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%).
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.
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.
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.
Earlier today we learned that the Third Estimate for Q4 real GDP came in at 1.4 percent (rounded from 1.39 percent), above the 1.0 percent of the Second Estimate.
Here is a chart of real GDP per capita growth since 1960. For this analysis we've chained in today's dollar for the inflation adjustment. The per-capita calculation is based on quarterly aggregates of mid-month population estimates by the Bureau of Economic Analysis, which date from 1959 (hence our 1960 starting date for this chart, even though quarterly GDP has is available since 1947). The population data is available in the FRED series POPTHM. The logarithmic vertical axis ensures that the highlighted contractions have the same relative scale.
The chart includes an exponential regression through the data using the Excel GROWTH function to give us a sense of the historical trend. The regression illustrates the fact that the trend since the Great Recession has a visibly lower slope than long-term trend. In fact, the current GDP per-capita is 10.0% below the pre-recession trend.
The real per-capita series gives us a better understanding of the depth and duration of GDP contractions. As we can see, since our 1960 starting point, the recession that began in December 2007 is associated with a deeper trough than previous contractions, which perhaps justifies its nickname as the Great Recession.
The standard measure of GDP in the US is expressed as the compounded annual rate of change from one quarter to the next. The current real GDP is 1.4 percent. But with a per-capita adjustment, the data series is currently at 0.54 percent. The 10-year moving average illustrates that US economic growth has slowed dramatically since the last recession.
Last week, SunEdison again delayed the filing of its annual report. It cited, among other things, “identification by management of material weaknesses in its internal controls over financial reporting.” While it blamed its computer systems, the initial delay was due to claims that arose in early March by one former and one current employee that its accounts weren’t accurate.
A lack of audited accounts could in-and-of-itself be a death blow for a company as indebted as SunEdison since lenders eventually can declare it in default. On the bright side, bankruptcy could release its yieldcos from their shackles; they are legally severable entities now worth four times as much combined as their controlling shareholder. Both are down by nearly 80% from their peaks last year.
SunEdison has voting control, but only a minority economic interest in the yieldcos. Their growth prospects are now far worse without a creditworthy parent. Yet their existing stable of projects are long term, tax-efficient and annuity-like.
With these yieldcos down sharply on SunEdison’s latest woes, opportunistic investors shouldn’t wait until the skies clear.
By Spencer Jakab
Updated March 22, 2016 3:38 p.m. ET WSJ
Analysts at Northland Securities began coverage on shares of Evoke Pharma Inc (NASDAQ:EVOK) in a report released on Wednesday, The Fly reports. The brokerage set an “outperform” rating on the specialty pharmaceutical company’s stock.
EVOK has been the topic of a number of other research reports. Zacks Investment Research raised Evoke Pharma from a “hold” rating to a “strong-buy” rating and set a $3.00 price target on the stock in a research report on Thursday, January 14th. Brean Capital restated a “buy” rating on shares of Evoke Pharma in a research note on Wednesday, March 2nd. Ascendiant Capital Markets upped their price objective on Evoke Pharma from $11.00 to $12.00 and gave the stock a “buy” rating in a research note on Monday. Rodman & Renshaw restated a “buy” rating and set a $27.00 price objective on shares of Evoke Pharma in a research note on Monday, March 7th. Finally, Noble Financial restated a “buy” rating and set a $22.00 price objective on shares of Evoke Pharma in a research note on Wednesday, March 2nd. One analyst has rated the stock with a hold rating and eight have issued a buy rating to the stock. The company has an average rating of “Buy” and a consensus target price of $17.72.
You Are What Your Parents Ate!
For its studies, the team of the Institute of Experimental Genetics (IEG) used mice that had become obese and had developed type 2 diabetes due to a high-fat diet. Their offspring were obtained solely through in vitro fertilization (IVF) from isolated oocytes and sperm, so that changes in the offspring could only be passed on via these cells. The offspring were carried and born by healthy surrogate mothers. This enabled the researchers to rule out additional factors such as the behavior of the parents and influences of the mother during pregnancy and lactation.
"The results showed that both oocytes and sperm passed on epigenetic information, which particularly in the female offspring led to severe obesity," said Prof. Johannes Beckers, who directed the study. In the male offspring, by contrast, the blood glucose level was more affected than in the female siblings. The data also show that - like in humans - the maternal contribution to the change in metabolism in the offspring is greater than the paternal contribution.
Possible explanation for rapid spread of diabetes worldwide
"This kind of epigenetic inheritance of a metabolic disorder due to an unhealthy diet could be another major cause for the dramatic global increase in the prevalence of diabetes since the 1960s," said Prof. Martin Hrab? de Angelis, director of the IEG and initiator of the study. The increase in diabetic patients observed throughout the world can hardly be explained by mutations in the genes themselves (DNA) because the increase has been too fast. Since epigenetic inheritance - as opposed to genetic inheritance - is in principle reversible, new possibilities to influence the development of obesity and diabetes arise from these observations, according to the scientists.
In their theories on heredity and evolution, both Jean-Baptiste Lamarck and Charles Darwin explicitly stated that characteristics and traits that parents acquire during their lifetime through interaction with the environment could be passed on to their offspring. It was not until the neo-Darwinist "Synthetic Theory of Evolution", which combines the theories of natural selection by Darwin and of genetics by Gregor Mendel, that the inheritance of acquired traits was rejected. "From the perspective of basic research, this study is so important because it proves for the first time that an acquired metabolic disorder can be passed on epigenetically to the offspring via oocytes and sperm- similar to the ideas of Lamarck and Darwin," said Professor Johannes Beckers.
