Ann: Positive Top-Line Results in DKD Phase 2 Clinical Study, page-509

1. The Effect of Treatment with Propagermanium Compared to Placebo on Measures of Estimated Glomerular Filtration Rate [ Time Frame: Twelve weeks ]
   Assessed by measuring estimated glomerular filtration rate.
2. The Number of Adverse Events with the Adjunct use of Propagermanium [ Time Frame: Twelve weeks ]
   Adverse events will be recorded by a patient diary and by site staff during site visits.
3. The Effect of Treatment with Propagermanium on Measures of Proteinuria as measured by ACR [ Time Frame: Eleven 24-hour urine samples at week -2, week -1, week 6, week 11, week 12. ]
   Assessed by measuring albumin/creatinine ratio at each end point.

ABOVE ARE SECONDARY ANALYSIS ENDPOINTS -WHAT DXB ARE LOOKING AT CURRENTLY.

Hi Silsol,

Unfortunately primary statistical endpoints were not met, with a 14% reduction average across the trial, but a 12% reduction in placebo of 12% = 2% average, and this is what RLG has based his analysis on (placebo adjusted numbers) that there was a rise in ACR of >25% in patients with a baseline ACR of between 30mg/mmol -57mg/mmol, which did not happen clinically, confirmed in the investor call, in question time.

RLG also stated 16/40, this is not correct, it was 14/40. But if you are looking at the mean across the trial & work out the range across the trial, I can see how he has come to this conclusion (statistically, not clinically).

We already know primary endpoints have not been met, statistically. So why would you expect a P value, on this @silsol? There is no statistical significance? I’m absolutely not being rude or sarcastic here. Primary Endpoints were not met. End of story.

HOWEVER:

Because 64% (26/40 (57mg/mmol or above) with a P value of 0.03 has shown an average of 18% reduction on top of placebo (so placebo adjusted) and 56% had a reduction in ACR of >25%, This was clinically significant.

I think we will see numbers quite similar across the trial clinically (with secondary analysis) with 2A but it will depend on what drugs patients were on concomitantly, including the SGLT2 class that really has become a SOC (30%-40% reduction on baseline ACR pre-trial, on this trial as SOC on top of ARB ~24%) not just for diabetic glycaemic control, but also CKD/DKD as well, particularly in the USA at present.

The inclusion criteria has not changed from 2A, it was 30mg/mmol. It was just that patients with a higher baseline ACR were recruited on that trial, as you correctly pointed out.

The 2 differences on this current DKD trial were:

1. Patients with a lower baseline ACR on Ph2b.
2. SGLT2 class has been far more widely used & prescribed to patients with DKD & also for glycaemic control in the past few years. Patients were to be on a stable dose on Ibersartan 300mg & SOC for glycaemic control/DKD for a run in period of 3 months or greater for trial inclusion. The SGLT2 class of drugs has only been approved for DKD/CKD recently on top of glycaemic control & more priority applications in to big Pharma after Invokana broke that 20 year drought with new therapies for CKD with an FDA approval in the USA for CKD

https://www.thepharmaletter.com/article/fda-green-light-for-invokana-in-diabetic-kidney-disease

more recently DKD in the EU

https://www.businesswire.com/news/home/20200701005847/en/European-Commission

And more priority reviews in this class of drug (the numbers are similar):

https://www.prnewswire.com/news-releases/sglt2-inhibitors-could-induce-a-seismic-shift-in-treatment-of-diabetic-kidney-disease-in-the-us-according-to-spherix-global-insights-301124724.html


You can add a stable dose of Ibersartan (75mg-300mg to the above in trial difference also (no 3), but I think the inclusion of patients only on 300mg was done for trial design rigour, crossover, double blinded interventional with quadruple masking).

As was mentioned by Nina, Profs Packham & Roger, any additive effect of DMX-200 on top of SOC (ARB+SGLT2) or Ibersartan (ARB alone) is one of the major things they are looking at, in this secondary analysis. With % in reduction in albuminuria already placebo adjusted, you can see that any additive or adjunct benefit or potential Legacy effect (working in synergy with another drug class SGLT2) + ARB, which I don’t believe would have been mentioned IF it were occurring in the first placebo group as well as first treatment arm, would be mentioned. This will all come out in secondary analysis, with a rigorous trial design & a crossover study (as ppposed to treatment vs placebo).

I’m pretty time poor at the moment, had a family emergency (all ok for now) plus work, but keep going with your discussions guys & girls .