I’ve taken up my full entitlement. I wanted to apply for more...

I’ve taken up my full entitlement. I wanted to apply for more but that's the limit of my anniversary present. Still have less than fond memories of around this time in 2020 when A2M and MSB came out of a trading halt.

Thank goodness we were at a winery at the time!

I’ve always said I accept the RISK of investing before FDA approval. I have more in this stock than I could comfortably lose but this is my chance to bet on myself, that my take on what’s going on (the hierarchy) in the world is correct.

I went to the AGM and I’ve been meaning to write up my notes but I’m very slow and have been distracted by other things, so I’ll have to leave it until the New Year. Many thanks to those who went and have generously shared valuable insights.

@Phaedrus it was great to meet you and I agree our long lunch was a hoot - I still chuckle at “The zombie wears Gucci”

I can verify your take on the AGM and the professionalism of the staff. I have a personal take on things that could be considered radical. SI said something very uncharacteristic and I suddenly thought I might know what this is.

My Challenge

@Southoz @DocMcstuffins @Pledge @whytee

The above posters have claimed MSB should have run a randomized trial/study. Whytee calls it a "proper" trial.

I ask these posters if, rather than repeatedly telling us, they could show it was possible by producing a design for a trial they believe investigators would likely agree to run and patients agree to enroll in, whose results could reasonably inform clinical practice for the condition of SR aGvHD.

Please correct if I’m wrong but what I’ve learned about randomization is this:

The purpose of randomization is to remove differences between the two arms. Any difference therefore can only be due to the controlled variable - the therapy.

There should be no potential for bias in terms of grading of severity for organs, recording responses to treatment, choice of treatment and dosing in the control arm.

The two arms should be balanced for age, gender, severity, organ involvement and other prognostic factors likely to affect response to treatment.

I take it that a blinded randomized study is the best way to remove the potential for bias. So, if you trial an IV product against a tablet would you have to give a dummy tablet to the treatment group and an IV therapy to the tablet group? If so, would an ethics committee be OK with this?

(I haven’t had time to look up how to blind in such a case but I found one RCT comparing oral iron with IV which was open label.)

We know that in severe GI aGvHD volume of diarrhea is not an accurate prognostic factor and evidence is that biomarkers (such as a liquid biopsy) are more reliable.

Southoz said in this post 71278789 that five years ago MSB should have done a randomized study, I ask if there were FDA validated biomarkers for upper GI, lower GI, skin and liver at the time?

Also, prior to Ruxolinitib approval, MSB could only have run a randomized trial against standard of care.

I had a go at trying to design one in this post 70277405 but I couldn’t come up with anything that would remove the potential for bias and be ethical and clinically valid (in terms of answering questions physicians would likely want to know).

After Ruxolitinib approval in 2019 MSB could have theoretically run a randomized trial against it.

The Neumann study was published the same year. I think this was likely an influential paper because it’s balanced and clearly and simply written.

All four patients with severe diarrhea died.

If a potential investigator isn’t aware of the Neumann study, they’re likely to know the appalling Reach1 results, where 10 patients had died by 28 and treatment was stopped due to AEs in a high number of patients.

Patients would have to be given proper informed consent in writing.

Ryoncil is a therapy that responds to the inflammatory milieu of the individual. It’s a reasonable hypothesis therefore that it ONLY works in children and young adults.

Surely you’d want to design a trial to see the effect in the subgroup of children aged under 12 who have a stronger innate immune system. This age group could not have been included as Ruxolitinib isn’t approved for them.

I’ll be interested to see how the above posters can overcome these challenges and look forward to reading what they come up with.

I wish this community a very happy festive season!