PCSK9 Drugs

Sanofi and Regeneron report "POSITIVE RESULTS" with Alirocumab (anti-PCSK9) from their first phase III clinical trial for LDL Cholesterol Reduction. LDL is the bad cholesterol, HDL is the good. These terms are unfortunate since the body has deemed both forms as necessary. Over time the body may build up LDL which is an indication that you are not regulating your diet and exercise properly. LDL cholesterol can build up on the walls of your arteries and increase your risk of heart disease. However we have to wonder how to interpret the accepted medical stance on cholesterol. 

In Good Calories, Bad Calories, Gary Taubes gives a history of cholesterol research. Not everyone agrees with the current information on cholesterol levels and the role cholesterol plays. The way in which some minds work is that if something is bad, it should be eliminated. That works fine if you are talking about crime in your neighborhood. But LDL is there for a reason. It is coded into our DNA. The question then is the range in which a healthy individual maintains LDL levels. If BigPharma wants to make drugs to help sick people mimic healthy people with regards to LDL levels, what is their goal? 

The mean low-density lipoprotein cholesterol (LDL-C, or bad cholesterol) reduction from baseline to week 24, the primary efficacy endpoint of the study, was significantly greater in patients randomized to ezetimibe (47.2% vs. 15.6, p < 0.0001)

Back to the concept of an accepted range. If their is a level too high there is a level too low. What does the 47.2% reduction in LDL from alirocumab vs 15.6% reduction from ezitimibe (Zetia) mean? One goal of Regenerons research is to determine  the lowest effective dose of anti-PCSK9 antibody. The reasons for this are best summed up by these findings.

The percentage of patients who reported treatment emergent adverse events was 78.4% in the ezetimibe group and 69.2 in the alirocumab group. The most common class of adverse events was infections (39.2% with ezetimibe vs 42.3% with alirocumab), which included nasopharyngitis, influenza, and upper respiratory tract infection. 

Like cholesterol, there is the good and the bad. We see that anti-PCSK9 products can lower LDL-C. They did not say if the people felt better or got healthier. They did not say if they could more easily and safely adjust a persons LDL levels into the range found in healthier people. The just lowered the bad. In the process they increased a range of infections that can be deadly to older people.

Check out this article on the dangers of PCSK9 targeted drugs. "New Cholesterol Drug PCSK9 Likely Is to Prematurely Kill You". If lowering you LDL levels is the good news, this has got to be the bad. Dr. Mercola brings up a few topics the Regeneron press release does not. There is a lower limit not to be crossed. Lowering your LDL levels to below 50 is dangerous. Your body needs cholesterol to produce hormones, cell membranes, vitamin D, and bile acids that help you digest fat. The most effective method of regulating your cholesterol profile is through diet and exercise. That's the good news. What about this added downside of dropping dead from anti-PCSK9?

Again we get the lower limit discussion that Regeneron has omitted from their world view of cholesterol. According to Dr. Mercolas' article, low HDL can lead to poor memory and a decline in memory for middle aged people. You may also experience violent behavior and aggression,  depression, suicide, cancer, Parkinsons disease, and heart disease. Dr. Mercola states that the odds are greater than 100 to 1, that if you are taking a statin to lower your cholesterol, you really don't need it. Statins are what the PCSK9 drugs are going to compete against.

Statin drugs, which one in four adults over 45 are using to protect their heart health, can paradoxically have significantly detrimental effects on your heart health 

Our understanding (our science) of cholesterol has been touched by the Cargo Cults. We have to look into these things that don't work and ask why. Not only do we muddy the waters with bad and biased pharmaceutical research, we create dangerous products for the most vulnerable. I think it is fairly clear that cholesterol research needs to be revisited, new guidelines need to be established and diet and exercise needs to be advertised. PCSK9 should be studied very carefully to make sure it does not reduce your own ability to fight heart disease and worse, to simply kill you. In my Utopia, all future studies would include a diet and exercise arm. If that were the case I am sure they would halt the study and never again allow a statin or anti-PCSK9 enter the body of a person capable of eating healthier and increasing their level of exercise.

Serepta Clarification

I saw a few comments on an investor website concerning my post on RiAN BioSciences and the Disappearing Bees.  It was accurately pointed out that I erroneously labeled Serepta as an RNAi company. I need to clear up my mistake. They are not an RNAi company. Their drug is a non-traditional RNA antisense product. They point out, "Unlike most other RNA-based approaches, such as small interfering RNA (siRNA), Serepta's technology can directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate or up-regulate targeted genes or proteins."

I simply lump all RNA drug companies together because I think targeting RNA is a mistake. I stand by that claim. Serepta, like the others, has some interesting chemistry in its product. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic structures modeled after the natural nucleic acid framework of RNA. They replace the ribose ring with morpholine which is linked through phosphorodiamidate rather than anionic phosphodiester bonds. You can get some of this stuff from a company called GeneTools LLC and start your own RNA company or just do some research with it.

Gene Tools, LLC produces and markets Morpholino oligos for antisense applications and ancillary products for basic research. We are also engaged in research relating to delivery of Morpholino oligos into cells and use of Morpholino oligos as probes and in diagnostic systems.

Morpholino oligos and the subunits used in their assembly were invented and developed at Sarepta Therapeutics (formerly AVI BioPharma Inc. and earlier ANTIVIRALS Inc.), the pioneer antisense company founded by James Summerton in 1980. Gene Tools manufactures and markets research quantities of Morpholino oligos. In Japan, Funakoshi Co. is the distributor of Morpholino oligos and related products. 

Lest people think I am against everything, I want to say that I love this kind of science. It is not unlike the work of one of my heros Gertrude Elion. Here she talks about her work with nucleic acid analogs:

The work became fascinating almost from the very beginning. We were exploring new frontiers, since very little was known about nucleic acid biosynthesis or the enzymes involved with it. I had been assigned quite early to work on the purines and, with the exception of a few deviations into the pteridines and into some other condensed pyrimidine systems, the remainder of my work concentrated almost completely on the purines. Each series of studies was like a mystery story in that we were constantly trying to deduce what the microbiological results meant, with little biochemical information to help us. 

