A New Adventure: Developing Treatments for Liver Disease

The lack of recent posts here has not been due to lack of interest or work in the main interest areas I’ve written about here: oncology, diagnostics, genomics, etc. Rather, a new adventure, Hepatx Corporation (www.hepatx.com), has demanded all of the extra bandwidth I have. As the title of this site (Biology, Etc.) suggests, topics that might be discussed can range across the field of biology. So, I’m happy to share that I will broaden the range of topics to include stem cells, regenerative medicine, liver disease, and entrepreneurship. I’m sure other topics will be added, as needed.

A bit about Hepatx and what we are trying to accomplish. As it turns out, there is a very large need for new therapeutic options in liver disease. Alcohol abuse and various forms of viral hepatitis have exacted the largest toll, however, concern is rising that an epidemic of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is underway, which will increase demand for treatments for scarred and failing livers. Literally hundreds of thousands of people in the U.S. are affected at a cost of multiple billions of dollars. Still the only treatment that works is transplantation. We started Hepatx to address this problem with new therapies that can improve liver function for these patients.

I will continue to post discussion of oncology and diagnostics, since this is still an area of active interest. Hopefully the reader will continue to enjoy this, as well as the broadened discussion around novel treatments for liver disease.

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Is Helix DTC Genomics 2.0?

Just a few years ago there were several prominent consumer genomics companies, including 23andMe, Decode, and Navigenics. Due to low uptake, problems with industry image and quality, and regulatory woes the larger players have one by one discontinued pursuing purely personal genomics as their main business. Even 23andMe, the stalwart of the field, has recently begun to look rather pharma-ish with multiple deals to sell its data for drug development.

Illumina recently announced that it was forming a new company called Helix that will operate in the consumer genomics space. The company promises to provide a high level of access for individuals to their genome data by partnering with third party vendors to bring genomic samples to Illumina, with consumers exploring their data through an open marketplace of on-demand applications provided by Illumina’s partners. One of the first announce partners is Laboratory Corporation of America.

This looks to me like a large, reputable firm that has made its name in other aspects of testing and genomics stepping into a void. It appears the venture will bring the concept of consumer access to genomic information to a new level. I’m looking for this space to heat up with more entrants.

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Continuing Fallout from the Decision to Overturn Myriad’s Patents

I follow the genetic testing field and have watched the field’s developments since the Myriad decision on patentability of genetic sequences with great interest. One very interesting and very important question is whether the ability to patent naturally occurring genetic sequences,as in the case of the BRCA genes, would impede innovation or not. The argument is that patenting genes is good because that will spur risk taking and investment because of the reward of monopoly. The countervailing argument is that such exclusivity restricts innovation by blocking risk-taking work to move that area forward.

I have no problem with companies making a lot of money from their innovative work. But, as a student of genetic testing, especially in oncology, I have been concerned that the tight control Myriad Genetics was exerting over BRCA testing (see any of the numerous news stories about Myriad’s lawsuits against competitors) might be causing others to stay away from BRCA testing, as this behavior was intended to do. None of the other genetic testing companies with the capability to develop commercially successful competing tests would go anywhere near this field as long as Myriad was threatening to sue whoever does.

This story in Medscape suggests that, now that Myriad no longer threatens to sue, that innovative new research is being done, publicly. As this story suggests, improvements in BRCA testing using multigene panels (which had excluded BRCA genes because of legal concerns) may be the path to more accurate and useful genetics tests for breast cancer risk than the single BRCA gene tests Myriad was selling.

To me, this suggests that the original allowance of patents on naturally occurring gene sequences was overreaching and, in fact, stifled innovation. Our system was set up to hash these things out in just this way, so I’m pleased to see what appears to be a successful progress through the gene sequence patent issue. It seems very likely that more cool innovation will surface in the wake of this legal battle.

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Circulating Biomarkers Dundee 2014 a Success!

Circulating Biomarkers Dundee 2014 was a great success! The leadership of Ed Quazi and Elisabetta Fineschi of BioteXcel Ltd. made for a very productive two-day conference with many key leaders in the field from across the UK.  Participants agreed that the utility of biomarkers will expand in coming years and have a positive impact on cancer care.  See video of Dr. Schuur and other participants here discussing the conference.

The decision was made to make the conference an annual event.  See you all in Glasgow on September 1, 2015!

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Was the FDA Right to Shut Down 23andMe’s Marketing?

