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Tuesday, December 31, 2013

Marie Hubers SEC Fine

The website Logical Fallacies is an invaluable tool for any scientist or person who wishes to battle the status quo and those who most benefit most from maintaining the status quo.  As stated in the opening paragraph of the website, "Fallacious reasoning keeps us from knowing the truth, and the inability to think critically makes us vulnerable to manipulation by those skilled in the art of rhetoric." Let's look into the logical fallacies surrounding Dendreons Provenge saga.

We have two sides, Dendreon and Marie Huber. One is a once-multi billion dollar biotech company. The other is a private citizen who took issue with the reasoning behind the approval of Dendreons Provenge. Both sides of this story have presented a scientific sounding argument in peer reviewed journals. Both sides appear to have had a monetary motive for practicing the art of deception. Both sides have been accused of some serious shenanigans. In the end, Dendreon is a company on the verge of bankruptcy and Marie Huber has been dragged through the mud.

Here is the final verdict as posted by a pro-Dendreon bully on the Wikipedia site:
Huber's contentions were ultimately exposed as a scheme to profit from speculation in put option contracts in the underlying security of Dendreon Corporation, which would have produced enrichment in the event the stock price were to have declined; the SEC accordingly found in November 2013 that in their reporting of Provenge, she and a colleague, via the dissemination of untrue statements and omissions of fact as a means to obtain money or property, violated Section 17(a)(2) of the Securities Act of 1933 (Securities Act), and imposed against each of them a six-month suspension, a $25,000 civil penalty, and a cease-and-desist order. - Wikipedia entry for Provenge 
"Hubers contentions were ultimately exposed as a scheme to profit from speculation..." The author here is referring to Ms Hubers "Alternative Explanation" as "contentions. This is an important point. The SEC report on Ms. Huber states:
After reviewing and analyzing the FDA documents, Huber concluded that 
the Provenge treatment was hastening the death of patients.  In June 2010, Huber began 
drafting a report for HFA-A, entitled “Provenge PhIII Trials – The Alternative Explanation 
of Survival Results” (hereinafter referred to as the “Alternative Explanation”)
The SEC report later makes the distinction:
A version of the Alternative Explanation was subsequently published in the “Journal of the National Cancer Institute” on February 22, 2012. The findings in this Order do not address the conclusions set forth in the Alternative Explanation. 

The SECs claims against Ms. Huber was that she tried to profit from her June 2010 Alternative Explanation report.
During the period of June 17, 2010 through July 12, 2010, Huber purchased $125,431 in July Dendreon put options and $110,627 in August put options.Huber also purchased put options in her mother’s account, and shared her analysis with friends and family who subsequently traded in Dendreon securities. The July put options that Huber purchased were set to expire on July 17, 2010, and had strike prices ranging from $10 to $30. All of the put options were “out-of-the-money” and most of them had strike prices of $25 or less.   Dendreon common stock was selling in the low to mid $30s.
Ms. Huber did her analysis in June 2010 and purchased put options in July. The argument that the Alternative Explanation report is thus a "scheme for profit" might seem logical on the surface. The problem is that the Alternative Explanation exists separately. Was it developed in order to short the stock? Or was it the impetus to short the stock? We don't know nor have we, nor the SEC, attempted to sort that one out.

The logical fallacy is called the Genetic Fallacy. This fallacy is committed when an idea is either accepted or rejected because of its source, rather than its merit. The idea that we are most concerned about here is the truth behind Provenge. Does it work? Is it safe? We mustn't make the Appeal to Authority and accept the FDA ruling, nor can we assume that the demise of Dendreon means Provenge doesn't work. Locially, there is still work to do regarding the Dendreon Provenge saga. One path we should take is in the practice of clinical trials and how a biopharma company interacts with the FDA. But we'll save that for another day.

I think the Genetic Fallacy addresses the Wikipedia damnation, along with all of the other detractors who wish to write off the scientific arguments made in the JNCI paper. The Alternative Explanation and the JNCI paper have not been called into question. The science is not the issue behind the SEC smackdown of Ms. Huber. The scientific method is a journey. It begins one day with a hypothesis. You test your ideas and maybe one day you decide to publish them. The merits of that journey remain untouched by Dendreon bullies and Wikipedia ghost authors.

Now then, as for Marie Hubers SEC troubles. Marie Huber recently made the following comments on the CCS from this post. 
  • A trial would have cost me at least a year and $100,000 -$250,000 in legal fees.
  • Settling cost me $25,000 and a 6 month suspension.
  • My legal defense bill over the 3 years of this SEC investigation has run into SEVEN FIGURES.
The terms of settlement prohibit me from making any statement other than "I neither admit nor deny the SEC's allegations". This means that YOU KNOW NO MORE AFTER READING THE SEC's ALLEGATIONS THAN YOU KNEW BEFOREHAND. An allegation, by definition, need not have anything behind it but the alleger's motivated imagination. Again, "I neither admit nor deny the SEC's allegations".

July 14/15, 2010: An anonymous report that I had written (exposing hidden results from the Provenge trials) was emailed to a bunch of biomedical folks (only 2-3% of whom were investors).

July 15, 2010: my employer files my report with CMS, identifying us as investment advisers.

August 5, 2010: I log the i.p. addresses of Kroll (private investigators) and Marsh McLennan (their former parent company), trawling through decades of archives of my personal website (

August 10-20, 2010: i.p. addresses from Seattle, WA, hit my personal website.

August 12, 2010: "Someone from Dendreon Corp" browses my LinkedIn Profile.

Sept 14, 2010: Mitch Gold approaches me, out of 300+ analysts who had just listened to his presentation at the Morgan Stanley conference (he does not know me, but I wear my distinctive long, curly hair down in order to lure him, and he obliges). After a little fun, Mitch reveals that he knows that I wrote the anonymous report on Provenge.

October 6, 2010: [I only learned this in 2013] the SEC contacts gmail regarding the account Jess had created to email my report.

The SEC settlement over my friend's distribution of a report I had written in 2010 is unrelated to my JNCI publication.

The JNCI publication occurred 1.5 years after my puts had expired worthless. I had no financial interest, in any way, around the time of the JNCI publication, or which could have been influenced by it. I was completely truthful in my disclosures to the journal, and given that the SEC had been all up in my business from early 2011 onwards, the settlement acts as PROOF of this.

I wished I HAD written in bold at the top of my report: "I believe so strongly in the shocking nature of the data that Dendreon has hidden and the only logical conclusions to be drawn from it, that I have bought thousands of puts betting on a decline of 30-80% in the price of DNDN stock over the next month". Maybe if i'd written that some people might actually have read it.

Anyone that did read it and understand it would have saved themselves from a 66% decline in the value of any DNDN shares they held in August 2011, when the "efficacy" of Provenge spoke for itself.

She ends with a logical fallacy of her own. The stock tanked in August because Mitch Gold made some promises he couldn't keep. He priced his product too high and didn't give his sales team a chance to make money. The efficacy of Provenge may have contributed to the doctors decisions not to prescribe the treatment but a stock price has no logic. 

