We have had a very important update to the protocols and observables since then, in fact on Jan 30th 2022 the update came through. Tonight we investigate what has changed, speculate on why it has changed and go through my view of some ramifications.
CHANGES
One of the fields that's exciting that has changed is the overall status of the trial. It's changed from NOT RECRUITING to RECRUITING. Good to see that status there officially.
Let the games begin...last phase...yes potentially a few years before the real juice is upon us...but this doesn't mean that we can't get good news along the way.
The first major difference between the two submissions lies in the dosing.This is what we had previously submitted:
2mg/kg calculated for ideal body weight (IBW) PPS twice weekly- 2 mg/kg IBW PPS once weekly + placebo once weekly
100/150 mg PPS ≤65/>65 kg IBW once weekly + placebo once weekly- placebo twice weekly
This is what we have now:
- 1.5 mg/kg calculated for ideal body weight (IBW) PPS twice weekly
- 2 mg/kg IBW PPS once weekly + placebo once weekly
- 100/150/180 mg PPS if ≤ 65 kg/ ≥ 65 kg and ≤ 90kg/ > 90kg IBW+ placebo once weekly
- placebo twice weekly
The important one is the introduction of the 1.5 mg/kg dose. Yeah so what Mozz, Why are you getting so excited about a teeny weeny meeny 0.5 mg difference?
Do you know how little that is.....Well here is a helpful clue, there are no less than 1 million milligrams in a kilo!
A SUBTLE DIFFERENCE
HOW does this tiny dosing testing change make any difference?
Let me take you through the figures...humour me for a sec...
32 million OA patients in the USA alone (Actually it's a lot more than just 32 million, according to the Arthritis Foundation and Dr D Felson, the numbers could be in the order of circa 90 million!).
So the conservative calc becomes 32,000,000 x a conservative slice that we may one day treat, lets take the slice/penetration rate of just 10%. Double this now for Europe and add perhaps a half again of those numbers for other markets...
Trusty calc please...
0 % of 32 Mil = 3,200,000 for USA plus 3,200,000 for Europe plus 1,600,000 for ROW = 8,000,000 patients
Wow, 8 million patients....and that's conservative!
Now multiply this by your teeny weeny meeny figure of just 0.5 mg......that's 4 million Mg....Mozz...it's mg....one mg is like nothing...correct, but multiply out this almost nothing and you get a something....
How much?
4 Kilograms of raw material which you now need to multiply out per Kg of body mass, average is prob around 70 Kg or so...
So the final Calc is about 4 x 70 Kgs = 280 Kgs...more than quarter ton of raw material per year at a conservative 10% penetration rate.
But I have forgotten one calc...that's per injection...we could have up to 12 injections (plus maybe a couple of boosters per year)...lets discount it back to only 6 injections for the initial course and on average lets say only 50% need an annual booster...so a total of 7 yearly injections....multiply the above calc by 7....
We get a Grand Total of 280 Kgs x 7 = 2 tons!
That's potentially per annum...that's also only 10% penetration, Humira remember had 65% peak penetration...
This is the potential saving we could have by a slight adjustment of our minimal dosing regime if it is anything less than the planned 2 mg/kg twice a week for 6 weeks...
OTHER CHANGES
The next change was the specifying of fixed dose weight bands....namely < 65 kg, >65 kg but < 90 kg and > 90 kg for 100, 150 and 180 mg respectfully.
The latest submission also incorporates more detail around the WOMAC scale and deals with the new dosing regime, the new 2 staged protocols and an introduction of PGIC (Patient Global Impression of Change) including "survey questions relating to activity, limitation, symptoms, emotions and overall QoL related to your arthritis".
(QoL is Quality of Life, a very important calc used in the valuation of a drug particularly from a payer's point of view, I'm planning a future post on this at a later stage).
The previously stated measurement of Responder Index (OMERACT-OARSI) have been updated to incorporate both stages of the initial part of the Third Phase.
Another hurdle that has been refreshed is the 25% hurdle in terms of pain, it has been updated to 30%. (The 50% hurdle remains as is). I wonder if this greater hurdle is due to confidence and to align it with general pain and functional improvements sometimes seen by (the so-called) std of care? It could be an easier sell to insurers that we are passing a higher benchmark?
In the Outcome measures section the introduction of investigation of Anti Drug Antibodies is newly introduced.
The next major change we see introduced with this new submission are structural observables.
I can't help but wondering if this ties in with a DMOAD type effect or is designed to become a prelude into a further required expanded study after our initial 008 study concludes?
Paradigmers, just take a look at the newly introduced structural phenotypes and pathologies now to be studied:
A) Change in subchondral BML area and volume on MRI from baseline at Day 168
B) The effect of PPS on subchondral BML volume and area on MRI and whether these changes correlate with clinical outcomes
C) Changes in joint synovitis/effusion volume on MRI from baseline on Day 168
D) The effect of PPS on joint synovitis/effusion volume on MRI and whether these correlate with clinical outcomes
E) Change in cartilage volume on MRI from baseline at Day 168
F) The effect of PPS on cartilage volume changes on MRI and whether these correlate with clinical outcomes
G) Change in bone shape on MRI from baseline at Day 168
H) The effect of PPS on bone shape changes and whether these correlate with clinical outcomes
I) Change in joint space width on MRI from baseline at Day 168
J) The effect of PPS on joint space width changes and whether these correlate with clinical outcomes
LEFT SIDE: None of these structural observations were in the study protocols... RIGHT SIDE: All new! Note- Left single click on image above to make it larger if too small to read.
Structurally significant? You bet...what an expansion of the plan....do you guys get a sense of where this might be going? I like what I see...just wait till the data comes out *fingers duly crossed*.
A few more exclusion type criteria were also added into the new protocols including the adrenal screening (ACTH test) cortisol concentrations, ie cortisol synthesis inhibitors also known as adrenal steroid inhibitors (2) at the insistence of the FDA.
Interesting to keep up with this site, worth checking in to the clincial.gov site periodically,
As always, DYOR
- Mozz
APPENDIX
Hey! You invested in PAR....There aren't a lot of us really, circa 15,000 shareholders...not a lot when you consider that the potential for this one is well ....errr.. quite large....Not tomorrow...not after 3 months...I'm talking years really....but here is a video from the one of the greatest in the world in terms of OA....Dr David Felson...its a short vid. but he says just how rare it might be to get a drug that has pain reduction, functional improvement COUPLED with structural improvement...a big HINT for us that PAR have included such tests now in a P3. Watch this space, only my views.
REFERENCES
1) https://clinicaltrials.gov/
2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080363/#:~:text=Adrenal steroidogenesis inhibitors, which act,treatment of CS [10].