My opinion: the FDA was right to act in November by asking 23andMe to stop marketing  its personal genome service.  Now, don’t get me wrong, I have been rooting for 23andMe to succeed at what they are doing in the Consumer Genomics (CG) space.  I have been hoping that “opening the door to the genome” would produce some interesting new insights about biology that might escape traditional scientific inquiry.  I have been hoping, too, that taking genetic information directly to the people might further empower individuals in the health care system and begin to counter balance the medical profession and insurance companies.  However, once the FDA communicated to 23andMe that their offerings looked like a medical device to the FDA and would the company please take certain steps, 23andMe’s choice was really to comply or break the law.  Based on what’s public, the action by the FDA in November should have been no surprise to the company.

So, the real issue that many are unhappy about is whether CG should be regulated at all.  Should the FDA have categorized 23andMe’s personal genome service as a medical device in the first place? There is room for debate on that point, however, I think at that time it was a reasonable position for the FDA to take (remember, in 2010 the CG industry was not without controversy over quality and utility, at least according to the GAO).  Furthermore, the industry, including 23andMe was distributing what had for many years been considered medical advice.  Why should the CG companies get to ignore regulations that other diagnostic companies are bound by?  I, for one, am generally pretty happy to have an agency try to make sure that the medical products that I use are of reasonable quality.  That is not the case in other parts of the world.

Since that time things have changed.  Some studies have shown that CG info is probably mostly harmless.  It may well be time to engage more deeply in the conversation over what, if any, regulations should bear on genetic information.  While many are of the opinion that there is no harm to one knowing one’s own genetic code, I’m not so sure.  I can certainly envision in a large population some subset of people deciding to take their health in their own hands and making a bad choice based on erroneous genetic information.  Maybe we should let them do that.  Maybe that is really what we are debating in the guise of the 23andMe/FDA issue.

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FDA Tells 23andMe to Stop Marketing: Death Knell for DTC Genomics 1.0?

The FDA on Friday published a letter  addressed to 23andMe’s CEO, Anne Wojcicki, telling the company to cease marketing it’s Saliva Collection Kit and Personal Genome Service (PGS). In the letter, Alberto Gutierrez, Director of the Office of In vitro Diagnostics and Radiological Health, describes the many interactions the Agency has had with 23andMe, informing the Company of the need to comply with the regulations and attempting to assist the Company in doing so. He also describes how 23andMe did not fulfill their promises to provide information to the Agency. I’m kind of surprised that 23andMe did not work with the FDA, since it ought to be no surprise that the FDA would order 23andMe to stop, given their apparent lack of compliance. Hopefully we will find out more about why the Company thought they could ignore the FDA.

Two additional thoughts that this development seems to support: the final bell for DTC genomics 1.0 and FDA is going to regulate genetic tests. 23andMe was really the last prominent player in DTC genomics left standing, after Navigenics and deCode were purchased by big Life Sciences firms with no apparent interest in consumer genomics. It sort of confirms that the space of unregulated genetic testing with medical information packaged alongside is rapidly diminishing in size and probably won’t exist in this form for long. It seems likely that these technologies and products will end up being regulated and available largely via prescription. Score one for the medical profession. However, there may well be a next chapter written and it could have some interesting twists. Say, for example, a 23andMe equivalent offers that service from an international location. I think it will ultimately be hard to hold a lid on consumer genetic testing.

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Where are we with Targeted Cancer Therapeutics?

In a recent project, I received a draft manuscript discussing targeted cancer therapeutics and companion diagnostics in which the writer made this statement: ”CML patients in treatment with Gleevec now have the same life expectancy as people without the disease, while suffering few side effects”. I was aware that many CML patients respond well to imatinib (Gleevec), but wasn’t aware that imatinib effectively cured these patients, as this statement implies. If true, this is a stunning success. I am more accustomed to reports such as this paper on gelfitinib resistance or this one on imatinib resistance, which bolster the view that resistance to targeted therapeutics is essentially inevitable.

I took a closer look at the paper that this statement was apparently based on to convince myself. The publication that seems to have been the focu s of the attention that generated statements such as that above was published in the Journal of the National Cancer Institute in 2011. The first author, Caro Gambacorti-Passerini, and his colleagues analyzed outcomes in 832 CML patients who had been treated with imatinib. The figure that encapsulates this phenomenon is Figure 2 from Gambacorti-Passerini et al. J Natl Cancer Inst, 2011, 103:553, reproduced here:

Gambacorti-Passaro Figure

Panel A is the incidence for several types of leukemia/lymphoma, CML is indicated by black triangles; panel B shows mortality for the same diseases, with CML again indicated by black triangles.

