I question the narrative that significant or overwhelming efficacy in CHF is ruled out because the trial wasn't stopped early.
My understanding is that the more DMC reviews passed the more likely a positive result. Speaking from memory( as I couldn't find this webcast on the website) around the time of analysis in 270 patients if I recall right, didn't SI mention efficacy (no specifics obviously) and for that reason discussions with pharma in the cardiovascular area had been "enhanced"? Also at the AGM, I was pleasantly surprised to hear that 1/3 of the way through the trial was meeting primary end points. I've long thought results would be positive by very modest but I'm beginning to rethink this view..
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EntrestoSI briefly mentioned Entresto at the AGM. Entresto is not exactly a new drug but a mixture of traditional valsartan with the new sacubitril. Sacubitril inhibits neprilysin action. The trial was stopped early due to efficacy. Inhibiting something can get quick results. Maybe the strain is taken off a failing heart but my concern would be additional strain on another organ (One of the side effects listed is renal impairment.) Paradigm-HF trial was designed with a run-in phase, which would weed out patients who were intolerant to the drug. Cardiologist Luis Correia says on Twitter that 'a pseudo efficacy was demonstrated by a trial which design promoted asymmetry of treatment between the groups.'
Below is the paper by Correia et al which discusses Entresto:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728601/Consistent with what Correia et al say back in 2016, are the online patient reviews of Entresto; these are the worst I've ever seen, full of anger and contempt and with specific details about side effects.. ,
LVAD TrialWe've had discussion on why the LVAD trial may or may not be the best indicator of success or failure in p3 CHF but there's something else I've been wondering about:
Yau et al (2019) say that the injection of stem cells at the time of surgery during a period of heightened inflammation may also adversely affect cell survival and paracrine signalling; however, a pilot trial showed a signal of benefit.
Writing in
Circulation, Proglajen et al (2019) say, "Although simultaneousLVAD and stem cell therapy appears more straight forward and feasible, this treatment strategy may significantly reduce the beneficial effects of the combinedtreatment approach as the local proinflammatory cytokine environment at the time of LVAD implantation andblind transepicardial stem cell injections adversely affectstem cell retention and survival."
Even so, results in ischemic patients were significant and 2 patients had devices removed at at day 94 and 141 after randomisation. I was interested in the discussion surrounding this and particularly long term follow up because it could further support the mechanism that patients go on to improve over a longer period of time (This mechanism is supported by Athersys' trial in ischemic stroke patients which showed no difference to placebo after 90 days but did after one year)
All things considered, I thought the odds were stacked against our cells in the above trial but they still showed significant benefit. I therefore don't accept that the so-called underwhelming results of the LVAD trial do not bode well for the p3 CHF trial.
Our cells showed good effect in GI bleeding, SI explained in a webcast that vessels were 'leaky and friable' I'm particularly interested in this and the subsequent discussion on the forum re endothelial dysfunction. Evidence is pointing that improving endothelial function could be the key to stopping progression.
Endothelial DysfunctionMarti et al (2012) say, "The endothelium is a mono layer of cells covering the inner surface of blood vessels. The healthy endothelium is a dynamic organ that regulates vascular tone by balancing production of vasodilators and vasoconstrictors in response to a variety of stimuli...Endothelium also provides antiproliferative and anti-inflammatory actions.
"Rajendran et al (2013) say,
"The endothelium is directly involved in peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, tumor growth, metastasis, venous thrombosis, and severe viral infectious diseases. Dysfunction of the vascular endothelium is thus a hallmark of human diseases."Please correct if this is wrong, but it seems endothelial dysfunction is also relevant to my experience with red skin syndrome in my immediate family. According to google, "RSS is a condition of vascular spasm rebound from the vasodilation effect of topical steroids. Topical steroids inhibit nitric oxide and deplete endothelial mast cells" It can take a very long time to recover from RSS, years in fact. There's a clear and observable connection between gut and skin; mainstream medicine is aware of the strong link, for example, between rosacea (a vascular disorder) and gastric disorders such as celiac disease, IBS and IBD.(The growing awareness in mainstream medicine that RSS is not rare is imo one further strike against steroids in GvHD.)
As far back as 2004, writing in the European Heart Journal, Fischer et al's findings in patients with CHF were 'consistent with the notion that endothelium-derived nitric oxide may play a protective role in heart failure.' There is a lot of literature on nitric oxide and cardiovascular disease.
Premer et al (2015) found that in patients with ischemic (n=6) and non ischemic (n = 16) HF, allogeneic injections of MSCs (but not autologous) resulted in an improvement in endothelial function. Thus imo the LVAD trial may be misleading and we could potentially see good results in non ischemic patients too in our p3 CHF. .
ConclusionAround the time of the interim analysis in 270 patients, a paper appeared in Nature that raised concerns about pluripotent stem cells potentially causing tumours. I read it and felt it was making a mountain out of a mole hill; we don't hear much about the collaboration with Cartherics but imo it delivered an important message that our cells can be used to fight cancer and most importantly, that MSB understands the mechanism behind the science.
The cells are not drugs and an entirely new therapy; SI said years ago that they start a healing cascade, that patients go on to improve over time; the concerns about potential malignancies; the longer a trial goes on the more valuable the data For these 4 reasons, I don't think the trial would have been stopped early and I don't think significant efficacy can therefore be ruled out
P3 results could be modest, lacklustre or really good. If we take the risk buying in before results we have to make our own minds up based on the clues available. No one should feel bad about influencing others; it's hard not to get excited about such revolutionary science. I think everyone can and should look into things deeply for themselves, things more important than the stock market.
GLTAH ALL IMO
(20min delay)