I believe Ms. Huber and her analysis of Provenge. She was brave to take the journey, even though she may have tried to turn a profit Wall Street style. What matters here is the way in which clinical trials are conducted and reported to the FDA and the rest of us. Big Pharma has the same for-profit motivations as anyone trying to short their stock.

Monday, December 23, 2013

Mala Aria, Italian For Bad Air

When the ancient Romans were conquering the world they became familiar with the disease malaria. They noticed a correlation between thick musky swamp air and the disease. They deduced that the bad air, mala aria in Italian, was the root cause of the disease. Whenever they encountered the disease they drained the nearby swamps. The solution worked. Of course, scientists later honed in on the real culprits, blood parasites transmitted by anopheles mosquitoes.

Rene Descartes said, "Good sense is, of all things among men, the most equally distributed; for every one thinks himself so abundantly provided with it, that those even who are the most difficult to satisfy in everything else, do not usually desire a larger measure of this quality than they already possess."

One of the greatest obstacles of drug research and development is in the assumption that we know how to do it. Coming from the billions and billions of research dollars and the thousands of disparate workers trying to make money for their employers, is the occasional FDA approval. From the approvals we occasionally get a new treatment that is useful. Like blaming the bad swamp air for malaria, we miss the mark when assigning cause and effect. If we dig a little deeper we find that only science brings about real change.

When a company fails to beef up their pipeline, the C-level execs take action to get rid of the dead wood. In the process, they may very well be axing the only chance science has to do what it does. In that moment, where people and ideas turn over, the C-level execs want you to believe that they have done some good. They are draining the swamp. No one has yet figured out how to research disease and develop drugs without simply spending money, starting and ending projects, and hiring and firing the usual suspects. We don't know what it is that made us succeed at the last project nor why we may be failing at the current one. We succeed quite randomly, if we are to be honest about our profession. If that is not true, and we in fact do have drug development experts, where are the lessons offered by the enlightened? Are we not in need of a larger measure of this quality than we already possess?

There are those, however, who lack the skepticism of the scientists. They are the capitalists.  They will soon be gathering at the 32nd annual JP Morgan Healthcare conference in San Francisco, Jan. 13-16. Luke Timmerman, industry cheerleader, announces the upcoming event:
So what about all the healthcare industry capitalists? Are you ready to make the most of this week when all the decision makers and big investors are together in about a five-block radius?
So much for journalism, this is going to be a love fest. The leaders are gathering. It is time for all good soldiers to make a good impression. The healthcare industry however, is one of many elephants in the room when thinking about the next American crisis. Scientifically, we still do not have a viable career path for our scientists. Financially we have a group of fools and fanatics gathering in a five block radius to talk about ways of profiting from a national disgrace, our healthcare industry.
The whole problem with the world is that fools and fanatics are always
so certain of themselves, but wiser people so full of doubts.
-- Bertrand Russell 

Luke has some advice for the decision makers, big investors and those who want to bend their ear.

Don’t get overscheduled. I’ve made this mistake many times. It’s normal to be such an eager beaver that you pack your entire calendar with 1-on-1 meetings, in 30-minute blocks, from 7 am to 6 pm every day. And that’s all before the evening receptions. 
What will the leaders, investors and journalists who reside over our healthcare system discuss. A reproducibility initiative to strengthen the scientific foundation of the industry? New ways of strengthening the scientific labor force? How well things have gone in the last 32 years? The leaders, investors and journalists may simply be there as the proverbial "bad air", dense, powerful, yet not directly responsible for the success of the industry. For 32 years the leaders have been gathering to inspire one another, resulting in a disastrous system of healthcare. But that is not what they are gathering to talk about.
This conference is one of the largest and most informative healthcare investment symposium in the industry, bringing together global industry leaders, emerging fast-growth companies, innovative technology creators and members of the investment community. 
Approximately 300 companies, both public and private, will deliver presentations to an estimated more than 4,000 investors.
Wouldn't it be interesting if these 300 companies delivered presentations to an empowered, non-biased, career stabilized group of scientists tasked with assessing the science?

Thursday, December 19, 2013

Dying Days

Each day my dad awakes to a breakfast of roughly 20 medications. He spent his life smoking, eating a diet of mostly processed food, and not exercising. Now at the age of 72 he is a very sick man. He's had several heart attacks, heart surgery, he has COPD, and his circulation is very poor. He has been in and out of hospitals and nursing homes 13 times. Each time he is released, he goes home and smokes, eats process foods and watches tv until his body gives out again and he has to dial 911. He has racked up bills of well over $700,000.

I've come to live with him to take care of him. Unlike the doctors, I follow the details of my dads end of life experience. His doctors have provided him with the prescriptions. Every now and again he visits them at the various hospitals where they work. They ask him how he's feeling and he tells them he feels terrible. He wants to hide things he thinks will jeopardize his autonomy, like that he has fallen. The brief conversations between the doctor and patient lead to the western solution to every malady, medication. A complex system, the human body at the end of its life, is treated by a simple system. Take old person to doctors work place, read a few vitals, have a talk, prescribe and/or adjust medications that are currently available, and/or maybe schedule a surgery.

The last nursing home experience seemed to transform my dad from a very sick patient to someone whom the authorities deemed acceptable to live on his own, with his sons assistance. Things have gotten worse in this first week. What took place inside his body? The excitement of going home after 2 1/2 months energized my dad. Day one back home he went through his mail, talked on the phone to family, and finished off the day with in his easy chair watching his tv. He also ate a double cheeseburger. The next day he began to feel worse. Since then he's been eating less, sleeping more and he has become far less steady on his feet. Was the cheeseburger a mistake? What took place at the nursing home versus my dads home? The pills and their doses were adjusted, but what was the real change that brought about the improvement?

Confounding factors, such as diet, exercise, and emotional state have not been considered. Some of the pills are simple compounds found in natural food such as KCl and folic acid. What if the patient has decided to give up their wicked ways and eat plenty of fruits and vegetables to get these nutrients? Would that alter the prescription? Then we have the Zoloft to treat depression. It's depressing to be this sick. Perhaps it is unnecessary to pharmaceutically deal with the fact that you are in need of so many pharmaceuticals. Let the patient be sad. Sadness, perhaps, is not a medical condition. To a doctor and the healthcare industry he, as a generic patient, has been understood. Sad? Zoloft. Next problem. To those of us outside looking in, the problem is that he is also a living breathing thinking human being. At the doctors he is probed and interviewed at regular intervals. New paths are set. If he gets worse, its because of the illness or the lack of following the path. If he stays the same or gets better, it's due to the path. Unknown to the doctors is the path outside of their purvey that might have an equal influence on his physical and mental well being.