Notice that the mortality of CML drop dramatically right around when imatinib was approved. We would like to do this with all cancers.

The caveat to the story that the writer in my project glossed over was that one of the enrollment criteria in the aforementioned study was that the patient be in complete remission at 2 years of treatment. That is to say, patients who did not respond to imatinib or relapsed prior to their 2 year anniversary were not included in the study. This criterion for participation means that this study examined survival of the patients with the very best response to imatinib. Now, it is still an impressive fact and excellent news for CML patients. It means that if you have a good response to imatinib, you are just as likely to succumb to another disease as to CML or, in other words, you have a normal life expectancy.

This got me to thinking. How are we doing with targeted therapeutics for cancer? Do other targeted therapeutics have a similar highly effective profile? Is the original statement that caught my eye just a narrow, subjective view of the situation for CML patients?

In upcoming posts I am going to take a closer look to see what lessons we might learn from this encouraging view of cancer therapy. I don’t think the effect will be quite as drastic for other targeted therapeutics, but I think it’s worth taking a look. Are those who respond well to some of these therapeutics essentially cured of their cancer? If not, what does the response look like and what does it say about where to go next. Stay tuned for future posts examining the impact of targeted therapies

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Gene Patents No More

As most of you know at this point, on Jun 13, 2013 the Supreme Court of the United States ruled essentially that native DNA sequences are not patentable subject matter.  The question ended up with the Supreme Court precisely because there are good arguments on both sides and, as you would expect, there was a lot of highly charged rhetoric exchanged leading up to the decision.  I’m not going to settle those questions here, but I did think it was worth a few moments musing about less technical aspects of patent issues.

I have tended to side with those who believe that gene sequences, at least the ones that exist in the body, should not be patented because they are a principle of nature—it just feels like giving too much away to me.  However, as one of the founders and early investors in Myriad Genetics shared in this article, without the monopoly guaranteed by a patent, investors would not have anted up to launch a company to develop the genetic tests, certainly not at that high risk time (circa 1991) when it was all but certain if these tests would be worth anything.  Others (e.g. this article have argued that the monopoly on the gene sequences that Myriad (and others, with respect thousands of other genes) have enjoyed have impeded progress in understanding genetic function and utility.

As with most persistent debates, both points of view are probably true in part.  From the perspective of the pro-patent camp, a large shift in how diagnostic products are developed that was necessary to bring tests such as these to market.  A huge promise of the human genome project was to provide for health care based on the sequence of an individual’s genome—personalized medicine.  But, it was a promise made, lo these many long years ago, when we really had no idea if it would actually work.  To get to market, we would need to generate a large amount of experience with these sophisticated new tests, the operating characteristics of which were largely unknown.  Would genetic prediction of cancer susceptibility actually work?  Would patients and doctors actually find the test useful?  Much different than measuring the number of white blood cells in a blood sample.

To get physicians and patients to order the tests, data on the validity of the tests was needed.  That required a lot of free testing to generate the data on the relationship between the gene variations and cancer incidence.  Myriad Genetics, as well as Genomic Health and other vendors of gene-based tests, have invested heavily in clinical validation of their tests in order to convince patients and physicians of their value.  Investors paid for much of this and patent monopolies were their reward.

On the anti-patent side of things, I wonder if Myriad Genetics has shot itself in the foot by jealously guarding its monopoly and appearing to be greedy (even after the Supreme Court decision, Myriad continues to aggressively pursue its perceived monopoly, see this article).  Stanford University and UCSF famously structured their genetic engineering patents to allow broad-based licensing, winning high levels of praise for licensing savvy and social conscientiousness.  Their patents did not meet the raucous challenges faced by Myriad.  In contrast, articles such as the one mentioned above  and this article decry the excessive costs imposed by companies of not only diagnostics, but therapeutics, as well.

Now I haven’t sat down and poured over Myriad’s (or anyone else’s) financial statements to ascertain if they really need to charge $4000 per test to recoup their investment and earn a reasonable rate of return for their investors.  But, what is clear is that that $4000 number is very high compared to what the world is used to paying for diagnostic tests.  It probably would have helped Myriad if they had been more transparent about why they needed to charge that amount, given that their soon-to-be competitors are planning to charge under $1000 in some cases.

