Hi all,
Just placing my thoughts in relation to achieving the secondary endpoint of the Healey Platform trial in relation to Slow Vital Capacity (SVC).
Successful Secondary endpoints will strengthen the FDA approval. They don't override the primary endpoints , but statistically they are of high importance to collectively achieve an outcome.
Healey Platform regimen states that six FVC function tests will be included in the first 36 weeks.
Being a heterogeneous ALS trial it is assumed that in relation to SVC. The ALS population is comprised of slow respiratory progressors are 14%, rapid respiratory progressors are 39% and stable low respiratory progressors are 47%.
https://alsnewstoday.com/news/lung-function-measures-help-predict-als-patients-prognosis-study-suggests/
How do we by using Pro Act going to isolate said groups in the trajectory table ?
https://pmc.ncbi.nlm.nih.gov/articles/PMC4239834/
Possibly, by calibration of Pro Act including incorporating random effects.
Are we testing the patients SVC prone or supine. In ALS I presume supine places pressure on the diaphragm to skew a result. Think body mass index . But to create discussion a higher BMI tends to increase longevity in ALS. Gets complex!
Sitting gives a higher SVC than lying flat or lying face down by approximately 8%.
I appreciate we have to use SVC as a secondary trial regimen but it worries me. Are we going to use a personalised prognostic model?
Another issue that concerns me about SVC values is the coming of the flu season in the USA peaking December to February.
How do we align the SVC values into a common number considering all the biases that could perpetuate.
My thoughts .
1. Will there be a framework for stratification strategy for the drug mechanism. So what I am saying in laypeople terms does Monepantel Nuz-001 affects can the results be hidden in mixed groups. If Monepantel NUZ-001 increases SVC as stated, if given to a slow progressors it may show of little benefit, thus the need for patient stratification.
2. Riluzole , no patient stratification and no quality of life data in their trial. We know what happened to them.
3. Most won't like this, is there a situation to clarify results to use a Healey Platform OLE for another 6 months. Maybe this won't affect top line results but will add science to establish if NUZ-001 does what we think.
4. Patients need to be stratified for stages of disease progression to also provide washed results. Remember it's a multi staged disease and Monepantel NUZ-001 may be exemplary in some disease progressions and maybe not in others. We need to micro analyse results. Can a sub population be more likely to respond ?
5. Calibration of Pro Act to include random events ( I mentioned the flu season) also predicting genetic, environmental, transient lung infections or chronic lung infections. Patients with ischemic heart disease that affect their respiratory volumes.
So a natural history study on each patient.
7. No one program can be developed like another to attain robustness of integral data.
This of course is in reference to the primary objectives as well, but I am concentrating on the secondary outcomes.
There is, I assume more, but that's it for my pay grade. Healey Platform is coming soon. No time to delay.
Kpax
(20min delay)