Dimerix (ASX: DXB) Discussion Thread, page-135

G'day @Owl vs Fox and @DoctorBrad - from going back and reading a lot of the posts on hotcopper over the past few years you've both contributed a lot of great info and seem to be the most knowledgeable on the DXB threads which is why I've tagged you here (without meaning to offend the other great contributors!). And good to see you still over here @Owl vs Fox. I think I first added DXB to my watchlist thanks to you during my days on ACW about 4 or 5 years ago.

Just a few questions if you have time.

eGFR Slope

1. Has there been any information published or comments from the company in the conference calls with respect to the improvement of eGFR Slope for patients on DXB-200 during any of our previous trials (based on the actual eGFR monitoring data, rather than a correlation from PCR or ACR reduction)?
2. The 2017 Phase 2a trial noted that there were no clinically significant trends in eGFR as part of the primary endpoint for safety. But I wonder if this was across the full patient cohort and not the post hoc analysis which showed a statistically significant reduction in uPCR (and also ACR) in the subgroup of patients with diabetic nephropathy. Can you recall if there was any specific mention of improvement to eGFR Slope for this subgroup?
3. Similar question for the 2020 Phase 2 trial for DKD. The subgroup which excluded patients starting with a baseline albuminuria less than 57 mg/mmol showed a statistically and clinically significant reduction in albuminuria versus placebo. The conference call for this trial is still available on the website which is good, but they didn't specifically address the monitoring of eGFR Slope, so again I'm just wondering if there's anything in the public domain that I've missed with respect to eGFR in this trial?
4. Probably the most relevant results for eGFR Slope for patients on DMX-200 with respect to our current trial would be from the 2020 Phase 2 trial for FSGS. eGFR was monitored during the trial but again I'm struggling to find any direct mention of eGFR Slope results. The presentation from Oct 2020 for positive additional data showed a slide (Slide 10) which focused on the relationship between eGFR Slope and uPCR based on a data from another study (Troost JP et al, Aug 2020). And this slide highlighted that "DMX-200 treatment resulted in clinically meaningful improvements in kidney function of FSGS patients" but it's not clear if this is a direct reference to a reduction of eGFR Slope from monitoring data, or if it has been inferred based on the data showing a reduction of uPVC. I don't suppose you could shed some light on this one at all? The main reason I'm asking this is because in a lot of the documentation from Dimerix they always include "a measure of kidney function" in brackets following any mention of eGFR Slope, but they don't typically do this when talking about proteinuria or albuminuria (even though it all flows through to the same goal). Was hoping they might have given away something on this slide without meaning to.
5. The statistical consideration for our Phase 3 trial is based on >80% power to detect >=1.68 mL/min/1.73 m2 per year for eGFR Slope. Is it possible that this would be the threshold for the primary endpoint? And based on this level of powering the study, could a lower result of say 0.9 (similar to Travere) still be statistically significant? I'm struggling to get my head around the sensitivity for powering clinical studies.
6. Finally - given that eGFR was monitored in all previous studies using DMX-200. Even though they haven't always reported this data they would obviously have it in their possession. I'm assuming that Advanz Pharma would have had access to it as well? Is it possible that they have a good grip on the likely effect of DMX-200 on eGFR Slope (both the magnitude and also the effect over time), or is it more likely that this Phase 3 trial is going to be the first real test?

Proteinuria

1. Similar statistical powering question to eGFR Slope - it looks like the >80% power to detect >=1.68 mL/min/1.73 m2 eGFR Slope is likely to equate to approx. 30% reduction in uPVC (if we assume that we will see a similar eGFR Slope result for placebo on Irbesartan in our trial, that Travere saw on their study which was a slope of 5.7). If we were to see only 17% reduction in uPVC (similar to Phase 2a results) rather than 30%, would the powering of our study tend to give more or less statistical significance to this result and would it be likely that it's still in fact a statistically significant result?
2. I just have a feeling that with the improvement to trial design for the eligibility criteria for the starting baseline uPVC, that Dimerix may very well be expecting to see a minimum of 30% reduction of uPVC across all patients on DMX-200 which is likely to be the reason for the statistical powering adopted for the Phase 3 trial. Moving from the 2017 trial to the 2020 trials and then onto our current Phase 3 trial, the eligibility criteria for starting baseline uPVC has been continually increased and gone from 130 to 150 to now 169.5 mg/mmol. Obviously this is due to trial data showing a higher reduction in uPCR in patients with a higher starting value. And I know we can't correlate proteinuria to albuminuria (or PCR to ACR) across different diseases and trials. But it's the same trend with ACR - in the 2020 trial those patients with starting ACR > 57 mg/mmol showed a higher and statistically significant reduction in ACR on DMX-200. Based on my calcs a PCR of 169.5 mg/mmol equates to an ACR of 85.6 mg/mmol (with a 95% CI of 51.0 to 143.7) - link here, which aligns well with this theory. When you isolate all of the past results which focus on subgroups with higher PCR and ACR levels it all tends to suggest reductions of greater than 30% has been achieved. So there's a lot of data that we have available to suggest that the Phase 3 will hopefully see at least a 30% reduction of PCR as well. Would you agree with this line of thinking or am I drawing a long bow here?
3. And lastly, do we think that the Part 1 data analysis in March will be reported to the market so that we can see the magnitude of the PCR reduction if it proves to be clinically and statistically meaningful? Or will we remain blinded to the actual numbers and only hear confirmation that the trial is continuing to Part 2? I think the magnitude of reduction in PCR is going to be really important in giving confidence to achieving the Part 2 endpoint in eGFR Slope. If Irbesartan is showing 30% reduction in PCR and DMX-200 is adding at least 30% on top of that reduction (for a min. of 60% reduction in total) then you would have to think that we're in a really good position to meet our eGFR Slope as well. Especially when Travere were showing promising signs with a total of 50% reduction in their recent FSGS trial.

Apologies for the long post....just a few things that have been rattling around in my head while I do my research. Really looking forward to seeing how things pan out this year and appreciate any feedback you can provide. Cheers...