Epigenetic drug development hits a road block

Epigenetics is getting a lot of traction these days. There are many reports in the literature of new discoveries, and there are numerous drugs in clinical trials. However, as was pointed out at a recent symposium (Third World Epigenetics Summit, Boston, July 24-26), the biggest barrier is the move from oncology to other disease indications. These include cardiovascular, immune dysfunction and diseases of the nervous system. While there are many basic science papers on these topics in the literature, no drugs have advanced to phase 3 trials. The fact that cancer is better understood on a molecular level than various other critical diseases means that model building for therapeutics is more straightforward in oncology. This gives an important advantage to this discipline, which allows it to proceed more rapidly. This situation will likely continue for the next few years.

I have just completed a marketing report for Kalorama which will appear within the next few weeks. Please contact me if you are interested in learning more about this expanding field of drug development.                                

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Startrek comes to Purdue University

As I mention on my web site, I have written a number of marketing reports over the years on a range of topics. Most of these reports describe various companies, their business strategies, their products and outlooks for the industries which are profiled. I frequently interview scientists and members of the business community, as I did in a report published last year on mass spectrometry (http://www.insightpharmareports.com/Mass-Spec-Report). Perhaps the most exciting encounter was with R. Graham Cooks, a professor at Purdue University.
Cooks described to me an amazing advance in mass spectrometry technology that he and his students are building, a hand-held device that can identify molecules from a distance. Ordinarily mass spec analysis requires that a sample be introduced into a vacuum chamber where it is ionized and its precise molecular weight is measured by deflecting the molecule through a magnetic field. Since no two large protein molecules have exactly the same molecular weight, the data can be fed into a computer which identifies the sample.
The devices being developed by the Cooks group employs desorption electrospray ionization or DESI, in which a solution is electrosprayed on a sample from a distance and molecules, dissolved in the solvent, are picked up by a handheld mass spectrometer which can identify them.
It’s easy to imagine the applications of a device that would be the size of the “Tricorder” on Star Trek, and could be miniaturized to the size of a cell phone. Medical diagnosis, food safety testing, quality control in manufacturing, environmental monitoring, airport security, the list is endless; all carried out rapidly and in the field.
Cooks believes that such devices could someday be cheap and ubiquitous; you can imagine checking out food quality at your local supermarket or water contamination in your swimming pool. Instantaneous, and practically cost free!
I asked Cooks when he thought such devices will be available in the marketplace, I guessed 10 years, but he cut that number in half.
It’s difficult to exaggerate the transformative effect that such devices will have on society.

An unusual Hollywood look at molecular biology

Hollywood offerings that take on epidemics invariably play fast and loose with the facts, so it’s refreshing to see one that adheres to rigorous scientific accuracy. Contagion (Warner; directed by Steven Soderbergh), which made the rounds last year, was produced in cooperation with the CDC. From viewing this film, their enthusiastic participation is hardly surprising. This production is well-crafted and suspenseful, concerning a catastrophic pandemic, caused by a meningoencephalitis virus. As the virus moves from host to host it recombines and picks up genome parts from various mammals that come in contact with one another in the course of food processing in China. By the time it enters the human population, it has acquired superbug status.

In this film there are no people turned into zombies, no pod people, no doomsday machine that destroys the human race and no scientists or pharma executives plotting evil schemes to take over the world. The film plays by the book and the conclusion is exactly what epidemiologists predict would happen if a virus were to morph into a highly lethal, easily transmissible agent.

However, I think the most interesting question raised by the film is not whether it is scientifically accurate in the way it depicts the unfolding of a modern plague, but what is the actual probability of such an event occurring. We really don’t know the answer, but we can make a guess, based on Baysian probability and the historical record. Assuming that conditions favoring epidemics haven’t changed that much in the past sixty years, the probability of a world wide epidemic caused by a newly-evolving pathogen, spreading like lightening through the naïve population is less than 1 in 60 per year, plus or minus the statistical error associated with this estimate. This clearly doesn’t include HIV/AIDS, which is not respiratory and is spread only through sexual contact.

This may not strike you as a very satisfactory answer, but unless such a cataclysm arrives on our doorstep, it will be the best that we can come up with.

Boozers are Choosers of Placebos

Boozers are Choosers of Placebos
There been a lot of talk lately about the power of placebos to produce health benefits, even when the subjects knew they were using a placebo. This makes establishing the positive performance of a drug candidate especially challenging, since a drug will not obtain approval if it does not exceed the performance of the “placebo arm” of a clinical trial by a statistically significant margin.This was noted recently in the trial of the alcohol dependence drug nalmefene.

