from PropThink via $VCEL Twitter
Vericel Corp (VCEL) cratered on Monday with details from a phase 2b study of its ixmyelocel-T cell therapy for heart failure, presented at the American College of Cardiology’s (ACC) 65th Annual Scientific Session.
Three weeks back, Vericel announced via press release that the phase 2b trial has been complete, with positive data. The stock climbed 50% initially, and doubled again in the following two weeks. At the time, Vericel offered no data from the study, except to note that the trial met its primary endpoint: treatment with ixmyelocel-T resulted in a reduction in the total number of deaths, cardiovascular hospitalizations or unplanned outpatient and emergency department visits in the 12 months following treatment, compared to placebo.
With details at ACC this Monday, investors aren’t so optimistic about the product’s commercial potential, sending the stock lower by 30%. First, baseline imbalances favoring placebo patients almost across the board could explain much, if not the entirety of, the out-performance of ixmyelocel-T-treated patients.
There has been considerable debate regarding appropriate clinical end points for phase II trials. Given that it is not practical to use “hard” end-points such as mortality or mortality plus hospital admissions, most phase II studies have employed a variety of different surrogates such as functional capacity, quality of life, heart failure symptomatology (measured as the New York Heart Association class), left ventricular remodeling and/or ejection fraction, biomarkers, or various different clinical composites. A second potential issue in the early phases of development of a novel therapy is there are often limited clinical data available to help guide selection of relevant end points. Often times this results in “rounding up the usual suspects (vide supra),” rather than trying to identifying target specific end points. Alternatively, when it is not possible to clearly identify a relevant clinical end point, phase II trial designs will often employ a panoply of surrogate end points, in order maximize the chance of finding a positive signal in phase II. As a result of these problems, many phase II study designs for novel compounds often do not test relevant hypotheses with respect to how a new agent might positively impact patients with heart failure, and/or are unnecessarily expensive.
Several potential explanations have been advanced to explain the why the surrogate end points used in phase II trials do not predict therapeutic effects on mortality and/or morbidity in phase III heart failure trials. The explanation that has received the widest acceptance, particularly by regulatory agencies, is that the surrogate does not reliably predict the overall effect on the clinical outcome . Rethinking Phase II Clinical Trial Design in Heart Failure
Hit the hard end-points but no support.
Gilead Sciences' (GILD +2%) acquisition of Nimbus Therapeutics for as much as $1.2B appears to have investors in a lather over other developers of therapies to treat nonalcoholic steatohepatitis (NASH), especially Galmed Pharmaceuticals (GLMD +38.3%).
With respect to the secondary endpoints of the trial, the components of the primary endpoint were also analyzed using the Win ratio in a hierarchical manner to incorporate both the incidence and timing of the endpoint components. The Win ratio result of 1.56 showed that more often ixmyelocel-T was the “winner” in that the time to death, left ventricular assist device placement, heart transplantation or time to cardiovascular hospitalization was shorter for placebo-treated patients, but this difference did not reach statistical significance. The time to first event was longer in the ixmyelocel-T group compared to placebo, but was not statistically significant. There were no significant structural changes in left ventricle cavity size or left ventricular ejection fraction as measured by echocardiogram in either the ixmyelocel-T or placebo groups. Both treatment groups had an improvement in the NYHA class and six minute walk test, with no statistical difference between the groups at month 12 using last observation carried forward.
n biology, explant culture is a technique used for the isolation of cells from a piece or pieces of tissue. Tissue harvested in this manner is called an explant. It can be a portion of the shoot, leaves, or some cells from a plant, or can be any part of the tissue from an animal, or from umblical cord tissue.
High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism.
Materials and methods
Twenty unmedicated males with prediabetes received 100 mg b.i.d. RVX-208 and placebo for 29–33 days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry.
RVX-208 treatment for 4 weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p ≤ 0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P = 0.01) and small-sized HDL particles decreased by 10% (P = 0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30 min later with a more sustained elevation (treatment effect, P = 0.003). There was a reduction and delay in total (P = 0.001) and oral (P = 0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P = 0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P = 0.016), with no effect on glucose oxidation or total glucose disposal.
RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.
hofno2003 • Jun 10, 2016 4:39 AM
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This is a very impressive case - because it demonstrated first time that CytoSorb could be used to manage hepatic encephalopathy which is a very serious consequence of terminal liver injury and where are no other effective means available to improve this inflammatory CNS condition!
Sentiment: Strong Buy
Hindawi Publishing Corporation
Stem Cells International
Volume 2013, Article ID 916837, 10 pages
Received 20 December 2012; Accepted 19 April 2013
Academic Editor: Pranela Rameshwar
Copyright © 2013 Lucio Barile et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cardiospheres (CSs) are self-assembling multicellular clusters from the cellular outgrowth from cardiac explants cultured in
nonadhesive substrates. They contain a core of primitive, proliferating cells, and an outer layer of mesenchymal/stromal cells and
differentiating cells that express cardiomyocyte proteins and connexin 43. Because CSs contain both primitive cells and committed
progenitors for the three major cell types present in the heart, that is, cardiomyocytes, endothelial cells, and smooth muscle cells,
and because they are derived from percutaneous endomyocardial biopsies, they represent an attractive cell source for cardiac
regeneration. In preclinical studies, CS-derived cells (CDCs) delivered to infarcted hearts resulted in improved cardiac function.
CDCs have been tested safely in an initial phase-1 clinical trial in patients after myocardial infarction. Whether or not CDCs are
superior to purified populations, for example, c-kit+ cardiac stem cells, or to gene therapy approaches for cardiac regeneration
remains to be evaluated.