I think of myself, this blog and why my message does not have an impact whatsoever. I have good points. The industries of biopharma and healthcare are sick. They need to be cheaper, more effective and offer more opportunities. More communication is needed. The science needs to be more rigorous. In spite of my reasoning and the solutions I have proposed, I am not taking into account the confounding factors. Society doesn't like a nattering nabob. An anonymous blog is a poor format to influence others. Just like the doctors and their pills, I am not taking into account the complexity of the system of which I speak. I might have a good remedy, such as the concept of certification of laboratory staff and their work, but I did so here on this blog. Like an ineffectual medicine, I introduced my remedy in the wrong place. It cannot reach the location where it will do the most good. Likewise, a medical remedy may work at a cellular level, in a mouse or culture dish, but how will we get the same mechanism of action to work in a person?

Note: That's just an example of a system that also doesn't bring about change. I write the blog for practice getting ideas out of my head. 

The Cargo Cult message here today is a lesson I am learning as I watch my dad struggle. It is not enough to memorize the parts of an airplane and what they do.

You can learn about the parts, who makes each part, what the name is in Spanish and know nothing about what makes the airplane fly. Now look at the human body:

Each part has its own doctor. The body however is more than parts. That is the area in which the Cargo Cults of medicine must study. What makes a body live, think, age and eventually die?

Doctors and pharmaceutical companies are also mere parts. The leaders of healthcare must invest in understanding the system of healthcare itself. How does the system effect an individual, such as an old man who takes 20 pills every morning. In time we should advance our understanding of life and death, the system we have to  deal with it, reduce the amount of pills, and paradoxically treat the body through all of its stages of life.

Friday, December 13, 2013

Zuckerbergs Nobel Prize in Life Sciences

I don't like honors either. From the Cargo Cult perspective, awards can be given in spite of the arrival of cargo. Imagine an award given to the tribesmen of Vanuatu for best ceremonial dance or best costume. The real award for the tribe would be the cargo. Without the cargo, an award will assuage the tribe and make them feel as though the leaders know what is being done right and what is being done wrong. The truth is that the leaders of Vanuatu do not know right from wrong, as we do in the west. They do not know what makes an airplane fly. Any such award ceremony would simply be another cargo cult ceremony. The people who decide on the winners of any award sell themselves as the deciders of good and bad. That in itself would be a great honor, to be able to tell the world what really matters.

Mark Zuckerberg and Co. have used their money to bestow an award to scientists. The Breakthrough Prize in Life Sciences is no doubt an award that the Silicon Valley gurus hope will solidify their names in the annals of scientific history. The judges who pick the winners will be the previous winners. The first 11 winners were selected by the founders, I assume. You can bet that there is quite a stir among the Nobel committee members over an award given by a group of Silicon Valley rich kids. Who gave these guys the right to create a life sciences prize? Money? Will there be an overlap of Nobel Prize winners and Breakthrough Prize in Life Science winners? Are they suppose to be on par with one another? Money-wise, the new kids on the block offer a better payday. Oh my.

The prize comes with a $3M paycheck, meant to excite young people about a career in science.
The prize is administered by the Breakthrough Prize in Life Sciences Foundation, a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career.

The next generation of scientists, like the current, is suppose to strive for science that is exciting at the fame and fortune level. The boring details of daily lab work will not get you this prize. The boring narrative of a failed experiment or failed idea will not get you the $3M. It must be exciting, breakthrough and worthy of an award, as decided by others who pursued and won the prize. You must be one of them. In terms laid out from The Amgen Study, you must tell "the best story".

According to the Begley, Ellis paper in Nature:

Some non-reproducible preclinical papers had spawned an entire field, with hundreds of secondary publications that expanded on elements of the original observation, but did not actually seek to confirm or falsify its fundamental basis. More troubling, some of the research has triggered a series of clinical studies — suggesting that many patients had subjected themselves to a trial of a regimen or agent that probably wouldn't work.

This is the kind of research that wins awards unfortunately. If you can spawn an entire field, people are going to take notice. It is known in the scientific community that you can spawn an entire field with a good story, not necessarily good science.

You will not see an award for people who sacrifice their own careers by retracting papers when necessary. You won't see whistle blowers get an award for jeopardizing their careers for the best interest of science. There is no award for "Most Reproducible" or "Best Designed Experiment".
As pointed out in the Begley, Eliis study:
In studies for which findings could be reproduced, authors had paid close attention to controls, reagents, investigator bias and describing the complete data set. For results that could not be reproduced, however, data were not routinely analysed by investigators blinded to the experimental versus control groups. Investigators frequently presented the results of one experiment, such as a single Western-blot analysis. They sometimes said they presented specific experiments that supported their underlying hypothesis, but that were not reflective of the entire data set. There are no guidelines that require all data sets to be reported in a paper; often, original data are removed during the peer review and publication process.
Scientific research that is reproducible, where authors pay close attention to controls and their own biases, is not part of the criteria for a publication, promotion or an award. It is good for your science but it is also a risk. What if your work is not reproducible, as was the case in 90% of the papers looked into by the Begley and Ellis in the Amgen Study? As we learned, nothing will happen. You can still get published, promoted and awarded a prize.

Therein is where we need to see a prize. Take $33M and set up a laboratory where a group of scientists accept "nominations". If you think you've got something that can stand the rigors of another group of scientists looking to poke holes in your theories and evidence, throw your name into the hat. The judges will judge based on communication of ideas, transfer of science, reproducibility and for potential. It is not important what a group of rich kids from Silicon Valley think of your narrative. That is only a story selected on a political level by award committee and their awardees. Something greater than them is happening in science and they are not worthy take interject themselves into this world with another million dollar prize. If only they would use the money for the good of everyone in science and set up a Begley/Ellis-like organization. Select 50 papers to test each year. Award those that are reproducible. Give booby prizes to those that are not.

Thursday, December 12, 2013

Enzyte, Religion and Juno Therapeutics

Enzyte is an herbal supplement that some claim promotes natural male enhancement. It is suppose to make your penis bigger. Its effectiveness has been celled into doubt. The original businessmen who marketed this product knew that there was no scientific logic behind the claim. That doesn't mean you have to throw in the towel. What made the leaders successful businessmen was the selection of the product, clever marketing, and the passive nature of some people who accept getting ripped off when it doesn't involve a lot of money. Because Enzyte is an herbal supplement no testing by the FDA is required. The company selling Enzyte, Berkeley Nutraceuticals Inc., went a little too far however. CEO, Steven Warshak was found guilty of 93 counts of conspiracy, fraud and money laundering, sentenced to 25 years in prison and fined $93,000. Berkeley Nutraceuticals had to forfeit $500 million. Several other executives were convicted of crimes but the company lives on. It is now called Vianda LLC and they still sell Enzyte. Hamilton County (Cincinnati OH) commissioners approved a $195,000 property tax break to the "new" company based on projected employment opportunities. They continue to receive customer complaints on the efficacy of the product and improper billing issues. 
During the Middle Ages there were all kinds of crazy ideas, such as that a piece of rhinoceros horn would increase potency. Then a method for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course into science. And it developed very well, so that we are now in the scientific age. It is such a scientific age, in fact, that we have difficulty in understanding how witch doctors could ever have existed, when nothing that they proposed ever really worked-- or very little of it did. - R. Feynman, Cargo Cult  Science
This little passage only applies to the efficacy of Enzyte. We know that profit is why government agencies support the continuation of this job creating business. Science and business/government in this case, are in opposition to one another. The former is only concerned with the claims of "male enhancement". The latter is only concerned with the interests of the company and the local economy. The customer is offered a useless product and freedom of choice. Scientifically it is a bad choice to pay for and use the product. It is snake oil. From a business and local government perspective, why not make a few bucks off of the naive? It's not a much money and it might even give the men a brief moment of hope.

