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http://seekingalpha.com/article/ ... -multiple-red-flags
Cellular Biomedicine Group Exposed: Outside CAR-T Experts Identify Multiple Red Flags
Must Read | Sep. 25, 2015 11:17 AM ET | 3 comments | About: Cellular Biomedicine Group, Inc. (CBMG)
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. (More...)
Summary
•A Chinese reverse merger that has tried to package itself as a valuable “CAR-T” player, Cellular BioMedicine Group (CBMG) owes much of its bloated valuation to misleading spin.
•CBMG has boldly trumpeted "positive" clinical results that actually look pathetic when compared to those reported by legitimate CAR-T players with far more impressive cancer therapies.
•Some independent CAR-T experts recently examined CBMG’s clinical trials and raised serious concerns about everything from the sloppy nature of its studies to the poor response to its treatments.
•One CAR-T expert questioned whether CBMG should even move forward with its plans for large-scale trials at this point, while another came right out and declared CBMG a "risky" investment.
•A recent addition to the Russell 3000, CBMG qualified for inclusion in that index after providing a U.S. address that’s located in a building with no sign of the company.
Author's Update (September 28, 2015): In the original version of this article, the author mistakenly reported that CBMG had also purchased an experimental CART-33 therapy for acute myeloid leukemia tested by its lead investigator on a single leukemia patient who died soon after undergoing that risky cancer treatment. One of the CAR-T experts who reviewed CBMG’s clinical results discussed that CART-33 therapy in his report as well. The author wishes to apologize for any confusion that resulted from the inclusion of that material.
Don't confuse Cellular Biomedicine Group (NASDAQ:CBMG) with the wildly popular CAR-T (chimeric antigen receptor T-cell) players that the company has set out to imitate. A Chinese reverse merger that traded on the penny-stock exchange until last year, CBMG has invested so little in its own CAR-T therapies - and those treatments have performed so poorly in clinical trials conducted with so little scientific discipline - (1) , (2) , (3) , (4) - that the company looks more like some phony Chinese knockoff than a bargain-priced version of the real thing.
Clearly smelling opportunity, CBMG shifted its focus to CAR-T therapy earlier this year after watching legitimate CAR-T players such as newly public Juno Therapeutics (NASDAQ:JUNO) and Kite Pharma (NASDAQ:KITE) suddenly take the stock market by storm. If CBMG really wanted to make a name for itself in the CAR-T field, however, the company probably should have spent a whole lot more than $2 million to pick up some discarded CAR-T technology developed by a virtual industry novice at a Chinese hospital linked to a horrific prisoner organ-harvesting scandal.
Talk about frugal. CBMG must have decided to cut corners on its corporate headquarters, too. Just pay a visit to 530 University Avenue, Suite 17, in Palo Alto, California, the address that CBMG lists for its home office, and try to find any sign of the company. A paid "gopher" has already searched the entire building for CBMG twice in recent months and wound up striking out on both occasions. No office or mailbox bearing the company's name. No building tenant who remembers the elusive company, either.
Big surprise: CBMG did not respond to telephone and email messages seeking answers to questions for this story.
As a Chinese firm that recently qualified for inclusion in the Russell 3000 index with the help of a U.S. address, CBMG better hope that it has established a verifiable presence in the building - or at least the country - that the company claims as its home base. With index-based funds forced to automatically purchase an estimated 830,000 shares of CBMG when the Russell 3000 added the company to its list, the firm's thinly traded stock could suffer a rather nasty hit of those funds suddenly released a flood of shares onto the open market.
Granted, CBMG needs more than a U.S. office (even a fancy one) to prove that it's for real. The company must produce some decent clinical data that's actually worthy of respect.
When a pair of seasoned CAR-T specialists recently examined the clinical trials conducted on CBMG's experimental cancer therapies, however, they seemed decidedly unimpressed, to say the very least. They raised all sorts of concerns about the poor design and weak results of those CAR-T studies: - (1) , (2) , (3) , (4) - with one of them questioning whether the company should even move forward with its plans to start testing its experimental therapies on larger populations of fragile cancer patients.
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"I assume that the low therapeutic efficacy and high rate and severity of side effects are due to the high cell doses and the low performance and fitness of applied cells," explained Dr. Hinrich Abken, an immunology professor at the University of Cologne in Germany with more than two decades of experience in the rapidly evolving CAR-T field.