There came a time where Gertrude had to go off the beaten path and deduce what the results meant. She went from chemistry to biology to "what do these results mean?" It is at this same juncture in the research process where GeneTools LLC and  Serepta parted ways. GeneTools LLC represents the science of PMOs versus RNA.  Serepta represents the business of drug approval. Somewhere between the work of GeneTools LLC and Serepta we enter the Cargo Cults.

Why didn't James Summerton make that journey? The powers of his PMOs as a drug, over RNAi molecules, are touted on the Serepta website:

• The ability to target specific gene sequences without non-specific interactions
• Safe at higher doses
• Able to UP and down regulate gene expression 
• Easier to deliver to specific cells
• Resistant to enzymatic degradation

The questions that AVI and Serepta had to answer was "what to do with it?" and "what do these results mean?" Serepta made some pretty astounding claims. Dr. Summertons PMOs have a superiority (as a drug) over the Nobel Prize winning science of RNA interference. 

A PMO is physically a PMO for sure. The mechanism of action is different. It may very well have the superiority over RNAi molecules that Serepta claims. But RNA deep inside a cell is the target. This is where the science gets soft. A Cargo Cult does not concern itself with the complexity of a cell. Gene expression is not within the purview of Serepta management. That is in the job description of a scientist, not a businessman. What management needs from the lab is positive results that can be used to sell their promise of cargo to investors. And they weren't getting it from their people in Oregon and Washington.

Serepta began in Oregon then moved to Washington then to Massachusetts in search of the magical Pixy dust that will turn PMOs into a drug. The inventor of PMOs did not have that Pixy dust nor did anyone in Bothell WA. What was CEO Chris Garabedian looking for when he sacked his Oregon and Washington staff and moved to Cambridge MA? You won't read about it on their website. You will read about PMOs and the work of the common scientists. What about that Pixy dust? What was the knowledge that could only be found in Cambridge MA that puts the 33 year science project on the final leg of it's journey? After 33 years we can now look to the skies and expect the cargo planes to come because some people on the east coast knew what to do with James Summertons PMOs. 

Investors are starting to have their doubts. Sereptas lead candidate is Eteplirsen:

Eteplirsen is a treatment for Duchenne muscular dystrophy, or DMD, patients, a rare genetic muscle-wasting disease caused by the absence of dystrophin, a protein that is necessary for muscle function. The disease affects one in 3,500 boys worldwide and is one of the most common fatal genetic disorders. Currently, there is no approved treatment for DMD.

Eteplirsen works by skipping exon 51, helping resolve a genetic mutation and allowing for the creation of dystrophin. This, in turn, corrects the body's inability to build muscle. Eteplirsen showed promising results in phase 2b studies, which, following a meeting with the FDA in July, led the company to report that the FDA was willing to consider those results as part of an early approval process. As a result, the company indicated its plans to file an application with the FDA in early 2014.

A good deal has changed since the July conversation with the FDA Several things have changed since that announcement. Most important, an announcement came that GlaxoSmithKline's (NYSE: GSK  ) and Prosensa's (NASDAQ: RNA  ) competing exon-skipping drug drisapersen came up short in phase 3 trials. In that trial, drisapersen failed to significantly improve muscle function despite showing considerable promise in earlier trials.

That late-stage failure kicked off a flurry of interest in eteplirsen. Investor hopes for early approval may have jumped the gun, however. Given that Glaxo's drug and eteplirsen similarly produce dystrophin by exon skipping, some are wondering if the FDA will back away from its earlier willingness to solely consider phase 2b data.

What interests the Cargo Cult Scientist the most is the disease. How does it work and are we ready to fix it? Apparently the approach Prosensa took was a little off. What were the details and why then does Serepta have a better shot with the same exon 51 skipping approach? Investors and biotech CEOs are speculators. Scientists find ways of injecting certainty into their predictions of future outcomes. Will morpholinos succeed where RNA failed? We will be watching.

Passion, Dispassion and Pink Ribbons

Raising money has become the priority, regardless of the consequences. 

It's almost as though our disease is being used for people to profit. And that's not okay. 

For people to finally rise up and object, they have to be aware of the lies they are being fed.

One more thing about this Atossa Genetics Cargo Cult. The three quotes above came from the Pink Ribbons Inc. documentary. There is a lot going on here and it's more than just pink ribbons and breast cancer. It represents all of the pharmaceutical industry. Dr. Quay has made himself a millionaire by running biotech/pharma highly questionable companies. He is not a breast cancer specialist. Previously he tried to sell us a nasal spray to fight obesity. He knows that disease is profit and he seeks the most profitable. We as human beings need to guard against profiteers who wish to fill the market with ineffective, poorly researched, poor quality, potentially dangerous products. Open the Atossa Genetics website. Do you see a color similar to the pink used by Susan Koman? Coincidence? The pink ribbon profiteers paved the way for the latest Quay invention. The product is cheap plastic suction cups made in China and a genetic test that the FDA says does not have sufficient quality control. The "National Reference Library for Breast Health" is not federal government institution. It is not a branch of the NIH or the NSF. It is something within the Atossa company. A company that uses the momentum of the money making pink ribbon machine to put more money into the pockets of a few Cargo Cult leaders.

The best way to conduct research is the opposite of what we see with the pink ribbon crowd. The best way to conduct research is to do so dispassionately. If we in the life sciences were to create a manifesto for living the life of a scientist it would have to include the idea of dispassionate research. We can be passionate about our science and our work. We just can't let our passion for anything get in the way of seeing the world for what it really is.

Dispassionate: Devoid of or unaffected by passion, emotion, or bias.