This leads me to the concept of religion and science. When you really want something to be true, you put your money where your heart is. Churches all over the world make money. They build buildings, pay their leaders and even do a little charity work. Yet religion is snake oil for the soul. There is no God yet every Sunday/Saturday and several times a day somewhere in this world, a preacher will stand up and go on and on about new thoughts they alone have dreamed up regarding their religion. Biopharma, likewise, sells hope, builds buildings, pays its leaders and does a little charity work. Oh yes, we have our charismatic leaders who could have just as easily made a fortune from Enzyte. What makes a biotech different from religion is the component of science. Unlike Enzyte, biopharma drugs must be approved by the FDA. The efficacy must be proven. Although not impossible, science makes FDA approval a complicated problem.

I did not say that the formation of a biotechnology drug company is approved by the FDA. Biotechnology drug companies are approved by investors. Investors really really want to make money, just like the leaders of Berkeley Nutraceuticals/Vivandia and local officials of Cincinnati OH. They do not follow the organized methods of science. Only some of the people at a biotechnology drug company must follow the scientific method.

Which leads me to Juno Therapeutics. This is the latest Seattle based biopharma company. Is it science or is it business? Is it a combination of the two? Is this of little interest to the locals in Seattle who see the $120M investment and call it a success?

According to Xconomy:
The company doesn’t intend to make a conventional pill in a bottle or targeted antibody drug in a vial. Instead, it plans to withdraw blood from individual cancer patients, re-engineer certain immune T-cells from each patient to turn them into super-aggressive cancer cell killers, and then re-infuse the “killer” T-cells back into the body. The great future ambition is to wipe out the tumors and create ongoing immune system memory and surveillance that can potentially keep cancer at bay for years.
Juno Therapeutics is an off-shoot of Dendreon. The CEO of Juno, Hans Bishop, is the former COO of Dendreon. The manufacturing and logistics skills learned through Dendreon will now be parlayed into Juno. The difference will be in the choice of immunogens/cancers Junos induced immune response will attack. In a Utopian world, Dendreon technology would have been the main interest in Dendreon, not Provenge. In a profit motivated world such as ours, a new company has to be formed to remove the stench from Dendreons financial failures. The technology of taking blood from a patient, sending it to a lab to generate an out-of-body anti-cancer immune response, then putting the cells back into the body, is indeed an advanced biotechnology. But so is making a pill.

In the Cynefin system of thinking, this technology is complicated. What is happening on the cancer cell side of the equation however, is complex. Juno has not solved the problem of understanding the cancer cell. Rather they have made the assumption that a cancer cell will have an Achilles heal. One Achilles Heal target means that the cancer cell side of the equation, according to the cynefin framework, is simple. Highly unlikely.
The big idea is in exploiting advances in understanding how to manipulate T cells to fight cancer,” said Larry Corey, the president of the Fred Hutchinson Cancer Research Center and co-founder of Juno.
What I am suggesting is that an even greater understanding of the cancer is required before you apply your T cell/immunology understanding. There is a leap of faith taking place.

Are the investors of Juno like the moneyed interests behind Enzyte? We all want to believe. There is a history of investments. Efficacy has long been an issue. In spite of the troubled past of immunotherapy for fighting cancer, the investments continue to pour in. Fortunately, biotechnology has its scientific side, along with the religious followers (investors) and the great story tellers. I want to follow this company carefully. Their claims have not been submitted to peer review nor have they signed up to present at any conferences. Rather than take the old fashioned science route (peer review) they have started a biotech company and not in a shy way. From my perspective as a long time student of the Cargo Cults, I find this to be suspicious. From a scientific standpoint, they aren't much more Berkeley Nutraceuticals at this point. They have a lot of money, a good story, and people who need what they are promising. The path forward will be beaten down for easy passage by those who want to believe, want to profit and those who want Seattle to take another run a becoming a biotech hub. I will hold onto my skepticism as always and keep my eye on Juno as much as possible. They have moved into the old VLST space, a place where a $50M biotech company once disappeared and no one knew about it for several months! That should not happen to Juno. The bold burst onto the scene should be followed up with an equal amount of attention to what comes next.

Wednesday, December 04, 2013

Marie Huber and Provenge

Oh my! Marie Huber fined $25,000 for making misleading statements about her Dendreon Provenge clinical trial study and violating the Securities Act for her role in disseminating the study! I talked about Marie Huber back in April 2 and April 4 of 2012. She is the former hedge fund financial analyst who walked away from a lucrative career, much like those I discussed yesterday. It's interesting to see this story one day after posting this quote from a government advisor from the tax haven The Isle of Jersey:
One of the things I found most peculiar working in the financial services was the culture of the workers themselves. Many of them are very intelligent people indeed. Lawyers, accountants, bankers, highly trained through Universities. Very privileged people. By and large, they hate their jobs. The jobs are boring, repetitive, stupid, but the money is fantastic. They know that the work they do is without worth. They don't create value in any economic sense of that term. 
Ms. Huber was a biochemist turned financial analyst who walked away from her financial job to use her science education to fight an evil she uncovered while analyzing the statistical analysis of Dendreon. She measured the measurements, something we see missing in the Cargo Cults of Biopharma. What she found was a concerted effort to hide possible harmful effects and spin the data to fit the narrative that originated this drug discovery project. The first rule we must have when working in  medicine (even though we're not M.D.s) is "do no harm". The courage to question Dendreon and the FDA, give up a high paid job, and offer up a scientific argument for all to scrutinize was a breath of fresh air. Not everyone saw it that way.

The SEC, the agency who could not find much of any wrongdoing on Wall Street throughout the economic meltdown the nearly crippled the world economy, felt the Ms. Huber had crossed a line. Read their report here. They fined Ms. Huber $25,000 for her attempts at influencing a lower stock price for the purpose of profiting by shorting the stock.