Since that our government grants patent monopolies for the betterment of our society in general, I wonder if it might be prudent for companies and other patent holders to consider public reaction to how they handle the right to charge what the market will bear.  If the public perception is that the patent owner’s behavior is not in the best interest of society, they may be sacrificing goodwill, which ultimately, in closely watched cases, such as this one, might tip the balance one way or the other.

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DTC Genomics: Opportunity Lost?

Once I warmed up to the idea of startup companies offering to sequence the DNA of anyone capable of ordering from Amazon.com, I began to look forward to what might come of this nascent industry. Enabling individuals to have their DNA sequenced certainly seemed like an out-of-the-box idea at the time. I wondered if a so-called paradigm shift might arise from placing genetic information, unfiltered and unadvised, in the hands of those whose genes were being sequenced. Here were (and still are) two of my chief hopes for paradigm shifting that might come from throwing the genetics box wide open:

  • Will breaking the “chain of command” on health information change how we think about healthcare? The initial response from the medical world to the DTC genomics industry was less than enthusiastic, ostensibly because of the potential for harm when the uninformed masses got their hands on their gene sequences. This turns out not to be true—there is no evidence of harm from accessing one’s own DNA sequence information. Furthermore, there has been neither a flood of buyers nor a spate of lawsuits. The collective yawn over the availability of DNA sequencing (initial excitement not withstanding) suggests this might be more of a step along the way than a cannon shot.
  • Will putting this information in the hands of all who wish to know change how we think about genes? Over the last 60 years we have become quite genocentric in our view of biology. Genes are the “blueprints of life”, an identifiable “first cause” that drives everything else in the living world. For example, the term “oncogene” suggests that we have genes whose purpose is to cause cancer. That is possible, of course, but that suggests that there is some advantage to the organism to develop cancer, which doesn’t seem likely. As I think of it, genes are a part of a system we call an “organism” and they are no more or any less important than proteins, carbohydrates, etc that comprise that organism. It may be that not all of the diverse causes of cancer are genetic and we need to take a more holistic view of disease pathogenesis.

Essentially, what I am hoping for with the emergence of the DTC genomics industry is that the “hive mind” might provide new direction on genetics and its role in health and society. We might get really novel answers to thorny genetics questions like “what happens to missing heritability and is it important anyway?” Might it also be enough of a nudge to permanently put the paternalistic relationship between physicians and patients in the past? My hope for the DTC genomics industry is that it will help us reach a more balanced view of the role of DNA in living organisms.

However, for the moment at least, it appears that the wind is going out of the sails of the industry. As evidence, here are some recent developments:

  • Over the summer Navigenics was bought by Life Technologies, Inc. Gone was an industry pioneer.
  • This fall, deCODE was bought by Amgen. Not a surprising end to deCODE’s rocky road, but gone is another industry pioneer.
  • Recent developments announced by 23 and Me (patent received, grants funded, seeking FDA approval for products) sound suspiciously conventional. Has 23 and Me lost its will to break the mold?

Will there be a DTC genomics industry 2.0? The failure of pioneering companies in any new industry is not unusual. Yet, I am hopeful that these shifts will still happen. It seems likely, though, that it will be new companies that move the field forward and that (as usual) it will take longer than it initially seemed it would.

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Time to Rethink Cancer Therapy?

In an earlier post, I wondered a bit about the ultimately causes of cancer.  For the last several decades cancer has been labeled as a genetic disease, an idea which we have chased with great fervor.  Yet, It feels to me sometimes as though the evolving story of the causes of cancer is like a hall of mirrors in an amusement park in that there seems to be an ever receding chain of causal genetic alterations fueling cancer’s inexorable progression.

The most visible of these alterations are in the growth modulating molecules of the cell.  Over expressed growth factor receptors or transcription factors, mutant signaling molecules, etc.  How did these components come to be broken?  Genetic insults of various kinds have been discovered, studied, and labeled as causes of cancer.  We are actually getting pretty good at intervening in some of these malfunctioning growth pathways that have been co-opted by cancer.  For example, antibodies that block the activity of HER2, the human epidermal growth factor receptor that seems in some cases to drive breast cancer proliferation are quite effective.