The way in which biotech and pharmaceutical companies get support for their work is by catering to the passion others have in finding cures for disease. At this point of my argument I might be tempted to quote Jonas Salk, "Can you patent the sun". It is a quote often used as the moral impetus to forgo patents and profits from vital medical innovations. To quote from this post from Roy Zwahlen in BiotechNow:

As pointed out by Robert Cook-Deegan at Duke University, “When Jonas Salk asked rhetorically “Would you patent the sun?” during his famous television interview with Edward R. Murrow, he did not mention that the lawyers from the National Foundation for Infantile Paralysis had looked into patenting the Salk Vaccine and concluded that it could not be patented because of prior art – that it would not be considered a patentable invention by standards of the day. Salk implied that the decision was a moral one, but Jane Smith, in her history of the Salk Vaccine, Patenting the Sun, notes that whether or not Salk himself believed what he said to Murrow, the idea of patenting the vaccine had been directly analyzed and the decision was made not to apply for a patent mainly because it would not result in one. We will never know whether the National Foundation on Infantile Paralysis or the University of Pittsburgh would have patented the vaccine if they could, but the simple moral interpretation often applied to this case is simply wrong.”

I used to live close to a Ronald McDonald House and the Seattle Childrens Hospital. Every time I went to the store I parked by the playground next to the Ronald McDonald House apartments. Little children, bald from chemotherapy, would be playing with their families. They just want to have fun and live life but soon you'd see them heading up the street to the hospital for God knows what. Given the opportunity to work in research you could use such an image to passionately pursue a cure. Once you start to look at the data however, you must put your passion aside. You must follow the precepts of the scientific method. It does not allow you to take shortcuts to save that one child whom you've just watched walking to the hospital. Likewise, your desire for fame and fortune should not affect the way you design experiments or interpret the data. It should not effect how you communicate your work.

With that in mind think about the brief history of Atossa Genetics. There is the off-pink color of their website. There is the the fact that 20 days prior to the recall we had this sponsorship of The Third Annual Power of Pink luncheon, fashion show and silent auction. There is also the issues raised in the FDA warning letter. In a dispassionate manner, I would you value Atossas charity towards the pink ribbon money raising movement and more than the quality of the product they intend to sell to women with breast cancer. Would you see their charity as part of their marketing plan? 

That is my passion, seeing the world as it really is. I do not see a negative side to pointing out a negative. A Pink Ribbon Profiteer is a bad thing and pointing that out is good. Poor quality science is a taking all of the money and power out of science. The passion people have towards ending disease leads them to donate money to organizations like Susan G. Koman. It leads them to cheer for the financial success of Dr. Steven Quay. However, we must be careful when dealing with our emotions. Others will use them against us. With science, we have discovered the way around all of this. With Cargo Cult Science the others have discovered a way around science. You can give money to charitable organizations, wear a colorful T-shirt, walk a 5K for the cure and hope something positive happens. You can also watch what they do with the money. Watch out for the Atossas because they want some of that money. 

Atossa Revisited

Atossa Genetics received a warning letter from the FDA back in February in 2013 regarding its breast cancer product. What they had was a suction cup device that would remove an aspirate from the nipple of a breast that would be sent off for breast cancer bio-marker tests. Last Friday, Oct. 4, Atossa announced a voluntary recall of their product. 

I talked about this company back in June of this year. Knowing some of the leadership was my first clue that this was a Cargo Cult Company. The next clue came when Atossa received a Form 483 from the FDA. Later they received a warning letter in response to the CEOs response to the Form 483. The latest action at Atossa Genetics does not contain the snarkiness from previous communications. Something is seriously wrong at Atossa. Let's take a look at what the employees think about working at Atossa, as posted on Glassdoor:

Poor management systems, written procedure is given but always changing that made people confused and frustrated. Anonymous current employee #1 

High salaries to compensate for working with high maintenance management. Poor business leadership and no reliable company plan leads to sporadic projects and mis-handled accounts. Anonymous current employee #2 

Gained good work experience and learned how to work with very difficult personalities. People quit and get fired left and right, there is no company culture and relationships between employees are discouraged because of management insecurity. People are only hired into management positions because they are friends or family of the CEO. VERY poor management structure, product is a lie (does not do what it claims to, cannot detect cancer) and FDA constantly writes letters to company about non-compliance. Anonymous current employee #3

Management is not getting a big thumbs up here. One thing I can add is that the CSO of the company is the wife of the CEO. She was a low level researcher at Nastech when she married Quay the CEO of Nastech and now the CEO of Atossa. This is not the way to hire a CSO. Had she missed out on the Nastech job, which almost happened, she may have gone the way of so many ex-Nastechians who haven't worked in biotech since Nastechs demise several years ago.

Atossa is now being investigated for possible violations of federal securities laws by Block & Leviton LLP and Finkelstein Thompson LLP. Just knowing about the management and the FDA troubles should have been enough to convince an investor to pass on this one. What other tricks could Quay and company have had up their sleeves? It is always a difficult path to try and lead others when you are unsure of what you are doing. According to the disgruntled current anonymous employees, management at Atossa is a problem. The FDA has come down hard on the company. In what other ways could Atossa directors have violated federal securities laws or breached their fiduciary duties to their shareholders?  If these lawyers come to the same conclusions that the FDA did back in early 2013, will that be enough to drive a stake through the heart of Atossa?

Going back to Quays previous Cargo Cult debacle, you can see that he has a talent for getting people excited about a project. Check out this unbridled optimism from Jim Cramers Mad Money. "When it coms to biotech, Cramer has generally stuck with three names: Celgene, Genzyme and Gilead. But he thinks Nastech has more ways to win than any of the others, and he likes it here along with the others." That was April of 2007. Then came October of 2007. Nastech failed to earn a $5M milestone payment from big pharma partner Procter and Gamble. Dr. Quay assured Cramer that everything was okay, not to worry. One month later Procter and Gamble bailed out, Nastech stock lost 40% of its value in a day and Cramer had to face facts. He was wrong. 

This is a blog about the Cargo Cults of Biotechnology and the Pharmaceutical business. In this world we have characters who thrive and make lots of money running fake scientific organizations. The people they fool are investors and more than a few tribesmen. Those who invest a chunk of time from their own careers take a hit as well. Cargo Cults are bad for your career unless you know how to win, like Dr. Quay. He isn't failing at what he does. He makes lots of money. Your money. If you want to make a profit by investing in a biotechnology/pharmaceutical company it must be remembered that this is a highly random business that attracts more than a few charlatans. The CEOs, the VCs, the Xconomists, the Bruce Booths, and many others are doing well in this world. How do they do it? Who keeps funding these organizations and their high paid leaders?

