Hi Torpy, a transcript from Bells Healthcare conference.John...

Hi Torpy, a transcript from Bells Healthcare conference.

John Hester asked Paul a question regarding the 2mg/kg dosing during the recent Bell Potter Healthcare conference. Here is a transcript.

John Hester said “Just coming back to one or two key points there. The 2mg/kg is the lowest effective dose. The lower doses in the 008 trial (Hester meant to say 002 Stage One) were proven ultimately to be not satisfactory. One of the negotiations you have with the FDA upcoming in 2024 is getting that 2mg/kg dose recognised as the lowest dose to proceed with. Now tell us a little bit more about that and some of the additional work that you have done to prove the safety of that dose”.

Paul’s response: “Sure. From the outset Paradigm has always used 2 mg/kg twice a week. So we have done that in the first phase two study we did which was in Para 005. And we also replicated it in Para 008. All of the Special Access and the FDA EAP patients were treated with the same dose.During discussions with the FDA the FDA noticed in one of our preclinical studies there was a vacuole which appeared in the adrenal gland of a rat. And the FDA noted that the human equivalent dose was 2mg/kg twice per week. That’s how we were dosing the rats.

And so the agency then said well we note that there other publications that have shown that the drug can be effective when administered once per week such as the Kumagai and Ghosh studies which both used once a week dosing. And we said well in our experience we found that the 2mg/kg to be the most effective dose. So they asked us to undertake some additional preclinical studies to show that the effect of the vacuole in the adrenal gland was not translatable into humans and it certainly did not provide adrenal insufficiency for the rats.

So we undertook an additional three preclinical studies showing conclusively that at 2mg/kg and much higher that the issue of the vacuoles was not replicated and we found that the rats did not suffer any adrenal insufficiency. So we were able to go and show that there was no effect of the drug at that dose in the adrenal gland of the rats.Also what we did during that first 600 subjects in Stage One of the trial if there were any subjects that had low cortisol levels those people were sent off to a laboratory for an adrenal challenge test which was is an ACTH hormone test. And again we found that there were no examples of adrenal insufficiencies.

So we have human data, preclinical data and we are going back to the agency and saying we’ve answered your question, the question was “Is this the lowest effective dose?” and we can now answer that and say the lowest effective dose in our hands is 2mg/kg and we believe that the drug has now been demonstrated to be safe at a preclinical level and clinical level”.