Yet, even when we do intervene with seeming effective tools, such as trastuzumab for HER2 over-expressing breast cancer, the cancer seems in most cases to rebound by activating still other pathways of growth.  It has come to be reminiscent of the proverbial leaky dike and us with not enough fingers to plug the leaks.

The genomic instability that is so characteristic of most cancers seems to be the driver of genetic diversity that provides resistant variants.  It appears that cancers “evolve” to a state of significant heterogeneity and the genomic instability seems to be a player in that process.  But, where does the genomic instability come from?  We can then propose a change in cells that causes genetic instability.  But, where then does that come from?  See what I mean?

This genetic, linear causation idea is the foundation on which our cancer therapy strategy is built.  Naturally, our combat strategy is direct.  Cut it out.  If you can’t cut it out, hammer it with chemicals or radiation.  If a little doesn’t work, then try a lot.  Too much cell division and DNA replication? Inhibit DNA replication.  Too much RAF signaling? Inhibit RAF signaling.  Battle this problem where it occurs: inside the cancer cell itself.  This strategy has produced some remarkable results; however, for most cancers, the fact remains that some cells inevitably escape destruction to arise as an even more fulminant tumor later.

The feeling of frustration in chasing cancer up the path only to have it resurrect out of seemingly nowhere still further upstream is a signal to me.  I have sensed in this frustration a signal to think about cancer pathogenesis and treatment in new ways, like I’m sure others have.  Recently I have been gratified to hear a number of researchers propose new views of what cancer is and new strategies for treating it.

I have been a member of a tumor microenvironment interest group for a while, mostly to keep an ear to the ground in that area.  Having spent many years trying to grow cancer cells in various ways, it is clear to me that they depend heavily on their microenvironment to survive.

Over the summer I noticed a few publications (see this news story in Nature Medicine for more details) suggesting that resistance to chemical therapy may be mediated by more than just the response of the tumor cells.  These studies suggest that the tumor microenvironment may provide protection from anti-cancer agents by secreting of growth factors from stromal cells intermingled with the tumor cells.  In one study, WNT16B growth factor secretion was induced in stromal fibroblasts, which in turn protected the cancer cells from programmed cell death.  In another pair of studies (here and here), stimulated secretion of hepatocyte growth factor from stromal cells attenuated the sensitivity of melanoma cells to BRAF inhibitors, one of our newest targeted therapeutic classes.  It seems that the effects of treatment are more complicated than we had thought.  Our cell-autonomous approach to drug development is probably too simplistic.  In retrospect, it seems obvious that we should account for the effects of other cells that, with the tumor cells, create the environment in which the cancer develops.

Rethinking cancer therapy has been proposed by Robert Gatenby and colleagues for some time now (see, for example, their article in Cancer Research in 2009).  Over the summer, Gillies, Gatenby, and colleagues published another paper describing how these concepts impact targeted therapy as progress in cancer therapy.  These folks have brought concepts from evolutionary biology and the control of invasive species to bear on cancer therapy.

Gatenby and colleagues describe a model for how evolutionary dynamics operate in the tumor microenvironment: phenotypic diversity, courtesy of genetic instability, provides the substrate for selective forces, provided by cytotoxic drugs, resulting in selection of tumor cells that can survive almost any insult.  Under this scenario, toxic drugs will select for some variant that will then proliferate to fill the niche vacated by the cells killed by the therapy.  Adaptive therapy is described as a potential solution to this problem.  In essence, adaptive therapy uses interventions that strategically impose a substantial evolutionary cost on cancer, thereby reducing its fitness to survive and ability to adapt to its new environment.

A high evolutionary cost means that interventions are difficult to evolve around.  To illustrate what these might be like, they draw examples from control of invasive species.  Might cancer be better handled as if it were an invasive species?  Two points that they make are 1) that eradication is often not possible and control of population size is the goal; and 2) the high-evolutionary cost interventions are often biological.

Although the cancer genome is an important component of the disease, it is becoming clear that there are additional facets of the disease, such as the interaction of the cancer genome with genomes in its environment.  Consideration of the role of tumor microenvironment modulation of therapy is a welcome expansion of how we think about cancer and our response.  Likewise, radically new strategies for cancer therapy, possibly like adaptive therapy, are welcome, as well.  Incorporating these new concepts into our view of cancer helps put us on the path to effective new treatments.

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