We at the CCS are not concerned with matters in the trade of biotechnology stocks. Ms. Huber and Jess Jones maneuvers to turn a profit off of the bad science of Dendreon does not diminish the science behind Ms. Hubers analysis of Provenge. In her own words to Pharmalot:

"I have agreed to a settlement with the SEC and I look forward to putting this issue behind me. I stand by the rigor of my scientific analysis and I shall continue to follow-up on the concerns that I expressed with regard to Provenge in the article published in The Journal of the National Cancer Institute ("JNCI") in 2012.
"My primary motivation has always been the well-being of patients and the safety and effectiveness of this treatment. The accuracy of my research and conclusions are not an issue in the SEC settlement; neither my findings on Provenge submitted to CMS in July 2010, nor the concerns set forth by my co-authors and me in the JNCI article were contested by the SEC. Since first submitting the article to the JNCI in 2011, I have had no financial interest in the fate of Provenge."
The SEC has used up their time and effort to correct Ms. Huber. I'm sure this was easier than digging into Goldman Sachs misleading statements to investors whom they encouraged to go long on stocks they were shorting. Who influenced the SEC to take up this small time issue? Perhaps Ms. Huber did practice the art of deception in her financial occupation. This is possibly a fair decision and fine. If only the scientific community had the same"stick-to-it" attitude of the scorned investment community, perhaps we would revisit the effects of Provenge. Did Dendreon practice the art of deception in their scientific work? Most importantly, has the recent introduction of Provenge to the medical community altered the mortality rate of prostate cancer patients.

Tuesday, December 03, 2013

The Short Term

In the documentary, "Let's Make Money" Hermann Scheer, a member of the German Bundestag describes the problems created by privatization of public resources.
Society is deprived of a certain good that the private investor is interested in for reasons of profit.
Universities and the value they have provided their societies are a "certain good". Biopharma is the private investor who is interested in the "certain good" for reasons of profit.

The documentary describes, among many other things, the sale of Viennese trams to a U.S. investor. After the city of Vienna sold the trams they had to pay for the rights to operate the trams. The city of Innsbruck sold its public utilities.
They are not interested in what happens after them. This short term attitude... the lack of a will to take responsibility for the long term... knowing it will be up to others to resolve the problems later... is characteristic of the neo-liberal era. In the neo-liberal era, everything is reduced to making the highest profits immediately. And this at any price. - Herman Scheer
Luke Timmerman wrote about 3 biotech comapanies he sees as not taking the neo-liberal path in this article:
The financial world today is obsessed with short-term gains. Many investors don’t want to bet on some hope for the “next Genentech” in hopes of making returns 20 years from now. They want to make money next quarter, they expect a bigger return, and they want less risk. 
The public Universities gave in to private investor money thanks to Judah Folkman.
In 1974, Judah changed academic medicine and Harvard University by accepting the first large industrial-funded research grant from Monsanto Company to support his cancer research. As a result, for the first time, Harvard permitted its faculty to submit patents covering medical inventions.  Judah’s successful experiment in corporate funding also paved the way for industrial support of academic research laboratories at universities and research institutions across the nation, which is commonplace today.
And we were off to the races. Judah Folkman got paid. What came after was the failure of his promise and a new paradigm that has created problems that Judah did not see as his. College professors and their graduate students spend most of their time thinking about money. Working in the business of science is like that described in the "Let's Make Money" documentary by an economic advisor to the government of The Isle of Jersey:
One of the things I found most peculiar working in the financial services was the culture of the workers themselves. Many of them are very intelligent people indeed. Lawyers, accountants, bankers, highly trained through Universities. Very privileged people. By and large, they hate their jobs. The jobs are boring, repetitive, stupid, but the money is fantastic. They know that the work they do is without worth. They don't create value in any economic sense of that term. What they do is allow capital which is being created in one country to be accumulated in a different country where it will become concentrated in the hands of a very small elite of the worlds population. Maybe less than 3%. 
Has science become this bad? We have very intelligent people who are very privileged. We help our investors and executive staff become wealthy but we are the first to go when an issue threatens the short term profit. Yet our jobs are boring, repetitive and stupid. A long term view that should be held by the young and easily manipulated laboratory workforce is that our older workers are unemployable. That is their fate if they fail to fight for a change. Our leaders are now businessmen. Our scientists are working at the Home Depot.

There is great value in a scientific mind. It makes the world a place where we can wonder, ask questions and find clever ways of getting answers. People with scientific minds help those around them by contributing to the body of knowledge that is passed down in our University systems. As we can now see from biopharma, starting in 1980, very little knowledge is being preserved for future generations. The knowledge is patented. The knowledge is of dubious accuracy. The knowledge is not subject to close scrutiny, as witnessed by The Amgen Study. The profits we seek may very well be the cancer that is changing the good name of science into a failing business model.

Monday, December 02, 2013

PharmAthene Theraclone Call It Quits

  • Forest Laboratories Inc. To Trim Jobs in $500M Restructuring
  • Eisai Inc. R&D Organization Undergoes "Transformation," Chops 130 Jobs
  • Merck & Co., Inc. To Shutter Irish Plant, 570 Jobs To Go
  • PharmAthene, Inc. Terminates Merger Agreement With Theraclone Sciences, Inc.

On of these stories is not like the others, at least not on the surface. The first three are typical Monday morning job loss stories from the Cargo Cults of BioPharma. The last story is about the failure of a new business model. The failure can be used however, to explain the massive layoffs among scientists who develop drugs.

On Aug. 1, 2013 PharmAthene and Theraclone announced:
ANNAPOLIS, Md. and SEATTLEAug. 1, 2013 /PRNewswire/ -- PharmAthene, Inc. (NYSE MKT: PIP) and Theraclone Sciences, Inc., a privately-held monoclonal antibody (mAb) discovery and development company, announced today the signing of a definitive agreement for the merger of PharmAthene and Theraclone in an all-stock transaction.
The combined company will be a fully-integrated and diversified biologics company with four clinical-stage product candidates targeting high-value commercial and government markets.  The merged company will combine vaccine and human monoclonal antibody expertise with a focus on infectious diseases and oncology, and will feature a robust discovery pipeline with four pre-clinical programs and multiple discovery candidates, along with three partnered products.
"A merger with Theraclone will significantly advance PharmAthene's goal of achieving broader portfolio diversification," said Eric I. Richman, President and Chief Executive Officer of PharmAthene. "As a company with multiple clinical, pre-clinical and discovery candidates targeting important indications, the combined company will have the potential to generate substantial value for stockholders through both corporate collaborations and the development of its own proprietary therapeutic mAbs targeting high-value commercial markets."
Mr. Richman continued, "The combined company also expects to be able to leverage non-dilutive government funding sources to support ongoing and future product development efforts, with the possibility to receive a share of revenues from sales of SIGA Technologies' smallpox antiviral, Arestvyr.  As a stronger company, with expanded access to non-dilutive funding, we expect to be solidly financed through resolution of the SIGA litigation."
Clifford J. Stocks, Chief Executive Officer of Theraclone, who will head the new company, commented, "By combining PharmAthene's strong vaccine and biologics development capabilities and government contracting experience, with our clinical antibody candidates and novel discovery platform we are establishing a premier biologics organization with multiple product candidates possessing significant near- and longer-term revenue potential in high-value commercial markets."
Then came some bad news last week:
Theraclone Sciences, Inc., a therapeutic antibody discovery and development company, today announced that it has received notification from the Biomedical Advanced Research and Development Authority (BARDA) informing the Company that their proposal, “Broad-spectrum anti-influenza A M2e fully human monoclonal antibody TCN-032: Determination of efficacy in serious influenza disease,” was not selected for funding under the current proposal. Theraclone submitted the proposal on August 29, 2013, to apply for government funding to advance development of TCN-032 into Phase 2 clinical development for serious influenza disease, including pandemic flu. - 
Note the hopes of the leaders from each Cargo Cult. They hoped to advance four drug candidates "targeting high-value commercial and government markets".  The merged company will combine vaccine and human monoclonal antibody expertise with a focus on infectious diseases and oncology, and will feature a robust discovery pipeline with four pre-clinical programs.  