Kurt Shilling tried to run a high tech company. He was a baseball player, not a businessman to be put in charge of a multi-million dollar company. He used his own money and now he's broke. Like Shilling, biotech leaders are trained in something other than business and management. They spend years learning one thing then switch to become businessmen. The difference between Shilling and the biotech leaders however is that the latter knows better than to use their own money. Dr. Quay has been at the helm of several companies that lost far more than Shillings company. He keeps coming back. Biotech leaders like Quay pay themselves with other peoples money and hope to get out before the day of reckoning. When they fail you will find them standing right there during the reckoning, denying any culpability. Atossa will be submitting new premarket application by the end of the month, covering the  collection, preparation and processing of breast fluid specimens. Was last Friday the day of reckoning for Atossa? The saga continues but it is more than just Atossa. It is a saga of a leader who creates jobs and builds excitement in the biotechnology business. Once again this leader has directed our eyes to the sky but no cargo came. Just the FDA and the lawyers showed up, wanting to shut the airport down, just like the others before. 

Peer Review Quality Assurance

Peer review does not employ the scientific method. Rather it is a system of endowing a handful of individuals with the authority to validate other scientists research without actually reproducing their claims. The system allows for the publishing of roughly 90% false information. It also creates the need for many to embellish in order to impress the journals. The journals and the peers are looking for the next big thing which is also not exactly what science is. More important to science is the truth. 90% false information is what happens when you start thinking too big. It happens when you start embellishing and over-interpreting your results. A peer review, publish-or-perish world is a recipe for disaster.

The last post was about an incomplete quality control evaluation of the scientific publication business. John Bohannon, science writer and PhD in biology, created a fake paper that should have been rejected. Instead the paper received the thumbs up in 157 of 304 open access journals. The next step of this experiment would be to create a fake paper to submit to paywall-protected, subscription-required scientific journals. Sentimentality or sympathy for the subjects hurt feelings should not prevent us from finding out the truth. The question we have started to work on is the quality control/assurance of published scientific research. The system is in need of an upgrade.

We have a quality control problem. The Amgen Study and the work of Dr. Ionnidis pointed out long before the John Bohannon sting operation that all journals have a quality problem. The Bohannon experiment was meant to enhance the image of the more prestigious journals but the lack of a comparison of the open access journals to Science/Cell/Nature left us to merely assume that Science/Cell/Nature are better. We can't make a judgement on a journals reputation however. It is the system that comes into question. Granted, Science/Cell/Nature will have better peer reviews, they are still merely peer reviews of a few anonymous peers. Since the more prestigious journals are sensitive, how could we study them without tricking them into showing us how bad they are too?

Check-list Manifesto! How would this work? Imagine creating a whole new system where one must register their research and the people conducting the work. This is sort of what happens when a clinical trial is begun or when a manufacturing plant runs a batch of drug production. A detailed process is developed over the course of considerable time, prior to beginning the actual work. The checklists here are detailed in quality management plans. The checklists are used to assure quality and to cover managements arses in dealing with regulatory agencies. We can do this too! The first box to check is to verify the players. As pointed out in the Bohannon experiment, the peers reviewing his paper did not even catch the fact that the authors listed and their institutions were fictitious. Checklist it!

Immediately we can see the difficulty in this undertaking. But since when has good science backed down from a challenge? This is the time that we must bend over backwards to make sure we are getting it right. Register your design of experiment. Register who is doing the work. Even if you are just going to verify the existence, quality or quantity of a protein via western blot, register that a western blot is going to be ran. In the QA box you must list how many times you ran the western blot and whether or not each one produces the same result.

Many people, especially the kind who become "peers" do not know the ways in which a western blot can be quality controlled. Manipulation of such images has been the cause of many a retraction. Using modern imaging technology however, you can have a time stamp and an original exposure setting that cannot be manipulated. That is quality. How do you control for that quality? Ask, in your checklist, how many western blots were run. Who ran the western. Do the western blots provide the same information from run to run, technician to technician, lab to lab... Using the density of a protein band and a known standard, what is the margin of error quantitatively? There are many such quality measurement that can be planned and incorporated into a checklist. At the end of such a quality control standardization, the checklist itself can be tested for its ability to maintain quality. Simply compare the new system to the peer review system.

There would be an outcry to going out and trying to fool the editors and peers working for Science, Nature or Cell. That is not what I am advocating here. Simply quantitate a protein in the western blot study I have outlined. Create the checklist, have several different labs run the westerns and generate a report, as outlined by the quality management plan, and be confident that your method is a reproducible and useful tool. Next, create a narrative where an elaborative RNAi experiment is to altar the quantity of the same protein tested in the western blot experiment. Don't fool the peer however. Just present them with a blinded experiment. They may receive real or faked western blot information. Let them use their peer review skills to pick out the real from the faked data.

There is a story out today about a two college professors who brought FDA advisory panels together with pharmaceutical representatives to "discuss" issues surrounding drug approval. This is similar to what we are talking about here today. Who gets a seat at the table? In this case big pharma was paying up to $35K to sit in on meetings where the FDA advisory panels fine tune their quality management plan. Why would big pharma pony up that amount of money to have a seat at the table? What would give these two college professors the audacity to even suggest the fee? These meetings still take place behind closed doors. The pharmaceutical companies just want a few more people to see and hear what is taking place. They are not paying for open access for all. Just a few more influencers whom they employ.

We, here at the CCS, believe that true open access and transparency is where science becomes useful. Patents, careerism, awards, financial gain all negatively effect the path of enlightenment. Peer review and pay-to-play secret FDA meetings are examples of poor quality management. We can do better.

John Bohannon and Science Are Afraid of Peer Review!

Derek Lowe has another interesting piece on a fun little experiment. It is glaring example of how bias gets in the way of everything. "Who's Afraid of Peer Review?" The author, Science, Derek Lowe and most commenters failed to acknowledge the similarity between the logic used in the fake paper and the logic of this experiment. First off, here is the experiment. Writer John Bohannon wrote a scientific manuscript akin to the Sokal Hoax. The author sent this manuscript to 304 publishers throughout the world. There were different names of authorship and fictitious institutions where they worked. The paper itself is full of easily spotted errors.

