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Sunday, September 29, 2013

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).
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. 

Friday, September 27, 2013

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 FovistaTM 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, FovistaTM 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 FovistaTM 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. FovistaTM exhibited a favorable safety profile and no significant safety imbalances were observed for FovistaTM 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?

FovistaTM 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 FovistaTM to induce pericyte stripping from newly formed blood vessels, the administration of FovistaTM 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.

Wednesday, September 04, 2013

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.