And it all fell apart a week after BARDA rejected Theraclones TCN-032 request for funding. As the Theraclone CEO stated in the hopes and dreams section (the press release) of their business model, PharmAthene was suppose to bring the government contracting experience. With the termination of the contract, a $1M termination fee is to be paid by PharmAthene to Theraclone. Thereaclone provided the drug. PharmAthene was to suppose to get BARDA on board. Did the drug fail to impress or did the government contract experts fail?

Either way, things didn't go as expected. One day before the cult leaders (shareholders) were to meet, both companies agreed that the plans they had made were not going to generate value. So much for combining vaccine and monoclonal antibody expertise. So much for their robust pipeline discovery and four pre-clinical programs. The reality of the proposed merger was that it was a bit more short sighted than advertised. One would think that something as simple as a failed attempt at funding wouldn't sink the promise of this combined biopharma company. 

The connection to the layoffs at Forest, Merck and Eisai is the business model designed primarily to make more money. Once again, George W. Merck:
"We never try to forget medicine is for the people. It is not for the profits. The profits follow, and if we remembered that, they have never failed to appear. The better we have remembered it, the larger they have been." Good medicine comes from good science. You have to remember how this science works. It takes many years from start to finish. Often times the finish is disappointing. To divest in the process because of the current lot of disappointments is a misunderstanding of timeline of this science." 

Wednesday, November 27, 2013

You Can't Be 20 On Sugar Mountain

...though you're thinking that you're leaving there too soon.

I continue on this thread of employment, unemployment and the impact of the layoffs in the biopharma industry (Cargo Cults). There is a story here that is not being covered by any news agency. The government uses statistical analysis to tell the story they need to tell, that things aren't so bad. From my LinkedIn account however, the people I have worked with in the biotech Cargo Cults are not doing so well. Especially those over a certain age. I'm focusing on laboratory work in honor of Frederick Sanger. Some people still value laboratory experience and lament that it is now considered a "Sugar Mountain" of sorts where only the young and vulnerable need apply. Here is a comment from a post on Dr. Sangers passing on the blog In the Pipeline that sums up this sentiment :

In academia of yore, it was usual for even the most senior scientists to perform lab work. A recently-deseased colleague of mine had the privilege to work with both Sanger and Perutz. Apparently, the latter would not take on grad students who got 1st class honours degrees as undergrads becasue he belived they must have spent too much time in the library and not enough time in the lab to achieve such results. My colleague worked in the lab until he retired aged 82. Washing glassware gave him time to think he told me. 
Contrast that with the "show me a scientist who is still doing bench work at 35 and I'll show you a failure" mentality that pervades academia today. Much better to spend half your life writing grant proposals to fund others to do the work than to do it yourself I guess. Me, I'm way past 35, but still do some lab work almost every day. It's the only way for me to stay sane.
As Dr. Sanger said, "Of the three main activities involved in scientific research, thinking, talking and doing, I much prefer the last and am probably best at it. I am all right at the thinking, but not much good  at the talking." What we are talking about here today is the thinking, doing and talking and the careers associated with this work.  

The New York Times ran an article last Sunday entitled, "Caught in Unemployment's Revolving Door" by Annie Lowrey. It begins with the story of Jenner Barrington-Ward who, at 53, has been unemployed for five years. She is soon to become forgotten. We don't learn much about her or what other factors led to her long term unemployment. She had last worked in the administration office at MIT. The story is about long term unemployment, a situation that tends to plague higher educated people who in previous generations may have been looked upon more favorably. A gap in your resume speaks louder than the words you actually write down.

According to the NYT article, we have what are known as structural and cyclical forms of unemployment. Cyclical unemployment is a temporary situation caused by a slack economy. Structural unemployment stems from a mismatch between what businesses want and what workers offer. In my last post I argued against the idea that biopharma job losses are cyclical. The losses are steady and they are unusually high, even when compared to high cyclical job losses in other industries. Our work force has been brought in to staff the endless new R&D paradigms and business models dreamed up by the managerial class. When their ideas fail, the laboratory staff tend to be the first to go. The constant hiring and firing of the laboratory staff has taken its toll.

Some people lose their jobs via uncontrollable circumstances. In good times they'll soon get a new job. In bad it will take a little longer. But long term unemployment on a resume is not seen through the lens' of good and bad times. It is simply a canary in the coal mine that sends the message that an individual is a problem employee. The "Thinking Fast" idea that pops into the hiring teams head is that the worker was bad, not the project they were working on. The "Thinking Slow" idea is that the individual works in a highly volatile industry and has little control over what his resume says about him or her as a thinking doing and talking researcher.

In biopharma, much of what begins as a promising new technology soon hits a snag. With poor tools such as RNAi and animal studies, a laboratory worker will produce less than impressive results. As new information comes in new people are hired to move the work forward. Thus what is cyclical is the nature of research. We have a history of short lived projects. Rather than working together and focusing on planning experiments using the scientific method, making all possible assumptions and anticipating negative outcomes, the leadership positions itself in the safest place possible. Careers are at stake. As one commenter said with regards to why animal studies are poor predictors for drug efficacy in humans:
Reproducibility is an issue. We can always trace this back to the low pay, no career development, no benefits, borderline abused individuals that give results they are expected to give to their PI. But that is never addressed and hand-waved away.
It certainly isn't hand waved away here at the CCS. The lack of career development and abused individuals giving only expected results is Cargo Cult 101. The argument here is that what we are facing is a structural unemployment crisis that generates a weak ineffective laboratory work force. The NYT article states that economists believe the strain of unemployment, plus the erosion of skills and loss of contacts that naturally occur, explains structural unemployment. There is also a bias against the unemployed that keeps long term unemployed from re-entering the work force. In biopharma, the laboratory work force faces all of the above, all of the time. The solution to both biopharma and their work force is to beef up the credibility of the laboratory.

Ah but I'm only dreaming again. When I was young I dreamed of living on Sugar Mountain with the barkers and the colored balloons. You can't be 20 on Sugar Mountain, though you're thinking that you're leaving there too soon. When you look at Sugar Mountain everyone is young. When you look at biopharma everyone is well educated. If you look closely you will see that the people only stay for a short time however. Where do the people go? It is hard to reinvent a person who has invested their education dollars in learning about DNA and proteins. They were trained to work in the lab. We've trained them to conduct research. They need a permanent place to be, think, talk and do.