The papers describe a simple test of whether cancer cells grow more slowly in a test tube when treated with increasing concentrations of a molecule. In a second experiment, the cells were also treated with increasing doses of radiation to simulate cancer radiotherapy. The data are the same across papers, and so are the conclusions: The molecule is a powerful inhibitor of cancer cell growth, and it increases the sensitivity of cancer cells to radiotherapy.
There are numerous red flags in the papers, with the most obvious in the first data plot. The graph's caption claims that it shows a "dose-dependent" effect on cell growth—the paper's linchpin result—but the data clearly show the opposite. The molecule is tested across a staggering five orders of magnitude of concentrations, all the way down to picomolar levels. And yet, the effect on the cells is modest and identical at every concentration.
One glance at the paper's Materials & Methods section reveals the obvious explanation for this outlandish result. The molecule was dissolved in a buffer containing an unusually large amount of ethanol. The control group of cells should have been treated with the same buffer, but they were not. Thus, the molecule's observed "effect" on cell growth is nothing more than the well-known cytotoxic effect of alcohol.

That is a control error that I have seen purposely used many times in my biotech career. Don't get me started. I think the experimental design for this hoax is exactly what I have been talking about for years. It's not unlike developing a card trick. You first must understand your audience. Then you fool them. What Bohannon has done here is to design an oversimplified version of the tricks many biopharma people conduct daily. The more advanced a Cargo Cult becomes the more sophisticated this sort of in vitro card trick becomes.

What did Derek Lowe and most of his commenter miss? They too were being fooled. One commenter, Virgil, pointed out:

As is being Twittered and blogged elsewhere, there are some pretty HUGE problems with this, which are being missed by the mainstream scientific media in its reporting....
1) It's a news piece by a journalist, NOT a peer reviewed scientific paper.
2) There was no "control" group (i.e., non open access, non predatory journals). I would bet this would get into some higher up journals if only he'd tried.
3) There's no analysis whatsover - did the acceptance correlate with impact factor for example? What was the average review time? How many reviewers (just one, just editorial review, or more).
4) This is not about open access, that just happens to be in the title.
5) This borders on human subjects/outcomes research, but the author is not at a university, does not have IRB approval, did not get any kind of informed consent from the persons involved. As such, it's easy to see why this would be inadmissible as a research paper.
If you or I had done this and tried to get it published in Science, we would be crucified, but apparently if you're a journalist then the standards don't apply. So yeah, maybe if the headline was "hoity toity old media giant, feeling the pressure from open access, tried to pull one over on their new business rivals", then I'd be more inclined to believe it.

This is the most interesting part of the hoax. It was published in the journal Science under the title, "Who's Afraid of Peer Review?". The implication is that a superior peer reviewed journal, is to be feared by anyone trying to publish bad science. Open access does not offer any real resistance to bad science. Yet as another commenter points out:

I agree with Virgil. Note that this study has been published in Science WITHOUT a control experiment. The latter should have been done by submitting the bogus manuscript to the same number of non-OA journals. What is this telling us about the scientific competence of editors of high-impact journals?
I feel like submitting the same article signed by the most famous scientist in that field. Any bet on what percentage of respectable journals would accept it with minor corrections?

The control in the cell growth experiment lacked the same concentration of EtOH. In "Who's Afraid of Peer Review?" there is no control group at all. It appears that the editors of Science and John Bohannon were afraid to submit this paper, with a proper adjustment of author and institution, to a peer reviewed journal. The cargo cult connection here is not that the manuscript is Cargo Cult. True, it was dressed up like a real science manuscript and received a stamp of approval by most of the editors of the open access journals. The Cargo Cult connection is the the title of the article. "Who's Afraid of Peer Review?" Science and John Bohannon are!

The best analogy I can see is the Wesson Oil example in CCS:

The easiest way to explain this idea is to contrast it, for example, with advertising. Last night I heard that Wesson oil doesn't soak through food. Well, that's true. It's not dishonest; but the thing I'm talking about is not just a matter of not being dishonest; it's a matter of scientific integrity, which is another level. The fact that should be added to that advertising statement is that no oils soak through food, if operated at a certain temperature. If operated at another temperature, they all will--including Wesson oil. So it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with.

Let's rewrite that with "Who's Afraid of Peer Review?"

The easiest way to explain this idea is to contrast it, for example, with advertising. Last night I heard that Open Access Journals publish bad science . Well, that's true. It's not dishonest; but the thing I'm talking about is not just a matter of not being dishonest; it's a matter of scientific integrity, which is another level. The fact that should be added to that advertising statement is that All Journals Publish Bad Science, if it is submitted by certain scientists. If bad science is submitted by certain scientists (and caters to the popular beliefs of the peers), it all might be accepted--including Peer Review Journals. So it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with. 

The difference between Science and the open access journals put to the test here was not examined in this article. To be fair, it was just an article and not a peer reviewed scientific paper. Yet it was approved and published in the journal Science. No one at Science, nor those in on the hoax bothered to address the obvious missing control, that of testing superior peer reviewed journals.

"it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with"

I loved this experiment nonetheless. The point I make here today is that the experiment is only half over. The next step is to set out, as John Bohannon did, to purposely fool the subscription journals. Scientists are doing it everyday. Long ago Alan Sokal laid out the criteria for how this is done. Think like Bohanno or Sokal. Think like Diederek Stapel or Silvia Bulfone-Paus. The more we study ways to fool ourselves and the journals, the further we depart from Cargo Cult Science.

Merck Job Loss

The slaughter continues. At the same time small biotech companies are experiencing a blitzkrieg of IPOs, Merck is slashing another 8,500 jobs and ending R&D projects the management sees as fruitless. Merck will see savings of $2.5B per year from this move.

8,500 human beings will get their pink slip, put their cubicle decorations in a box and make that sad walk to the car. This on top of the already announced 7,500 job losses previously announced by Merck.

Man this blog is depressing! Sorry.

