viewed as a different company. I also think that any discussions we are currently having will step up. I also think the chance of funding this beast (P3) will become more of a reality.
Think about it from the funder's point of view. You commit to P3 funding which in itself will be de-risked, ie not all the money has to be forked up upfront, it's done in milestones so the initial sum is the only sum at risk initially. If PAR progress as consistently as they have so far in terms of the data, we will get the next installment etc.
Lets go!
I also think that once the needle continues to move along in terms of the clinical trial, the chances of regional deals also materially increases.
There are many alternatives available for us once we get through the next hurdle. Once a few start climbing on board, there are others on the sidelines that will also want in. Our current SP is so low, it will be a very compelling proposition at these lower prices.
In my personal view, the next 2 months or so are very critical but could indeed be very pivotal!
(20min delay)