"From the scientific point of view, I recommend to improve the current protocol of both T-cell manufacturing and patient care in order to obtain success rates in the range of the competitors before starting a Phase II trial. While hard to evaluate without knowing details of the protocol, some steps in the whole process still are likely sub-optimal and may need substantial improvement before entering large-scale trials."
Report Card
No kidding. Simply compare the results of CBMG's most recent CAR-T trial with those reported by genuine leaders in the field. As illustrated in the handy chart below (the first of several that include clinical data on rival treatments supplied by a detailed industry report), CBMG's experimental CART CD-19 treatment for leukemia stands out as the worst performer - by far - in that group of otherwise promising cancer therapies.
table
For its part, CBMG has tried to make excuses for the low success rate of its CAR-T therapies by claiming that the patients who participated in its clinical trials entered those studies with particularly resistant forms of cancer and/or without the benefit provided by preconditioning chemotherapy. The patients who arguably fared the worst in the company's CART19 trial for leukemia actually did receive preconditioning chemotherapy, however, while those who fared the best - including at least one patient who also received a highly effective cancer drug in addition to the experimental CAR-T treatment - required no preconditioning chemotherapy due to the mild state of their disease.
Check out the chart below for details about each patient's original condition, chemotherapy treatments, reported side effects and survival rate following the company's experimental CART therapy.
CBMG CART19 trial: Patient outcomes (from worst to best)
table
* From CBMG's most recent quarterly report: "The treatment program design of this study is very stringent. Our higher-risk patients did not receive conditioning chemotherapy, which is known as a beneficial facilitator of adoptive T cell therapies."
The results of CBMG's remaining CAR-T studies look pretty dismal, too. In two trials, designed to test the company's CART30 and CART20 therapies as treatments for different types of lymphoma, the patients tended to fare measurably - if not significantly - worse than those fortunate enough to participate in larger trials hosted by the competition.
See the charts below for details about the size of those trials and the success rates of the competing CAR-T treatments.
CART Studies on Hodgkin's or Non-Hodgkin's Lymphoma (NHL)
table
* One complete response by a patient who entered the trial with only residual disease and four partial responses (one lasting only three months, another lasting just four months and the remaining two lasting six months each)
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"It's true that CBMG's clinical trial results … are not as impressive compared to other groups in the U.S.," noted Dr. Pranay Khare, a professional consultant who specializes in the manufacturing process used to develop effective CAR-T treatments. "I may be wrong, but it feels like the authors were under pressure or under influence to get clinical trial results …
"Of course, investment with this quality of data would be risky," Khare emphasized. Moreover, "this quality of data would NOT be appreciated in the CART field."
Overblown Hype
CBMG has managed to win glowing reviews from a handful of promotional biotech "analysts" who should spend a little more time on their homework, though.
Just last week, for example, CBMG secured a ringing endorsement from a pair of analysts interviewed by a biotech newsletter that the company happened to sponsor. "It's all about data for John McMamant and Jay Silverman," The Life Sciences Report assured when introducing the duo, who then proceeded to name CBMG as one of their favorite stock picks based upon a rather generous impression of the company's CAR-T portfolio.
Maybe those new CBMG cheerleaders paid a little more attention to the company's positive spin than they realized or would care to admit. Listen to a sample of their rosy analysis, and see if it sounds more influenced by CBMG's clinical data or by the company's bullish sales pitch.
“
"Cellular BioMedicine is putting together a huge portfolio of assets in cancer - and specifically in immuno-oncology - that it will be able to sell," they gushed. "Basically, in less than a calendar year, the company has created an immuno-oncology portfolio that has already begun to generate data on par with anything else being developed, at least in the first generation ...
"The key for this company is data, and it has delivered some," they continued. "We have already seen signs of efficacy with the technology, and we have more data coming this fall. This technology is for real."
Picture CBMG taking a deep bow.
If CBMG basked in the glory of that welcome praise, the company must feel downright spoiled by all of the favorable research coverage that it has received from a former consultant who fell in love with its stock and soon turned into the firm's most loyal cheerleader. Within a few short months of collecting his consulting fees, LifeTech Capital analyst Stephen Dunn started promoting CBMG as a promising Chinese biotech company armed with valuable CAR-T technology worth a potential fortune. Even though CBMG had paid less than $2 million for those CAR-T therapies and should have known that at least one of them had fared poorly in early clinical studies published before those assets actually changed hands - (1) , (2) - Dunn immediately increased the value of the company's CAR-T portfolio all the way from $25 million to $129 million and practically assumed that all of those treatments would perform well enough to advance through the entire clinical trial process.