It brings to mind the many times I lost a biopharma job and what it meant to me and my career. Each job loss lowered my value. It doesn't matter that none of the companies I worked for are still in business except for the last. I established a history of 2 to 3 year stints at places no one has ever heard of. The people I worked with however were no different from one company to the next. We had good and bad, as is the case in any company. The bad ones that I've worked with were really bad. The good ones tended to be more adaptable to new situations, more open and honest and less antagonistic. There was a confidence that came from being good at what they do.

I do  this little thought experiment where I match up the people I've worked with. I have list, as everyone does, where I rank people who have worked in similar areas. For example, Pierre is the best protein purification specialist I have worked with and Hana is the worst. What would happen if those two had to work together at a company like Merck? Pierre had a PhD so he would be the boss over Hana in any biopharma company. Hana was absolutely clueless and like to show up for 5 hours a day. In this environment I assume that Hana would be let go and Pierre would establish an irreplaceable group of downstream process specialists. When Merck sets out to lop off 20% of the work force, Pierre and his people get to stay. But then, how do we know that Pierres superiors aren't more like Hana?

A real life experiment like this took place at my last job. We, a small biotech company, had an antibody drug but no manufacturing expertise. No one working at this small biotech company had ever seen the inside of a manufacturing plant where antibody drugs are made. We hired a CMO to take our master cell line and magically provide us with large quantities of our drug. For some reason, the small biotech had two upstream process development groups however. Neither group could establish a coherent, scalable, reproducible, method for growing our cells. One of the many problems was that the leader of group 1, Katie, would not share information with the leader of group 2. To remedy this situation we hired John, an upstream process development expert, from our CMO to lead a unified upstream process development team. He showed up and  began meeting his new team. Katie met one on one with John and went through three years worth of her work. I could see them through the glass wall of Johns office. Through the glass I could see Johns mood changing from glad, to sad, to mad in just a few hours of first meeting Katie. Within three days John had had enough. She had not produced one bit of upstream process knowledge that John could use. This was his new job and he had nothing to go on. John tried to fire Katie. Katie however was a favorite among the leadership. In a month John quit and Katie stayed.

Imagine now 16,000 people leaving Merck. How many Johns and Katies were there at Merck? How many Pierres and how many Hanas? It is not an option to assume that the CEO of Merck developed a scientific method to eliminate just the Katies and Hanas from his work force, sparing the Pierres. From my experience, not even a small biotech of roughly 40 people can sort out the wheat from the chaff. That is the problems with a Cargo Cult, when the planes don't come, whose fault is it?

It's our fault. We are not standardized, certified, highly qualified professionals. We are a random ensemble of college graduates inventing our jobs as we go along. How do you cure cancer when your boss gives you an antibody and tells you to get busy? There is no manual telling you what to do? Just a boss telling you what the data is suppose to support. Could we get the 16K former Merck employees together to write a manual on drug development? Could they write a book similar to the one that ex-Pfizer employees would write?

16,000 more biopharma experts are going back on the market. Who wants them? How does the next company determine the value of such individuals knowing that Merck turned them down? They will have a greater value than myself or my friend who just started a part time job at Home Depot after 20 years in biopharm. We come from places like Amgen, Gilead and a large assortment of 2 and 3 year jobs at places no one has ever heard of. We have worked with all kinds. Ex-Pfizer, ex-AstraZeneca... There is nothing special among us nor this new graduating class of 16,000 ex-Merck employees. They are all now just like us, just not as long term separated from the Cargo Cults.

So as to not end on a super depressing note, I will put it this way. This new group of 16,000 people are getting on a raft that will take them further down the river. It may take you to a better or a worse place. There are no guarantees. But it is the Katies and Hanas who most fear the unknown. They will stay right where they are for as long as they can. Get on the raft and go somewhere else. If I am correct in assuming that this is a Cargo Cult world, Merck will lose Katie/Hana/John/Pierre in equal numbers. It's all random. Mercks ineptitude will neither grow nor shrink. They'll just have less people to pay. Merck will thus have more dark days ahead. Get on that raft and go somewhere else.

Dude Where's My Clinical Trial?

When does the media report on an advance in disease treatment coming from science, biotech or big pharma? It seems to be when science, biotech or big pharma tells them to do so. What I want to do here is show you a brief history of reporting on a new drug in development. The target is IL-6. See here for a little anti-IL-6 information and here for IL-6 and Crohn's disease. 

The pill we will be following comes from BMS and is known as BMS-945429. 

This is a monoclonal antibody against IL-6 and is in clinical trials for cancer, rheumatoid arthritis and Crohn's Disease. The trial for Crohn's Disease has been terminated.

First, let's look at the reports of the initiation of the trial (NCT01545050).
Xconomy
BioMedicineClinical Trials GPS  still recruiting???
PR Newswire
Puget Sound Business Journal
The search results come in two forms. 1) Alder (the biotech who sold the rights to the antibody to BMS) gets $3.5M milestone payment... and 2) BMS initiates clinical trial (ID# NCT01545050). The first kind of result is a narrative that implies success on the part of Alder. The second kind of result is just the facts on the trial. The question to be answered is why was the trial terminated? 

A quick search however, yields no results that explain what happened with this trial. The narrative style of reporting is completely suspended. Only on the factual search results can one find out that the trial has been terminated. Why do I care to connect the dots between the facts and the reporting of the trial?

As mentioned in the biotech cheerleading organization Xconomy, "...the product has more potential uses than that, and now Alder is pulling in some more cash as Bristol-Myers is advancing the drug as a treatment for Crohn’s disease." Can the loss of this trial be attributed to a caveat on the claim of "more potential uses"? 

If it is worth reporting on the potential of a drug, why is it not worth employing a little journalism to find out how that potential turns out? The potential, after all, is just the hype offered by the company. Whose job is it to follow these promises all the way down the road? 

When you report the existence of a clinical trial, all outcomes should be reported. Premature termination of a trial is an outcome. 

Biotech IPOs

2013 has been a rebound year for the biotech IPO. Here is a summary from back in mid-August from Mathew Herper of Forbes. Here is Bruce Booth. Here is Xconomy. Over $3B has been raised in IPOs for biotechnology pharmaceutical companies this year. The question is why.

Here is a sampling from the above authors.

