In Part 1 we had a bit of an overlook at some competition to iPPS. In part 2 I want to cover one more with a certain fact that might just amaze you. I'll also spend some time going a bit deeper to illustrate what a safety profile actually means for us, in particular, just how we compare with what's out there for OA pain and what this might mean for our chances of success.
HUMIRA
A comparison of drugs in the OA space also should include Humira. Humira is the brand name for Adalimumab owned by the large BioPharma called Abbvie.
Abbvie's blockbuster Humira.
Don't forget HA is predominelty used for RA not OA. The good thing here for us is that while they show no efficacy for OA, we do show efficacy for RA. This hasn't been strictly tested but there is some anecdotal evidence.
Now Humira is a real paradox for me. It has some really excellent qualities...but there are a few, how do I say this, disadvantages. Let's cover the good stuff (for them) first.
Wow what a drug...it's so good that it's been classified as a DMARD, that means....
Disease Modifying Anti Rheumatic Drug
It's not only good on paper and in the lab...it's great out in the market...sales? 6
Look....
It so good that I like to base our own projection of iPPS sales on something like this model.
Over $200 Billion of cumulative sales since inception.7
However, all is not well in paradise for Humira.
Humira had it real good for years...but dark clouds are a comin'.
They have two threats now....
The first one is more recent, biosimilars, think of these as copies after patent protection. They have had a good run, I mean 22 odd years of increasing revenue is quite a feat, I dunno how many of us reading this Mozz post will still care about iPPS in twenty years from when we get licensed. Not because I don't think it will still continue to give...because some of us are going to be too old to understand and process what's actually going on *eep*.
The second thing that's somewhat against them is AE's.
Now AE's are classified like this:
"The company has faced several lawsuits over Humira side effects".
"Humira lawsuits claim the drug caused deadly fungal infections, nerve damage and cancer".8
Would you believe there have been 169,000 reported serious adverse events?
But even that isn't the crazy stat.
I'm so tempted to turn it into a Mozz Quiz®. These quizzes are now finally getting International recognition.
For our international readers, a special tonight, a double pronged Mozz Quiz® !
A little background first, in my rough estimate, there have actually been about the same number of injections of iPPS and Humira so far. So they should be fairly comparable on a dosing basis. Eg. $200 Billion divided by a very rough average of $2000 a pop.
HOW MANY FATALITIES HAS iPPS - V- HUMIRA HAVE WE HAD?
A) iPPS 45, Humira 120 ?
B) iPPS 17, Humira 60?
C) iPPS 10, Humira 140?
D) iPPS 189, Humira 14 ?
Well the answer is......
iPPS 0 (zero) (zilch) (nothing) (Not a one)
Humira 13,000
That wasn't a typo.
Thirteen thousand fatalities!!!!
Hellloooo is anyone reading this?
Can anyone reading this here post get any sense of the potential here for us? It's all about Safety, it's all about Pain relief....and as a bonus iPPS gives us Function improvement, durability and it's NOT INTRAARTICULAR !
My include those features stated above and potential DMOAD as a super bonus. That, one day in the future, will be our winning hand.
Now let's go a little deeper.
A DEEPER DIVE
Remember that 1 Year Pain chart PAR presented, let's take a closer look:
I've labelled the above with numbers from 1 to 11:
1 - HA and Triamcinilone. We have all heard of Hyaluronic Acid, the wonder molecule.
Triamcinilone is a new one to me, but it's a steroid. Some patients have reported more severe problems :"Brain, spine, and nerve problems (eg, paralysis of the arms and legs, stroke) have been reported in patients given with this medicine as an epidural or as a needle placed into your spine". 9
See also Point 9 below.