Monday, November 25, 2013

The Hardest Times at Cargo Cults

Imagine working in a Cargo Cult. You're coming of age and the tribal leaders assign you a position in the watch tower. You are issued your coconut-stick head set and given detailed instructions on what to do. Each ceremony you do exactly as told and you look to the skies. The planes never come. As a young person you have only heard of the planes and the cargo, never seen them. After a while you start to wonder wherein lies the problem. Is it you? Is it the old lady with the barbed wire wrapped around her body (the radio lady)? It couldn't be the leaders. They know too many details about the ceremony. What if they have it wrong though? You wonder if the chief really is communicating with the people in the airplanes when he channels them through the radio lady.  Could you take the chiefs place and talk to them?

One day you awake for the biggest ceremony of the year. The annual Cargo Cult Superbowl! Everyone attends. All hands are on deck and everyone is believing to the best of their faiths ability. You take to the tower, don your headset and perform the ritual you were taught. You look to the skies. You look to the Chief and the radio lady. You wait and wait and once again, no airplanes come. As dawn comes you come down from the tower to return to your hut to sleep. No cargo will be waiting for you when you wake. Just rice and berries as usual for you daily meals.

What year is a good year in the Cargo Cults? Did you almost see an airplane back in 94? When you've got a group of people who have never seen the airplanes land, you have a problem. Somehow you have got to get people who have failed and succeeded on your team. The best example I have from my career was when the large successful contract manufacturing organization banned our director and his immediate reports from participating in the process development of product. Our people had neither failed nor succeeded. They had showed up to work for years (still do) with the "fake it til you make it" philosophy. The CMO had had enough and they called us out. They exercised the option in the contract to exclude members of our team from the alliance between our two companies.

I saw myself as the young boy in the watch tower watching the empty skies. One day I came across this CMO and a few others who I believed had seen the planes and the cargo. The CMO had been in business for many decades and had made drugs for many companies. The other people I met taught classes in process development and they made sense when they spoke, unlike members of my tribe. I wanted out from under the leadership of those who have neither failed nor succeeded to learn from those who had. My tribe let me out but in a manner that would exclude me from participating with other tribes. I had had enough of everything I had done before, but I still had an interest in the biotechnology of drug manufacturing. After so many years of working in biotechnology, I finally had enough information to decide where I wanted to work.

The layoffs are the direct result of the Cargo Cult mentality. The layoffs are business as usual. The layoffs are a business decision that replaces actual changes to the role that kid up in the watch tower needs to have value. For those who think they are seeing a surge, check out this article. According to the author there had been a perceived lull in job cuts that had been moving at a "breakneck pace starting in 2011". In reality, 8,793 jobs were lost from January to August of 2013. In 2012 9,626 jobs were lost, only 9% more. When Mercks job cuts are accounted for, 2013 is going to be a worse year than 2012.

Just to randomly check a few other data points, here is an article from 2002. How about 2009? 2007? If you look hard enough you will find that only a handful of companies have succeeded at bringing a drug to the market. Those fortunate enough to have that experience have much to teach. However, they too live the perilous life where important decisions made by others can bring their employment to an end. When a good job turns south and is eventually terminated, the value of that employee is only in that employees understanding of what happened. In order for that person to go on and contribute to the improvement of the biotech industry, they must understand what went wrong and find a new position that specifically intends to mitigate the risks that ended the last position. If a person has real value, the position must extract that value.

In the history of the industry we have always had hard times. Layoffs became the norm long ago. Just as the leadership class has yet to solve the mystery of generating value from the lab, so has the laboratory class.

Recently Frederick Sanger died at the age of 95. He left behind much to study. He won two Nobel Prizes in Chemistry, one for his work on the structure of proteins and a second for contributions concerning the determination of base sequences in nucleic acids. A man such as this was certainly a member of the leadership class but he included a followership role with science as his boss. He worked in the lab! While we've created a thousand hierarchy structures, business models, six sigma black belt methodologies and restructured our laboratory working class into a dizzy group of unemployed Home Depot employees, one guy had an interesting life. From Wikipedia:

He declined the offer of a knighthood, as he did not wish to be addressed as "Sir". He is quoted as saying, "A knighthood makes you different, doesn’t it, and I don’t want to be different." In 1986, he accepted the award of an Order of Merit, which can have only 24 living members.
In 2007 the British Biochemical Society was given a grant by the Wellcome Trust to catalogue and preserve the 35 laboratory notebooks in which Sanger recorded his remarkable research from 1944 to 1983. In reporting this matter, Science noted that Sanger, "the most self-effacing person you could hope to meet", was now spending his time gardening at his Cambridgeshire home.
Sanger died in his sleep at Addenbrooke's Hospital in Cambridge on 19 November 2013. As noted in his obituary, he had described himself as "just a chap who messed about in a lab" and "academically not brilliant".

If you care about science you should aspire to be this humble. The Cargo Cult boys and girls who work up in the  tower are working in boring mundane jobs. However, our responsibility is to demonstrate value. We are hired to develop drugs. The question is how much our work contributes to the big picture. We try and try but every year we face hard times. The hardest times for the laboratory workers are not a particular year or a tough economic downturn. It's a season that comes over and over in the life of the lab. The hardest times come when everyone is sent home and the labs sit empty. At any given moment in our industry, hard times are happening.  

For those roughly 9,000 who lost their job in October of this year need to know they are joining another class of roughly 9,000 men and women who lost their biopharma jobs in October of 2012. This is bigger than them. They work in a Cargo Cult. Frederick Sanger did not. Somewhere we too should be able to find a lifetime of productive scientific work. A little humility and unpleasant lab work will lead to the kind of work that serves as the proverbial shoulders of giants for future geniuses to stand upon. We should aspire to simply be chaps who mess about in the lab. Those who tell the best stories are those whom we should watch closest. 
Sanger, F. (Annu. Rev. Biochem., 1988, 57, 1): "Of the three main activities involved in scientific research, thinking, talking and doing, I much prefer the last and am probably best at it. I am all right at the thinking, but not much good at the talking."

That is the difference between successful scientists and successful Cargo Cult Scientists. The CCS thinks up narratives and talks about them. The weakened laboratory class is sent to the lab to "do". These are the people who are most vulnerable during the hard times. It is fortunate for the scientific community that Frederick Sanger did not have to work for biopharma. 

Thursday, November 14, 2013

Sarepta Therapeutics

I've talked about Sarepta here and here. I've talked about RNA drugs often. Here and here for example. In 2006 Jim Cramer of Mad Money was touting a biotech company that later tanked because one of the many pluses was their RNAi program. RNA drugs replaced the DNA drug projects that had failed miserably the decade before. RNA soon began suffering from the same issues as the DNA drugs, efficacy in the human body. Along the way however there was a Nobel Prize for its discoverers and wild investments that followed. The mania to turn this science into a pharmaceutical product, asap, stems from a fundamental misunderstanding of how a specific cell produces just the right amount of a specific protein to participate in the function of the entire living organism. Those who attempt to throw a little more nucleic acid into the body and hope that it cure diseases are grossly underestimating the complexity of our DNA.