With some stocks boasting double- or triple-digit percentage gains from their offer prices, many biotech watches just want to know to things: is this a bubble, and how long will it last? - Mathew Herper 

Outperformance of a “mere” 1000 basis points by a sector may sway a generalist fund manager’s allocation models; a differential of 10,000 basis points definitely will.  This sector differential means that any generalist fund manager who hasn’t had enough weighting to biotech in their portfolios over the past three years has likely underperformed indices, and those with overweight positions have done remarkably well. - Bruce Booth 

There are some promising companies in this 2013 class, but they aren’t that promising. It all looks like the herd is moving into biotech, out of fear of missing out on the next big thing, and desire for the quick buck. - Luke Timmerman

The investors have to cloud up their minds with basis points and performance indices. The pundits fear a bubble. The Cargo Cult angle here is that no scientific breakthroughs are available to explain any of this. As Mathew Herper points out, the IPO mania has offered up a stem cell, a synthetic biology and gene therapy company. Why should they succeed now where their predecessors failed? Can allocation models, basis points and performance indices explain any of this?

These new public companies do not represent a new breed of biotech-pharmaceutics. For example, Biospace has announced yesterday that Ophthotech Corporation pulled in $167M. Ophthotech is developing "novel therapies for age-related macular degeneration (AMD). The field of angiogenesis offers up a therapy for AMD in the form of vascular endothelial growth factor (VEGF) inhibitors. According to BioCenturys' BCIQ, there are 54 compounds in active development that target VEGF or its receptors, not counting line extensions of approved VEGF and VEGF receptor inhibitors. What does Ophthotech bring to the world of VEGF inhibition?

Ophthotech has completed a multicenter, randomized, double-masked, controlled Phase 2b clinical trial evaluating the efficacy and safety of Fovista^TM administered in combination with an anti-VEGF agent for the treatment of patients newly diagnosed with wet AMD. The trial included 449 patients at approximately 69 centers in North America, South America, Europe and Israel.
In this study, Fovista^TM 1.5mg administered in combination with Lucentis^® (ranibizumab injection) demonstrated statistically significant superiority compared to Lucentis^® monotherapy based on the primary endpoint of mean change in visual acuity from baseline at 24 weeks. Patients receiving the combination of 1.5 mg of Fovista^TM and Lucentis^® gained a mean of 10.6 letters from baseline on a standardized chart of vision testing compared to a mean gain of 6.5 letters from baseline for patients receiving Lucentis^® monotherapy, representing a 62% comparative benefit from baseline. Fovista^TM exhibited a favorable safety profile and no significant safety imbalances were observed for Fovista^TM combination therapy as compared to Lucentis^® monotherapy.

The endpoint for a clinical trial of a secondary treatment the is the foundation of a company that just pulled in $167M is seeing eye chart. What does Fovista do on its own?

Fovista^TM is designed to target platelet derived growth factor (PDGF) and in combination with anti-VEGF drugs disrupt the formation of abnormal new blood vessels in wet AMD. It prevents PDGF from binding to its natural receptor on pericytes, thus causing pericytes to be stripped from newly formed abnormal blood vessels. Left unprotected, the endothelial cells are highly vulnerable to the effects of anti-VEGF drugs. Because of the ability of Fovista^TM to induce pericyte stripping from newly formed blood vessels, the administration of Fovista^TM in combination with anti-VEGF drugs is likely to inhibit abnormal new blood vessel growth associated with wet AMD more effectively than anti-VEGF drugs alone and may also enhance neovascular regression.

Fovista does not treat AMD on its own. The end point is the eye test and not a quantitative analysis of abnormal new blood vessel growth associated with wet AMD, the hallmark of the disease. Fovista is now ready to enter a phase III clinical trial. It seems like a huge risk to go public at this point. Why don't the investors simply offer up $167M to pay for that phase III trial? Why bring the market and their speculators to gamble on the road ahead? Science is not about speculation.  Luckily Ophthotech has another drug in clinical  trials.

Ophthotech has completed a multicenter, ascending-dose, parallel-group, open-label Phase 1/2a clinical trial evaluating the safety and tolerability of ARC1905 administered in combination with an anti-VEGF drug for the treatment of wet AMD. ARC1905 was generally well tolerated in this trial when tested in combination with anti-VEGF treatment.

VEGF is nothing new. A science czar would be most interested in how this group of scientists measure anti-VEGF treatments. In cargo cult terms, we want to see the technology development report on the angiogenesis assays.

Ophthotech was one of the last IPOs so far this year. Lets look at the first IPO of the year, Stemline Therapeutics. This company targets cancer stem cells which is a baby in the scientific world. Cancer steam cells are in the initial stages of research. Like most cancer theories, cancer stem cell theory is not clearly understood.What Stemline does is to take a home run swing at one of the best knuckle balls ever thrown. What does Wall Street see?

This has a far greater impact than a phase 2b clinical trial that uses an eye chart test on the stock market. Stemline is success without scientific backup. Money is what this is all about. Scientifically speaking, there is no there there.

Cancer stem cells is an exciting idea. Cancer stem cells were discussed in the documentary "Forks Over Knives". Perhaps there is a signal in our DNA when the telemeres get too short. A signal is sent out and our built in expiration mechanism is triggered. CSCs represent a legitimate basic research opportunity. There is controversy still, which is good. Controversy is where a good scientist will sink his teeth in. Wikipedia:

The existence of CSCs is a subject of debate within medical research, because many studies have not been successful in discovering the similarities and differences between normal tissue stem cells and cancer (stem) cells.^[7] Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required forcarcinogenesis, and to sustain the growth of a tumor since differentiated cells (constrained by the Hayflick Limit^[8]) cannot divide indefinitely. However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties, there is no incentive to focus on a specific subpopulation. There is also debate on the cell of origin of CSCs - whether they originate from normal stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).

So what is the science behind the biotech IPO craze? Wouldn't it be fun to be that group of scientists whose job it is to test the tests. Take the technology transfer and match what has been said with what you find in your research. Rather, the work has been handed over for clinical trial analysis. During that time stocks will rise and fall based on speculation. Scientifically speaking, biotech IPOs do not represent an exciting time. Cargo Cult Scientifically speaking, perhaps the IPOs are the cargo. And the cargo has landed. You just need to know if you are receiving the cargo or if your investment is the cargo.