“
"With four human clinical and two preclinical programs in immuno-onology, CBMG is now the leader in China for this promising cancer technology," Dunn proclaimed at the time.
"We are expecting all four CAR T-cell drug candidates to advance into Phase IIb/III clinical trials treating various forms of leukemia and lymphoma, as well as lung cancer. (Meanwhile), it is important to note that comparable valuations in the CAR T-cell space are significantly higher than our $129 million valuation of CBMG's CAR T-cell program and could represent significant upside to our target price, as more details and timelines emerge."
With CBMG spinning the weak results of three CAR-T studies since then (one of them published months before the company bought its new cancer therapies), Dunn has responded by dutifully following management's lead while steadily boosting the estimated value of the firm's CAR-T portfolio from roughly $130 million to $170 million for no apparent reason.
Last month, however, CBMG ran into an unwelcome obstacle that forced Dunn to slash another lofty projection and should have taught the analyst an important lesson. When CBMG supplemented its cancer portfolio this summer by paying $4.25 million for an experimental vaccine (using its stock to cover a major chunk of that bill), Dunn promptly added a staggering $110 million to his already generous valuation of the young biotech company. That projection soon proved wildly optimistic, however, when CBMG suddenly found itself on the hook for expensive clinical trials of its new vaccine after the original sponsor elected to shift that costly burden to the company instead. With that program thrown into jeopardy, Dunn cut the estimated value of CBMG's new vaccine in half but found a way to offset much of that reduction by quietly assigning even more value to the remaining assets in the firm's cancer portfolio.
CBMG better hope that it can escape punishment for yet another nasty surprise. Within days, CBMG will share the clinical results of an experimental CAR-T therapy for lung cancer and other solid tumors that (absent some kind of fluke or miracle) could soon make the firm's CAR-T portfolio seem like a total failure.
Given the lack of clinical evidence to suggest that CAR-T treatments even work on cancers outside of certain types of leukemia and lymphoma - far less challenging targets that nevertheless responded poorly to the company's own therapies - CBMG cannot easily spin the results of that study without catching the attention of curious industry leaders capable of seeing right through its positive hype. If CBMG feels tempted to take its chances, the company might want to spend of few moments reviewing some of the red flags raised by CAR-T experts who examined its previous trials so that the firm can better calculate its odds of success.
Expert Opinions
Dr. Khare identified a number of serious issues that make the company's CAR-T trials look downright sloppy and the poor quality of its clinical data seem even worse. After scrutinizing the firm's CAR-T studies, he specifically (and, in some cases, repeatedly) emphasized the following:
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"Overall, the investigator tried to achieve too much information from a small trial. The trial has too many variables, including patient diseases, dose infusion, autologous and donor-derived CART19 infusion, etc. There is a lack of proper controls in experimental procedures."
"The information provided in ClinicalTrials.gov and the data provided in the accepted manuscripts is very different … According to ClinicalTrials.gov, the genetic modification of patient-autologous or donor-derived T cells with anti-CD19-CAR anti-CD20-CAR or anti-CD33-CAR was performed using retroviral vector-transduction. But in all the manuscripts, the group is using the lentiviral vector method. I hope the group understands the difference in these two vector systems … For me, the change in viral vector is really a lack of knowledge or literature understanding."
"Most of the CART researchers, including us, define the dose before trials. It could be a definite dose or dose per patient body weight or dose per tumor volume. Surely, it seems that the CBMG group has not presented any rationale for their dose selection. The trial was performed in China, and I am not aware of their IRB rules and regulations, but dose selection suggests their lack of scientific understanding."
· "The change in the normal infusion process by the CBMG group is very disturbing, unless there is a scientific rationale. In the CART field, it takes two or more weeks to prepare a patient's cells, but to infuse them at different times does not make sense. Second dose infusion in some patients is very disturbing and was absolutely not part of their therapeutic regiment."
"The group thinks that CD3 staining is their CART20 cells. It's just a speculation and not a good way to show data … To presume that CD3+ cells are CART is naïve and surely needs to be confirmed with additional reagents or methods."
"Other CART researchers have prepared several reagents to identify and confirm the presence of live CART from cell culture, blood and tissues obtained from patients. cells, either from cell culture or from blood and tissues obtained from patients … The CBMG group has spent very limited time to understand the utility of these reagents and mainly uses the qPCR method, which can be informative, but other data needs to be collected to confirm the findings … This feels like a lack of scientific understanding and ignorance" on the part of the CBMG group.