2 Celecoxib is a NSAID. Symptomatic relief only.10
3. Betamethaosne is another corticosteroid. It also acts somewhat as an immunosuppressant.11
4. Glucosamine - The jury is out on this one, there isn't a lot of evidence for adverse side effects but longer term usage needs to undergo more testing as there could be ramifications for patients with allergies using this as one of the main sources is Shellfish. There is a little mixed evidence as to the efficiencies (they tend to go up with increased and prolonged usage but this then has more propensity to cause problems like allegfeires or even insulin resistance.12
5. Etoricoxib
Somewhat similar to Ibuprofen, it results in symptomatic pain relief however it comes with warnings about increased blood pressure with use.13
6. Naproxen - One of the more popular ones, however longer term use has been associated with increase chances of stomach ulcers. It also can escalate risk of heart failure and or kidney failure. Use with caution! 14
7. Nimesulide -Another type of NSAID Symptomatic relief but look out for side effects with evidence of some Serious Adverse effects too. 15
8. Vit D - I was a bit surprised to see this one on the list and the efficacy based on the chart isn't totally immaterial however, the greater evidence of the relationship between Vit D and OA is weak at best.
"Regarding OA initiation in humans, the small number of published observational studies suggest a lack of association between induction of OA and vitamin D status Most randomized controlled trials were performed in White OA patients with relatively high vitamin D status (>50 nmol/L). These studies found no benefit of vitamin D supplementation on OA progression". 16
Having said that, even if there are subtle benefits there certainly aren't AE's associated with taking a tablet a day.
9. HA on it's own has been administered fairly widely. It's hard to get accurate stats but here is an indication:
"The data showed a significant increase in the overall use of HA services during the study period: from 1,090,503 services in 2012 to 1,209,489 in 2018". 17
There have been guidelines stating generally that HA administered directly into the joint has limited effects:
"However, as reflected by the 2013 AAOS guidelines, available evidence does not meet the minimum clinically important improvement thresholds for patients with knee osteoarthritis".
Indeed the number of HA injections for this purpose in the US is starting to drop. If anyone can get the equivalent stats for China I'd be interested in the numbers.
Yeah wait Mozz...I don't get it, if you rate HA as such a supremely beautiful molecule, how is it that the efficacy as displayed above in point 9 is pretty pathetic?
Ahh glad you asked.
Our bodies don't want a concentrated delivery of it plucked from some random Rooster and then injected intraarticularly from outside ...we want it to be produced by our very own cells from WITHIN!
Yes yes, a good source of HA...but is this how we really want it?
Can any of you reading this just imagine that lovely thin synovial membrane comprising of thousands upon thousands of synovial cells all secreting out the Higher Weight HA molecules and slowly contributing to the supreme visco-elasticity of the synovial fluid, the very cushioning and lubrication for the subchondral cartilage that you and I are both definitely depleting over time? I want the young HWHA fluid I once had some twenty years ago plus.
This is the actual raw power of your drug.
Mozz note: I've highly simplified just a fraction of the biology here, check out Appendix B at the end of this post to get a small sampling of just how complex the biology actually gets!
10. Here is where products like Voltaren (Diclofenac) fit on the scale...
There are some hints of warnings here, take a look at this one for example: 18:
Look I'm not totally against such products, if my fingers and wrists were riddled with OA , I'd seriously think about using some of these products when the pain got bad. But knowing what's coming, iPPS, I'd endure the pain till it was on the market, HANDS DOWN! With any luck, it will only be a year away...C'mon TGA !!
Mozz Note: Hand OA as declared by Paul Rennie back in 2019 was the joint that displayed the best efficacy from iPPS. I won't ever forget this fact that he told us.
For the readers of Mozz posts over the last 4 years - In case you are wondering why I harp on about that...how many intra articular shots are you gonna be able to have in each and every joint in your Wrist and Fingers!!!
After about number 9 on the above chart I reckon there is not much relief to be had. Maybe there might be some that work for a few patients, but certainly nothing at scale, even leaving aside the safety issues.
One I would like to point out is Sprifermin (11), it might show some structural benefits but it isn't going to have a big uptake if it has very little symptomatic benefit and certainly needs to be taken intra articularly. I understand that something is better than nothing, but this won't hold a candle to what iPPS is showing.