March 10, 2016 8:00 AM
The trial met its primary endpoint of demonstrating a reduction in the total number of deaths, cardiovascular hospitalizations or unplanned outpatient and emergency department visits to treat acute decompensated heart failure during the 12 months following treatment with ixmyelocel-T compared to placebo.
“The results of the ixCELL-DCM study, which we believe is the largest randomized cell therapy trial to treat congestive heart failure completed to date, demonstrated a statistically significant and clinically meaningful reduction in cardiac events in patients who received treatment with ixmyelocel-T compared to placebo,” said Dr. David Recker, Vericel’s chief medical officer.
The trial was designed to provide approximately 80% power to show a 46% difference in cardiac events for ischemic DCM patients treated with ixmyelocel-T compared to placebo. A total of 114 patients were treated in the ixCELL-DCM clinical trial at 28 sites in the United States.
Ixmyelocel-T is a patient-specific, expanded multicellular therapy manufactured from the patient's own bone marrow using Vericel’s proprietary, highly automated, fully closed cell-processing system. This process selectively expands the population of mesenchymal stromal cells and alternatively activated macrophages, which are responsible for production of anti-inflammatory and pro-angiogenic factors known to be important for repair of damaged tissue. Ixmyelocel-T has been designated as an orphan drug by the U.S Food and Drug Administration for use in the treatment of DCM.
Yup! Market order most likely.
After Hours Volume: After Hours High: After Hours Low:
1,000 $ 7
(17:36:52 PM) $ 7
Price objective basis & risk
Aduro Biotech, Inc. (ADRO)
Our $40 PO is based on a probability-adjusted NPV analysis using a weighted average
cost of capital (WACC) of 10% and a terminal growth rate of 3%. We value the CRS-207
program at $20/share, ADU-S100 and other CDN candidates at $9/share (20%
probability of reaching market), milestone payments at $2/share, and cash at $9/share.
For CRS-207 in pancreatic cancer, we assume a 35% probability of reaching market in
pancreatic cancer and 30% in mesothelioma, based on their respective stages in clinical
development. For the CDN program, we assume a more conservative 20% likelihood of
reaching market given that it is still in preclinical development.
Risks: (1) failure to demonstrate efficacy and safety of CRS-207/GVAX in pancreatic
cancer, and CRS-207 in mesothelioma, (2) failure to advance key pipeline candidates,
such as CDN candidate ADU-S100, (3) competition from companies with competing
platforms (e.g. Advaxis) or drugs in development for the same indications or cancer
Analyst Ying Huang.
My problem here is that all the probabilities are less than 50%.
ECLIPSE top-line results expected in May/June
The Phase 2b ECLIPSE study comparing CRS-207/GVAX to chemotherapy in roughly 300
pancreatic cancer patients is expected to report top-line data in May/June. Event rate to
date is as projected and ADRO anticipates to release top-line results in May/June. The
trial is 80% powered to detect a HR=0.67 and one-sided α=0.15. Recall the Phase 2a
study demonstrated a significant survival benefit for CRS-207/GVAX compared with
GVAX alone (6.1 vs 3.9 months). In 2H16, we expect interim data from Phase 2b
STELLAR study with CRS-207/GVAX/Opdivo and the design of the pivotal trial
comparing CRS-207/GVAX to SOC chemotherapy.
ADU-S100 ready to move into clinic
The initiation of a Phase 1 trial with ADU-S100, a CDN targeting STING, in cutaneously
accessible advanced/metastatic solid tumors or lymphomas is imminent, with the IND
accepted and first clinical trial sites already open. Initial data are expected in 2017.
Given that ADU-S100 stimulates T cells, combination studies with checkpoint inhibitors
are, in our view, sensible and could be initiated as early as this year. In collaboration with
Novartis, ADRO is working on CDN formulation for systemic delivery as well as a CDNbased
antibody drug conjugates. ADRO is also developing STING-antagonist for
infectious diseases outside of partnership with Novartis.
Don’t forget antibody pipeline and mesothelioma program
With the BioNovion acquisition in late 2015, ADRO has a strong preclinical monoclonal
antibody (Ab) pipeline. The first program targeting BCMA is slated to enter the clinic in
mid-2017. Anti-CTLA-4 Ab is up next, which could have an improved safety profile given
lower dosing requirements. ADRO is collaborating with Genmab on the development of
bispecific-Ab. We also expect top-line results from the Phase 1b mesothelioma study in
1H16. Based on positive preliminary data and discussions with regulatory authorities,
ADRO plans to advance the front-line CRS-207/chemotherapy.
Jeff Gundlach held his latest webcast on markets and the economy, called "Connect the Dots," on Tuesday.
The big takeaways were:
The Federal Reserve has no business raising rates right now. Markets aren't pricing in a hike this month in, and no one has forgotten the volatility that ensued after the first hike in December.
The rally in risk assets is near its end. Stocks have 2% of upside but 20% of downside. And there's still time to wait for commodities to cheapen more before buying.
There isn't a strong case for an imminent US recession.
Negative interest rates are bad for the world. They are having the opposite effect on currencies like the Japanese yen, which has rallied instead. They are also hurting European banks.
As of December 31, 2015, we had cash, cash equivalents, and investments of $120.0 million, consisting of cash and cash equivalents, as well as short and long-term investment grade available-for-sale securities. In January 2016, we raised an additional $61.8 million from the sale of 2,875,000 shares of common stock.
As of February 18, 2016, the number of outstanding shares of the registrant’s common stock, par value $0.001 per share, was 21,417,219.