Dr. Abken found the company's CAR-T studies problematic as well. He identified a number of weaknesses, too, including (among others) the following:
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"The success rate of the CD19 trial (first 9 patients), as reported by the press release (March 25, 2015), is far below the overall rate at other centers. The same applies to the published data on the first 7 patients treated in the CD20 CAR-T trial … The CD30 CAR-T trial has a lower success rate compared to the Baylor College CD30 trial" as well.
"Patients experienced substantial side effects, as far as reported. For instance, CD19 and CD20 CAR-T treatment was associated with high-grade GvHD toxicities with above-average frequencies, including Grade 4 GvHD."
"Of note, side effects like 'cytokine storm' and vascular leakage syndrome are more likely and more severe when high cell doses are applied. The high cell dose may therefore contribute to the high frequency of side effects seen in the CBMG trials. On the other hand, increase in cell dose does not compensate for low fitness of engineered T-cells, which points me to assuming that the fitness of applied cells may not be optimal."
"The CAR-T trials stand isolated in CBMG's overall clinical trial program. The other programs aim at treating cancer-unrelated diseases, like degenerative disease and osteoarthritis, or the programs use other technologies and cells, like human adipose-derived progenitor cells. I cannot see a link between these programs or an added value by combining (them)."
"Dr. Han (the lead investigator in charge of the company's CAR-T trials) is said to be a 'renowned key opinion leader in the cancer immunotherapy field' (press release Feb. 9, 2015) … PubMed records more than 40 publications by Dr. Han; however, only two of them are on adoptive cell therapy with CAR-modified cells … I myself, working in the field of CAR-T cells since the very early beginning - (NYSE:FOR) more than 20 years - do not know Dr. Han and do not remember a major scientific meeting where Dr. Han showed up with his own data or innovative strategies. I do not see Dr. Han as an outstanding expert in the field of CAR-T cell therapy."
AXON,VTVT,CBMG,Shkreli's Folley...no wonder the shine is rubbing off bios lately,frauds,scams and shysters...imo.
It is even more prudent to do your DD,read everything you can get your hands on and make educated choices with your biotech investing dollars.Looking for a quick million usually is a bad reason to invest and a quicker way to lose your shorts,no pun intended. A company with sound science,a track record and a pipeline of different potential products is the way to make solid and continued stock gains. Companies that buy cast off,discredited,and discarded technology usually send up red flags...imo.
Well done Mellissa.
27 Sep, 11:19 AMReply
Update from author Melissa Davis: CBMG has responded to this article with such a weak rebuttal that the company may have actually managed to undermine its credibility even more. For starters, CBMG never even attempted to dispute the fact that its U.S. "headquarters" – supposedly located in a building with no sign of the company – looks totally bogus. Instead, CBMG spent most its time trying to spin the weak results of its clinical trials yet again, while making a rather dubious claim in an effort to exaggerate a minor (and understandable) mistake.
Specifically, CBMG stated the following: "At no time has CBMG acquired CART-33, which is a classification of which the company is unaware." In the press release that CBMG issued when the firm decided to shift its focus to CAR-T technology earlier this year, the company announced that it had purchased "Chinese PLA General Hospital's ('PLAGH,' Beijing, also known as '301 Hospital') Chimeric Antigen Receptor T-cell (CAR-T) therapy and introduced Dr. Wei Dong Han – the lead investigator in charge of presiding over its clinical trials -- as a "renowned key opinion leader" who had conducted "several preliminary clinical studies" focused on various CAR-T therapies. At the time, Dr. Han had published the results of only two CAR-T studies, one of them a case study on a leukemia patient who received an experimental CART-33 therapy and died soon after undergoing that risky cancer treatment. If CBMG conducted any due diligence at all before it purchased the other CAR-T technology developed by Dr. Han, the company must have at least known about his CART-33 therapy whether the firm decided to purchase the rights to that particular treatment or not.
CBMG also raised another concern that seems a bit unfair. The company warned against lumping CAR-T treatments for Hodgkin's and non-Hodgkin's lymphoma together, even though its lead investigator has specifically described his trial as a study that's designed to include patients suffering from both of those diseases.
Finally, in a letter sent by its law firm, CBMG complained that it never got a chance to answer questions for this story due in part to a delay caused by "the 12-hour time difference to China." How telling. CBMG must have forgotten that its executives supposedly run the company from some elusive "corporate headquarters" that's located right here in the United States of America instead!
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