“When "we need greater censorship" and "for the greater good" start being bandied about, it's time to sit up and take notice. Your notion that a RCT in aGVHD is "for the greater good" is a myth. I'm currently working on a piece to show this in great detail; however, if that's what is necessary to end the atrocity of Ruxolitinib remaining on market and being given to patients with grade C/D GI, then maybe that will be done”
Well said. Funny that…i am working on a piece doing exactly the same, but I have too many competing tasks at the moment to finish it .
Fundamental to the piece will be the recognition that TH1 and TH17 subsets are critical pathways for acute sr GVHD is relation to suppression of the bodies inflammatory responses ….however, whilst we are dealing with a T cell mediated disease , once the epithelial layer is damaged in the GI crypt , in my opinion, Ruxolitinib has not shown any durable mortality benefit on severe grade patients .. but shows excellent initial responses in those presenting with less severe skin sr aGVHD or the 50% of largely lower risk GI grade 2 who have extremely low mortality risk ). The challenge now is for Mesoblast to enrol in a new Phase 3 trial a risk stratified group drawn from the approximately 14% subset of the total patient population who are nonresponders to current treatment options. Silviu is confident that they know exactly how to identify this patient group and so long as the FDA agree we should be able to prove it (famous last words) !
The durability or response and overall survival data of Ruxolitinib in severe grade GI acute sr GVHD personally gives me great cause for concern. If the fact that 45% of patients are unresponsive to treatment (principally those with high risk GI ..who invariably die ) does not concern the FDA, it should do. It makes a mockery of the clinical trials system but i believe this is largely attributable to the surrogate endpoints used as well as the best available therapies applied as a control in the Reach 2 trials. @JB1975 is right to defend the FDA process in relation to ensuring key quality attributes in cell characterisation and cell potency matrix assays attributes which are essential quality control to ensure batch consistency, so that each patient is assured they are receiving the same potent product as given to patients in GVHD001 . WE ALL GET THAT. What I find extraordinary about Klinker et al is that for all their cogent research they seek to rely on the IDO pathway (which IS key to the initial response to immunosuppression of key inflammatory cytokines. I take the latter for granted but I am more concerned about the paracrine factors which actually repair the epithelial layer and saves the patients life !In the words of Richard Gere … Big mistake …HUGE. The world is just beginning to work it all out ..hence the link above to the NIH publications which uses the polite term…”novel mechanisms “ in our understanding of the disease (sic) . Mesoblast is ahead of the curve because they had the clinical data as did the MAGIC consortium who treat over 600+ new patients each year from the network of over 100 hospitals in the US and worldwide who are affiliated to them .
The irony is that I believe “novel” the part of Mesoblast’s therapy which actually makes the critical intervention to prevent death is not part of the quoted potency assay but I have given you a clue hidden in the publications above. Let’s see how long it takes @JB1975 to work out the real factors which make Ryoncil so effective in gut repair. Meanwhile I guess we will just have to listen to those who ignore there own expert committee and the use of validated proteomic biomarkers which are far more accurate in terms of risk stratification than deeply flawed clinical scoring systems used to validate FDA clinical trials ! The benefit on a randomised controlled study to eliminate confounding factors is unlikely to show statistical significance in a small size sample , if the patient population is not risk weighted to severe grade disease….but we are dealing with an extremely small orphan disease population. For many of the of the patients identified as low risk , the I use of steroids may actually be having a negative mortality benefit because of immune suppression being compromised. Well i guess to be fair the FDA now appear to have conceded efficacy in the latest CRL and are now focussed on a potency assay. This is itself is a challenge when an identical product from the same donor with identical potency would in theory still obtain varied response invivo…because each patient will present with different immune responses. I will shortly provide some up to date slides presented by Prof Levine which specifically addresses many of the issues above. OP
Meanwhile the FDA are hard at work (only joking )
Please do not rely on the facts , opinions and bad humour presented in the above post when making an investment decision .
(20min delay)
