MOZZ OARSI 2023 - NOTES, page-78

MOZZ NOTES - PART 4 - CTS - Competitor Analysis


The poster @goldmad requested an analysis on the competitors that presented at the Clinical Trial Symposium held back on March 16th.


Remember, there are my own personal thoughts through this post, I might have missed stuff, its not intended to be a comprehensive analysis, I may have inherent bias etc. Also, a number of these presentations didn't really actually talk about how well their drug is performing, they talked a bit about how they worked (MOA) and the trials but at least in some cases there wasn't a lot of data that was presented.

Look out for some concluding thoughts at the very end of this post.




BIOSPLICE(Lorecivivint)
Jeymi Tambiah

Update on the Lor program broken into two parts. Part 1 - Trials that have been completed, 2 phase 3 trials last year.

Part 2 - ongoing trial update and share the challenges/learning's

Part 1 - Inarticulate Dirk inhibitor, enters nucleus. Disruption via inhibition in terms of inflammatory pathways. Safety study, moved onto a P2a study, target population identified Phase 2B study - pain primary endpoint metSS attained over placebo for a number of different PROs

In 2019 we moved on to commence two phase 3 trials (OA10), pain trial 12 week endpointOA11 was a combined pain and structural study over 1 year, medial JSW as an endpoint. We recruited a restrictive patient population having a JSW between 1.5 to 4 mm at baseline and allowing BMI up to 40 in inclusion.

Both trials did NOT meet their endpoints

OA11 did not show structural progression. Covid affected trial conduct OA 07 OA long term progressesOA21 - Initiated another pain trial We looked at our clinical characteristics. In OA10 Placebo was same but treatment effect of Lor. was lower

Conclusion
In terms of structural effects in terms of advanced patients, 20 to 30 patients, awaiting more data, at month 11, no difference between placebo/active. In single blinded arm at m24 the LOR subjects have maintained their JSW. Though early and small numbers, seems like there is some structural benefits in both arms, placebo and active.

In Pain Womac, SS in terms of pain against placebo. Lor appears to be safe, medial JSW benefit at 24 months after repeat injections. These studies are ongoing.

Short term pain effect can be demonstrated with less baseline structural damage. There does seem to be a long term structural benefit.



Mozz Notes^®


PROS: Seems like their current trials are better structured to possibly show some worthwhile data here

CONS: Route of Admin is intra articulate, data needs to be properly investigated, past results haven't been awesome

TIMING: Sounds like it is a number of years off still, then will also be subject to what FDA thinks of the data. Currently running two P3.



Grunenthal - (RTX - Capstain)
Andrea Derix

TRT 7039Buffered version of resiniferatoxin, Receptor Nociceptor nerve fibres. Plays a role in pain receptors. RTX activates calcium ion channels into nerve endings, result is long lasting but reversible retraction of nociceptor nerve fibres.

Analgesic effect. Has been explored by many groups in-vitro

Potency of RTX compares well to other capstains (1000 fold in some cases). Pharmacology has been characterised in some in-vitro studies. Pain responses returns naturally over time and correlates with expression of nerve fibres.

Analgesic effect even after 100 to 200 days in canines. Clinical Program - We think this compound has the potential to be a treatment for moderate to severe pain in regards to OA. Best for patients that have failed other std. of care. Phase 1 and 2 Program comprised two open label studies - dose escalating exploratory trials. Difference was in the doses.

Overall 120 patients have been exposed in P1 and Phase 2 programs. Phase three ongoing, started last year, Global Program, EU, US, Japan, LATAM.1800 randomised patients, two trials.02 single dose01 patients are getting two intra-articulate doses (separated by 6 months).(Up to 4 total injections for some patients)

Primary endpoint at 12 weeks, Womac pain, follow up at 52 weeks Secondary endpoints also being studied.

Mozz Notes^®


PROS - Good pain relief

CONS - Sounds like it is essentially blunting the nerve fibres, not a structural remedy.
Pain ("not insignificant") can be experienced in the administration of this solution.

TIMING: "Upon completion, the Phase III programme is intended to enable marketing approval for RTX in the EU, the US, and Japan. Grünenthal aims to submit a new drug application in 2024, leading to a potential market entry of RTX in 2025". ³

Novartis - LNA043
Matthias Schieker

Update on currently recruiting studies. Two divisions ; Early and late stage trials. Today - Early Trials discussion - 30 OA trials until 2015.7000 patients in late stage that have failed until 2015.

Currently running 5 compounds in 6 studies. We have approx 1000 patients in studies today. We are highly committed to turning this around and developing drugs in OA.2 Year study - trying to find the population where the drug has an effect.

Canokimab - Anti IL1. 138 patients - enriching the study for synovitis - study is ongoing. Regenerative Compound - small study to understand anabolic imaging In licensed compound from Merck - Pain endpoint, DMOAD investigation 98 patients, study has just started recentlyNrp3 inhibitor Anti Inflammatory compound.