I look at it like a view from an airplane flying out of LAX. You look down and find Venice Beach. You know where the sand hits the water but you can't make it out from that distance. It's the mile high view obscuring details. In the case of looking down at a cell from a microscope, we can't see DNA. We can see the nucleus but we can't make out the details of the DNA inside. We have learned a great amount and harnessed that knowledge to now be able clone genes, sequence DNA and so on. But we can't actually watch the things that take place with our DNA that regulate protein expression. Just as I can't make out where the sand reaches the water from my seat in the airplane, I can't see the protein expression machinery in action. I take a pipette and add some RNA to a cell culture and often times measure something other than the expression of the protein I'm trying to knock out. Now just imagine adding some RNA to a human body and measuring something like a miniscule effect in very sick people like those suffering from Duchenne muscular dystrophy.

Eteplirsen works by skipping exon 51 to overcome a genetic mutation to allow for the creation of dystrophin. This single solution is alledged to correct the body's inability to build muscle. The end point that Sarepta reported to the FDA was not however a detailed view of that mechanism of action. Rather they chose to remain in their mile high view and ask the FDA to look out the window while they spun their narrative. After a few more data points were added to the big picture, such as the failure of exon 51 skipping Prosensa in a larger study, the FDA decided they needed to see more rigor in Sareptas scientific method. Sarepta now has to add new endpoints, a longer study duration and a larger study population. Based on this new demand by the FDA to get more information, Sarepta lost $750M in market value this Tuesday.

The question I have for those who try and bring up the human side of the story and how this effects the patients is why are they bailing out? If the caring investment community and the leaders of Sarepta thought the 12 person trial was sufficient for a fast track approval by the FDA, why don't they think that the data offers some predictive powers over what would come from a more detailed study? The pot of gold still remains at the end of this journey. It's just gotten a little tougher. The Sarepta crew are one mile up in their airplane looking down at Venice Beach. The people in the watch tower have instructed them to take another pass and get a closer look at the beach before they move on. Are they afraid that they don't have a clue where the water really is?

The reason Sarepta is in business and has burned through well over $320M without putting a single drug on the market is due to the fact they are targeting RNA. The smoke and mirrors approach has them in trouble once again. They didn't spend that $320M studying Duchenne muscular dystrophy. They spent all of that money and still can't think of more convincing evidence for their product. What we on the outside know is that they are in business to make money. If they believe in their medicine they should forge ahead. The 12 patient sample size was enough for Sarepta to tell the FDA and the investment community that they are on to something that will help these boys suffering from DMD. The same fame and fortune awaits, it's just gonna be a little bit harder now. Now is the time when Sarepta has to stick to their guns and finish what they started. We've heard the narrative and we've heard about the results that has given people hope. We need to know more about this new exon skipping method, not just for DMD but for other single genetic mutation disorders. Either outcome, positive or negative, the patients and the scientific community have an interest in the scientific work of Sarepta.

Friday, November 08, 2013

BMS in Seattle

Bristol Meyers Squibb spent $885M on Zymogenetics. The guys and gals who spend their work life serving a company like Zymogenetics inevitably get notified that their efforts will be rewarded with a termination. These individuals now have to go forth and convince another company that it was BMS and/or Zymo who made the mistakes. To add to the pain, the researcher must make this case without bad mouthing their previous company!

The reason for the acquisition of Zymo was primarily for Zymos interferon alpha product to fight Hep C. The job cuts in Seattle are being made as BMS' moves out of the Hep C, neuroscience, and diabetes areas. One has to wonder what value is left in Zymogenetics? The individuals who are being cut apparently only had value in the Hep C space. They are not researchers. They are Hep C Zymogenetic workers.

I have long railed against the notion that a research professional is only valuable in the field in which they have been working. In a non-cargo-cult world a researcher is a cog in the machine that conducts research. Put ideas into the machine and out will come the results that are nothing-but-the-facts-ma'am. In this fantasy world, the researchers at Zymo would be given new research projects, not pink slips. Having the ability to move from Hep C to cancer to diabetes would create a research department that relies on the scientific method more than the cargo cult mentality. The researchers would be partners in ending things that need to end. When their careers end with their projects, they will act in their best interest, not the companies.

Right around the time BMS was sniffing around Zymo they had a team conducting due diligence on an anti-IL6 antibody from a small Bothell WA biotech called AlderBiopharmaceuticals. They paid Alder $85M with milestone payments up to $764M. In June of 2011 BMS paid Alder a $15M milestone payment for the launch of a phase II Rheumatoid Arthritis trial that they reported on last week (positively) with no mention of milestone payments. This could mean trouble for Alder. The workers at Alder are in a typical biotech quandary. Their jobs might be in jeopardy and there is nothing they can do. The lead candidate is the money maker. The rest of the pipeline is window dressing.

What would an Alder worker have to tell BMS if their job wasn't on the line? The diseases the IL-6 crowd fights are Rheumatoid Arthritis and cancer. Genentech already sells Actemra, which is an antibody against the IL-6 receptor. The BMS/Alder drug is different in two ways. It binds to IL-6, not the receptor of IL-6, and it is expressed in Pichia pastoris yeast. The norm in biopharma is expression in Chinese Hamster Ovarian (CHO) cells such as the CHO platform employed by Genentech for drugs like Actemra. If BMS and their anti-IL6 drug is going to compete, they will have to also compete with pricing. That means they will have to somehow compete with the CHO platform. Do the workers at a small biotech even understand what they are up against?

The claims at Alder:
  • The cost of producing mammalian cell cultures is US$300 to $1,000 per gram. Alder’s microbial cultures cost a fraction of this amount.
  • Over 75% of antibody manufacturing capacity is held by a limited number of companies. Alder provides an alternative manufacturing process that avoids this bottleneck.
This is quite a claim. Having witnessed the pricing fiasco of Seattle based Dendreon, one has to wonder if Seattle has the right kind of talent to properly factor in the cost of providing a drug product. They have not produced many research professionals who are highly skilled in dealing with manufacturing. Cargo Cults specialize in the narrative. Manufacturing and engineering issues cut through the BS of cargo cults. Did BMS truly find the Pichia pastoris story convincing? The biopharma world, one would think, would be banging down Alders door to get at their manufacturing technology. It is not. Alder claims that their system "scales rapidly to 50,000 liter tanks" Compare this to Genentechs 15,000 liter tanks in Oceanside CA where Actemra is made. One can assume the CHO platform at Genentech expresses somewhere between 3 to 5 grams per liter. What is the Pichia pastoris expression level?  

The workers know but their jobs are on the line. Keep positive or parish. In spite of the unbridled optimism of Seattle biotechies, the layoffs and the confusion around Alder underlies the Cargo Cult nature of this business. The people being laid off at Zymo had no control over the competition against interferon alpha. The workers at Alder have no clue about big pharma manufacturing issues. The things that take away from the value of these researchers are things they have no control over. Like the Cargo Cult watchtower worker, the fact that the planes do not land has little to do with what is going on in the watchtower. It's something else. You can go back to watchtower school or you can work a little harder to find out why these things keep happening. 75 people at BMS, 160 at Ariad, 500 R&D jobs cut at Novartis... Just another week in the Cargo Cults.