RAiN BioScience and The Disappearing Bees

RNAi and all RNA drug projects are doomed to fail. RNA and gene expression are too complex for mere mortals to regulate. We must leave that up to our DNA and the wisdom within. That doesn't mean that human beings won't succeed at selling each other drug products that tout RNA as the API. It just means that something other than scientific evidence will be needed to convince the FDA that you have a treatment for some disease. Cargo Cult Science will be needed. Once approved, RNAi proponents will have been vindicated. In the end, RNA will enter the body and quickly be reduced to an assortment of nucleic acids.

The questions I want to bring up today is 1) what happens to the PhD and laboratory staff who work on dead end Cargo Cult projects like RNAi and 2) what can we learn about their disappearance?

Most RNAi companies called it quits in the past five years. There is one company that has survived is called Serepta Therapeutics. From Wikipedia:

Incorporated in 1980, the company maintains some laboratory capability in Bothell, Washington and Corvallis, Oregon. As of 2008, the company has 170 issued medical patents, and over 150 patents pending.^[1] The company changed its name from AVI BioPharma and stock symbol from AVII in July 2012 to Sarepta Therapeutics and SRPT respectively.

I wonder how many of those patents are gene patents? 

 The company is a great example of a Cargo Cult Airport. They have rearranged their airport many times in many ways. The company began with the name AntiVirals Inc. in 1980. Later they changed the name to AVI BioPharma and then later to Serepta Therapeutics. They have changed locations from around Oregon, then a big shift to Seattle Washington (to attract the big brains) and then to Cambridge MA to attract "the right people". The Seattle move was a bust. They have burned through over $320M since 1980 and they have yet to bring a drug to the market.

What happened to the PhDs who were not invited to Cambridge? They are now known as RNAi experts, not as research professionals. Therefore they need to do something with RNAi.

Enter RAIN BioScience, a new Seattle biotech started by two discarded Serepta PhDs. Imagine the interview process at Serepta when the employees were arguing to keep their jobs. Serepta management took their patents and technology to the east coast. Those people who established the legitimacy of the science, however, were brought in to question. The two guys who started RAiN, somehow, did not make the cut.

The company, RAiN, is still a mystery. Yesterday on Biospace it was announced that Seattle had this new biotech in town.  RAiN BioScience is a Delaware corporation that will make therapeutics for unmet medical needs using antisense technology. Antisense drugs cannot enter cells well so RAiN BioScience will develop technology to help the RNA reach their intracellular sites of action. The project will be validated with an anti-cancer target.

So that is where two of the RNAi PhD castaways washed up. They are not alone however. Lets look at a few of their predecessors.

PhaseRx, an RNAi Delivery Technology company, founded in 2007 by a few local Seattle suspects. Two PhDs came from Marina Biotech, an RNAi company with "world class expertise" in delivery. From their website:

PhaseRx was conceived on the basis of using novel polymer technology to deliver siRNA. The Company's proprietary technology is a new type of synthetic, multi-functional polymer exclusively licensed from the University of Washington. The polymers come from the laboratories of Patrick Stayton and Allan Hoffman at the University of Washington, which have world-class expertise in fine-tuning the polymers to meet intracellular and in vivo delivery needs.

They too aim to treat cancer. They are several years ahead of RAiN but the two project in their pipeline are still in the early preclinical research phase. The latest news release was in January of 2011 and they have no jobs listed. Financing beyond their initial $19M has not been reported.

Agave Pharma Inc. was founded in 2009 by a former PhD from Marina Biotech. They have 4 employees and they specialize in novel nucleic acid delivery technology for RNAi therapeutics. Very little information can be found on their progress. 

Halo Bio RNAi Therapeutics founded in 2011 by Todd Hauser offers an RNA drug that consists of three separate double-stranded RNA regions that form a star. Indeed their website is pretty slick, even offering an Ap for your I-pad. When you click on "delivery" however, nothing comes up. The website also seems to exclude common details such as management, directors, location... It is not clear if they are still in business. 
____________________________
Part II  

There is documentary on the disappearance of honey bees worldwide. It's called Vanishing of the Bees. In this film the first warnings of the vanishing of the bees came from bee keepers. Men with their boots on the ground who open up their cages to find that their bees are gone. I submit that the rest of the world is not going to hear about the Vanishing of Biotehnology from the likes of Xconomy or the greatly reduced staff at the local newspaper. It won't come from the workforce who take their lumps and come back for more. They won't rock the boat. It will come from me, the Cargo Cult Scientist! Or someone else who gives a crap. There is a story to be told out there about the comings and goings of the biotechnology, the PhDs and their science. The science is questionable. The way in which we deal with it is far more telling. 100 years from now RNAi will mostly be forgotten because it is Cargo Cult. We'll learn more about RNA and it's role in gene expression regulation, but this little history of jumping the gun to make our fortunes from RNAi will fade away. Useless poetry. The machinations of a dying science and its practitioners however, will serve as a warning. 

The lesson I have learned here in Seattle is that RNAi delivery became the scapegoat for the jumping of the gun. It is a big issue among the PhDs closest to the laboratory. It cost them their jobs. We have no way of knowing what would have happened had they gotten their RNA to the target cells, but we know that the new pseudo companies intend to address this issue. We also know that the PhDs are starting to pile up at this very juncture, delivery. I haven't even mentioned the consultants here in town. 

Why haven't they all gotten together to figure this thing out? Why so many silos? Where is the RNAi book club of Seattle? Do they all intend to work alone on promise of RNAi delivery and ignore the hype?

I know they are dying. Like the bees, they just aren't there anymore. My LinkedIn account shows me what my newspaper and what Xconomy does not see. They are disappearing. They pop their heads up in companies like RAiN but you don't hear much about them beyond the initial hype. My old co-workers aren't updating their accounts with exciting new jobs. The little sparks like RAiN BioScience would be fun to watch grow, but if PhaseRx, Agave, Halo and all of the other unreported efforts are any example, RAiN will simply fade.