Need to really know the MOA's. Anabolic treatments need to be much better


Mozz Notes^®



This speaker didn't really touch on the data or how the various trials are actually going. The speaker did give us a story which became a bit of an insight :


"When I was in medical school 25 years ago, the first Tnf-alpha inhibitors were introduced for RA patients, when I was a resident Bisphosphonates were established for osteoporosis. When I was a Professor at University, I helped launch Denosumab for osteoporosis (A biological) and I still hope we can manage to solve the OA problem. I think there are so many parallels with regards to RA to Osteoporosis to OA...and I do hope that before I retire someone has managed to come up with a treatment for OA. I do think it is ready to be there." .

PROS
Seems like there is some good data with this drug despite also having some past concerns?

CONS Intra-articular.
Serious and sometimes fatal infections may occur during treatment with canakinumab.⁴
Immunosuppressant.

TIMING: Approx Oct 2025.⁵


Trialspark - Speirferman
Presented by Steve Kaltibiano

Insights from Clinical trials Anabolic agent. Been around for a while, hasn't been in clinical trials and publications.
Challenges in this field, pain and function are primary outcomes.

Survival of the knee. We have had three studies to date. First study, patients that were scheduled for TKR's to check safety and tolerability Phase 1B in primary Knee OA patients - dosing analysis Phase 2. Forward trial, encompassing around 500 patients in total separated into 5 groups.

We do have effects of sprifermin on structural modification, Cartilage regeneration prospects. Higher dosed groups had better results but we did NOT see effects on pain and function. There was also a fairly large placebo effect here.

⁹



Mozz Notes^®



Just growing cartilage doesn't necessarily and automatically translate to patients and regulators benefit.


Dosing - need to analyse 4 times over two years -v - 2 times over two years. Relationship between cartilage thickness and pain and function isn't an obvious one.

PROSSuper they are getting some cartilage regeneration.
May be good for some specific slice of the OA population.
Preventative use? Pain and function can get worse as OA progresses.

CONS
Yes but no pain and function improvement? This is key...this is primary. Need to characterise the symptomatic endo types better. They sounded quite confident but didn't show the data, isn't that telling?
MOA not too clear.

TIMING: 2b ('SPRING') trial to start this year.⁶


Key Mozz Point it was interesting to hear this speaker discuss how there are two distinct areas to be addressed, symptomatic -v- structural.
Our iPPS is showing real efficacy in BOTH of these distinct areas.....i n c r e d i b l e





Moebius & Sun Pharma
Moshe Weinstein


MN-II lead molecule - larger liposomes, reduced friction and pain in joint. Stays on surface of cartilage. There is no active molecule within these vesicles.

It acts by coating cartilage.Persistent lubricating of cartilage.Joint lubrication MOAMechanical effectsPhase 2 B proof of concept study

Dosing by increased volume as opposed to concentration. (Cant increase concentration).3 and 6 ml dosing3 ml p 0.085
Primary not met.

Durability went out to 26 week time point6 ml did not differentiate from placebo at any point. But Weekly Ave daily knee pain - both robust and durable of 1 and 3 ml doses -v- placebo Rescue medication - in all groups, patients who received MN II the use of rescue medication reduced over the first 8 weeks. Placebo stayed the same. Similar trend in pain over first 8 weeks.

No AE'sConclusion - beneficial and durable effect over placebo. Weekly daily pain better endpoint than purely Womac.


Mozz Notes^®


PROS
Good results in terms of lubrication of cartilage. Has been shown to reduce some amount of ARGS.(Aggrecan degradation)Can result in less cartilage degeneration (32% )
Good effects better than HA injection treatment potentially.

CONS
Intra articulate
Only symptomatic relief
Interesting but at the end of the day lubricating, not DMOAD.

TIMING Top line P2b results just released in May 2023.

"While the study did not achieve statistical significance on the primary outcome measure, it did show
meaningful and sustained improvement across several clinical measures". ⁷


XALUD THERAPEUTICS
Howard Rutman XT-150

iL10 targeting - inflammatory cytokine Plasma DNA (gene) therapy Phase 2 B done289 patients.
Variability in Womac pain

NO AE's.
Challenges patient outcome scoring has been a challenge -Variability


Mozz Notes^®


PROS
Localised pain relief observed Sustained pain relief after 36 weeks in canine studies.
Good safety data

CONS
Single Targeting.
Intra articular
Longer term studies required.
Negative impact on enrolment - pain (assume this is intraarticular).

TIMING: Phase 2b results just released.⁸



Genascence - GNSC - 001
Thomas Chalberg

Gene Therapy Addressing IL-1Early stage - Phase 1 complete.


Mozz Notes^®


PROS
Improved structural observations Improvements in animal models.
Only mild to moderate localised side effects.

