General Discussion, page-43

Hi All,

Sorry just read these posts. Interestingly, the recruitment period was 2014 - March 2016 & they are only just publishing this research now? (July 2020). Very Interesting!! Recommendations were to look at dosing of PG for DKD.

Ph2A involved dose escalation & TID dosing. Following this DXB completed a Pharmacokinetic study prior to Phase 2b (2a in FSGS) for an extended release tablet of PG to be administered BD (twice daily) & this was found to have greater efficacy, I’m not a pharmacist, but it doesn’t look like 30mg daily immediate release would be able to cover a 24 hour period with half-life of PG.

https://www.asx.com.au/asxpdf/20180108/pdf/43qny6ptbf950r.pdf

Just to put things into perspective for current trials, yes at @afreak, the successful FSGS trial was dosed at 120mg BD with a stable dose of Ibersartan 300mg daily.

For DKD, it’s also a stable dose of Ibersartan 300mg daily (prior in Ph2A allcomer trial, it was a stable dose of Ibersartan 75mg-300mg) and BD extended release dosing (Ph2A PG dosing was TID 80mg I believe). I am not sure regarding the dose for DKD trial, but it is possible that it may be 120mg BD.

As Dr Brad said, it’s a very small dose used in this 12 month trial commenced 6 years ago in Japan (30mg daily) & PG has been used in Japan to treat Hepatitis previously. What I find fascinating is why publish now? Is it because DXB have now possibly validated some of this earlier data & really when you look at trial limitations & recommendations, this is only complimentary to the work DXB are doing now.

This previous trial in Japan was randomised for DKD to 1:2 usual therapy to PG plus concomitant usual therapy. 29 patients enrolled: 10 on usual therapy, 19 on PG, with 1 patient withdrawing from the trial at 3 month follow up due to difficulty getting to the trial site (fair enough).

Baseline characteristics are noted in Table 1 & what placebo vs PG patients were on (as some have been looking at already). 10/29 patients were on an ARB. The plasma concentrations of PG were measured at 1 and twelve months & were lower than the level of detection in 3/19 patients, although during interviews on visits stated they were adhering to doses over the 12 month trial.

I think that dosing, timing & concomitant therapy have been addressed since this early pilot study from Japan and from what we have seen already with FSGS results & now awaiting DKD results with DMX-200, may have triggered publication on PG in DKD?. Consider the patents of Dimerix also.

Looking back, we do have a patent application in Japan which is more limited than other jurisdictions (EU/USA), however if you look to the Pharmacokinetics study above ANN (2018) patents are granted for extended release PG (dosed BD).

https://www.asx.com.au/asxpdf/20170131/pdf/43fmylqcj674dr.pdf

I think that what people need to remember is that there can be many failed earlier trials related to dosing, half-life etc in a drug that has very convincing evidence that it will be efficacious & helpful. It also doesn’t mean that the same drug (even a blockbuster drug) will have the same dose or regime in different diseases for the same drug.

GLTAH