The part of iPPS I love is that it is so, so consistent. Specially somewhere close to the top of that bell dosing curve. We get this accepted and into a Phase 3 and if it shows results anything similar to 005 and 008, I can't express to you the eventual uptake rates. We don't even need vast slabs and percentages. We need a sliver.
Going through the above competition brought back a memory, the memory of me attending OARSI, where I heard presentation after presentation of the competition and the research, not a single one came up on the radar as having either good symptomatic relief or positive structural efficacies WHILE AT THE SAME TIME BEING SAFE.
Not one.
To have both and to do so safely, of course subject to a Phase 3!...well the early signs are amazing.
JUST AROUND THE CORNER
What indeed is just around that corner? Anything good?
According to me it's literally days away from TGA determination, maybe it's this week, maybe the next? What does that have to do with competition?
A whole stack, have a read:
"The determination application will include information from a manuscript detailing the outcomes from the PARA_OA_008 phase 2 clinical trial and a manuscript providing a comparison of iPPS clinical data with other available treatments for osteoarthritis".19
PAR submitted a subset comparison manuscript of iPPS with what's out there to the TGA. Fellow holders, YOU and I both know what's out there, very little and very destructive. If the manuscript contains any sortta details that we are seeing as presented by the Good Doc Ahuja, we should be a in very good place.
Let's wait and watch with fingers crossed!
Not advice
Mozz
APPENDIX A
The below is an extract from a patent document covering inflammation, it's quite a read and supports the data that PAR presented. It's also what the FDA support, to have a decent and genuine OA solution one needs BOTH components, symptomatic AND structural. Giving mere pain relief isn't enough, there needs to be a link between pain and function. It's no wonder PAR have BOTH of these as their primaries.
In case you are brand new to us, drugs that bring down pain aren't in our league. What do I mean by this? Well they are essentially masking pain. They aren't addressing the underlying cause.
Since the discovery of aspirin, many other compounds have been produced which are claimed to be more effective than aspirin. These include such compounds as the phenylacetic acids exemplified by ibu profen and more recently identified compounds such as naproxen and sulindac. Strong anti-inflammatory potency has been achieved with the corticosteroids (e.g. hydrocortisone, dexamethasone, prednisolone, methylprednisolone, betamethasone, paramethasone, and triancinolone) as their water soluble and insoluble derivatives and these are also widely prescribed. However, all of these prior art compounds and compositions whilst displaying satisfactory analgesic anti-inflammatory properties, in that they relieve joint pain to a certain extent in most cases, any beneficial effect that they have in restoring joint function is usually only transitory. Furthermore, prolonged therapy with these prior art compounds and compositions while providing continuing pain relief for many sufferers can lead to breakdown and failure of connective tissues, particularly articular cartilage which in fact may exacerbate the problem. 20
APPENDIX B
How about this one....there is a stack of complexity embedded into just the synovium. The more recent research depicts this complexity and one paper highlights the fact that there is a lot of cross talking that goes on with different types of synovial cells and the cartilage. This all comes down to cell signalling and the various different types of synovial cells that are present. No doubt iPPS has a big role to play in different ways, cell signalling and the reduction of inflammatory cytokines is just one facet where it plays a role: 21
Yeah that's quite a full on pic up there
I'm not sure how many of you have read down to this little bit but a healthy human synovium for example in the knee joint contains between 0 and 4 mls of synovial fluid! Some 300 joints in your body glide nicely because of synovial fluid.22 It is postulated that inflammation and thus OA primarily starts at the synovium.23
iPPS has shown in a small number of n that it can reduce synovial inflammation. I look forward to our P3, it may not report specifically on the synovial observations, but the rest of the endpoints and observables could be quite remarkable.
include those features stated above and potential DMOAD as a super bonus. That, one day in the future, will be our winning hand.
(20min delay)