CONS
Early in life cycle.
Single Targeting.
Intra-articulate Gene therapy - New frontier - is it really safe?
Need longer term studies


TIMING: Early stage, P1 completed.

Kolon Tissue Gene
Sungsu Han
Gene Therapy

Challenges, what is a clear measure of structural improvement needs to be related to symptomatic improvements

Mozz Notes^®


PROS
Phase 3 study in USA being carried out

CONS
Has had chequered past but perhaps that shouldn't affect current and future trial.

Intra articular DOAD questions, can it positively affect structure? Can be some unwanted affects eg: Most frequent adverse events in the INVOSSA group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%).¹

Need to undertake longer term studies to rule out safety concerns


TIMING P3 Primary due Aug 2024, Secondary Aug 2025. ^10,11


Pacira Bio sciences
Ron EllisPCRX-201 - Gene Therapy
ExparelNerve Blocker.
In market now as a pain relief post surgery.¹²

Similar to a local anaesthetic, numbing the pain.


Mozz Notes^®


PROS
Doesn't completely block IL1, as we have seen with iPPS, the beauty is that it is not blocking...it downregulates.
Seems like the data so far is good.

CONS
Intra articular
Long term studies needed in new field of Gene Therapy








MOZZ TOTAL SUMMARY

I walked into the CTS thinking all these guys HAVEN'T PAID to get in here, they have bene INVITED! I was a little wary that what I hear may actually be decent competition...

I walked out of the conference feeling so good...there were NONE of those other guys that could say that they are done...
They are the grail...
They have the grail
The grail is us.



_{Choose well my friends...don't just go for the glamour of single targeting drugs, gene therapy, etc...think natural...try something that's been proven over decades...}


Yes there were a few that showed promise...but again, there was only ONE that showed that they had Structural as well as Symptomatic.

Who was the one?




Yeah us.


Now its going to be fairly easy for me to be biased and believe us to be hands down the best...but the proof will be in the pudding and that pudding is going to be ready in a few years...maybe less...maybe a lot less?

Who knows....


IN MY OPINION

Hard to say which is the best of rest, perhaps Kolon Tissue's Invossa is a one to watch...again the Jury is out as to how safe this new tech actually is, yes short term no serious AE's is good, but cancer watch? Other ramifications when it gets out into the wider community??? Another one to also watch is Lorecivivint, seems like there is at least some symptomatic and structural observations here but perhaps it will be more targeted on a certain slice of the OA patient population?

Now its going to be fairly easy for me to be biased and think that...but the proof will be in the pudding and that pudding is going to be ready in a few years...maybe less...maybe a lot less?

Who knows....

Certainly it was a worthwhile though a little arduous, exercise reflecting back on my notes and what the presenters said. Would I go to OARSI again? I think I would but it would be an easier job both physically and mentally if our dear share price were slightly north of where it is now. Lets see!



For those that haven't seen it, have a flick through our presentation (Appendix below) shown by Dr Skerrett on the night ...it was difficult for Dr Skerrett to get through all the material in such a short time, she did a really good job, the audience weren't investors and fundies...it was purely scientists, surgeons and academia.



DYOR applies



Mozz










APPENDIX




Link to PAR Pres: https://paradigmbiopharma.com/wp-content/uploads/2023/03/PAR_OARSI_CTS_Mar_2023.pdf

Here is just one slide that I liked but the entire pres. is worth a flick through. Check out those p values below and consider how small the n is ...it's this data that excites me.







REFERENCES

1] https://www.oarsijournal.com/article/S1063-4584(18)30203-6/fulltext#:~:text=Conclusions%3A%20INVOSSA%20was%20associated%20with,hold%20potential%20as%20a%20DMOAD.
2] https://hotcopper.com.au/threads/the-comparative.7276854/?post_id=667174113] https://www.biosplice.com/clinical-development/detail.aspx?id=204] https://www.grunenthal.com/en/press-room/press-releases/2022/global-clinical-phase-iii-programme-for-resiniferatoxin-rtx4] https://www.drugs.com/mtm/canakinumab.html#:~:text=Serious%20and%20sometimes%20fatal%20infections,stomach%20pain%2C%20or%20weight%20loss.
5] https://delta.larvol.com/Products/?ProductId=6a7ae9b1-465b-4f2c-9554-4e537cdbb8ad
6] https://ard.bmj.com/content/annrheumdis/82/Suppl_1/1025.full.pdf7] https://sunpharma.com/wp-content/uploads/2023/03/SUN-Moebius-Medical-Press-Release.pdf8] https://www.biospace.com/article/releases/xalud-therapeutics-presents-clinical-data-on-xt-150-in-knee-osteoarthritis-at-the-2023-osteoarthritis-research-society-international-world-congress/
9] https://clinicaltrials.gov/ct2/show/NCT0583589510] https://www.tissuegene.com/en_US/clinical-trials
11] https://clinicaltrials.gov/ct2/show/NCT03203330
12] https://www.exparel.com/patient/faq