The drug is touted as the first treatment to counter heavy drinking, and indeed the Phase III trial showed an impressive 66% reduction in total alcohol consumption. But the drug, which presumably eliminates the brain’s pleasure response to drinking, doesn’t fare so well when you shift from percentages to numerical comparisons with a placebo. In fact, in three different trials, the reductions in alcohol consumption and binge drinking days slid dramatically, but so did the behavior of those on the placebo and the results were statistically indistinguishable.

These observations are in line with a CBS 60 Minutes story (http://www.cbsnews.com/8301-505269_162-57380096/inside-60-minutes-placebo-story/) on placebos versus antidepressants, in which the psychologist behind the study stated that there was virtually no difference in response among patients in the two groups.

So what can we conclude from this? First of all, our minds are very powerful, perhaps so powerful that they may exert profound influence over the pleasure responses that drive our behavior. Secondly, without rigorous double blind studies that deliver large, repeatable, highly significant differences between the arm of the trial that gets the actual drug and the arm that gets the placebo, there is NO reason to adopt the drug in question. And finally we must accept the fact that there is not a shred of scientific evidence to support the alternative (“herbal”) medicine industry, since rigorous studies have never been done with such remedies.

A wide range of estimates of drug development costs

For years analysts have been kicking around the figure $802M as the cost of developing a new drug, inflation-adjusted to $1.3B today, based on a study by Joe DiMasi and colleagues (J Health Econ. 2003 Mar;22[2]:151-85). However, Donald W. Light of the University of Medicine and Dentistry of New Jersey and Rebecca Warburton of the University of Victoria in Canada scoff at this number and have published papers in which they claim the true cost is much, much less, perhaps $60M per drug. Now comes Matthew Herper who writes in Forbes that if you divide the R&D expenditures of the major pharma companies by all the drugs that received FDA approval over the last 10 years, you come up with an astronomical figure of $4 BILLION per drug.

As policy wonks are fond of saying, “this is clearly unsustainable.”

So we have a wide range, about two orders of magnitude. At the low end of the estimates, this figure would seem to justify raging against the pharma companies as greedy profiteers, while the high estimates, in the billions, would appear to vindicate the pharmaceutical giants for the astronomical costs of medicines, especially biologics.

My own opinion is that the high figure reflects some padding, but even if you factor that in, you’re still going to wind up with real sticker shock. And these numbers don’t take into account the contribution of the publicly funded research through NIH or private foundations.

The cost of failure is reflected in these figures; many, many drugs fail late and costly. Moreover there are challenges in developing therapies for complex and poorly understood diseases, combined with bad decision making on the part of the companies. However you slice it, the costs are unsustainable.

Eventually, technology will develop the tools for more foolproof screening, and basic science will discover the fundamental causes of diseases such as Alzheimer’s. But it’s not clear that this will come soon enough to prevent havoc to our healthcare system, which already is in difficult straits.

Stem Cell Scams

Probably one of the nastiest and most cynical scams in circulation are websites that promise cures for childhood diseases through the use of stem cell technology. There are lots of them, all over the world, but especially in China. They are pricey, charging huge sums for a treatment that has little chance of success, and can pose serious health hazards. There have been no documented cases of cures for these conditions, ranging from cancer to genetic disorders to spinal cord injuries. But numerous deaths are known to have occurred. A recent Reuter’s story states that the Chinese central government has ordered a halt to these stem cell mills, but it is unclear whether they will be able to enforce this ban, since many of the clinics are run by well-connected interests. In any event, desperate parents can find plenty of other outlets eager to take their money in Mexico, the Caribbean, Turkey and South America.

The CBS investigative program Sixty Minutes did an excellent story recently on a stem cell scammer, who is probably out of business by now. Unfortunately there is a legion who will take his place.

One of the most serious problems with the public’s understanding of stem cell treatments is the fact that bone marrow contains blood-forming stem cells, and these elements have been used successfully for years to treat a variety of hematological diseases, including cancer. This approach, however, is totally different from the idea of using embryonic or adult stem cell to treat genetic disorders or traumatic injuries. While this is an important area of investigation, it is years away from routine application. In the meantime, people hoping for a medical miracle had better consult reputable medical authorities before they trust their lives and the lives of their children to quacks and charlatans.

Inclusion bodies in the bioprocessing industry

Recombinant proteins are often produced for commercial ventures in E. coli, the molecular biology workhorse. However, foreign proteins are frequently improperly folded and are recognized as such by the bacterial cell, which responds by encasing them in inclusion bodies. This strategy may be a wise approach from the bacterium’s point of view, but not for the researcher, since it brings synthesis to a crashing halt.

But new technologies are available to combat this frustrating situation, developed by the company ProFoldin (www.profoldin.com/). According to research scientist Dr. John Shen, PhD., his approach is to isolate the offending inclusion bodies containing the mis-folded protein and refold them using their proprietary solubilization and refolding technology.

This still leaves the investigator with the challenge of determining that the protein is folded correctly. One can do this by measuring enzyme activity if your target is a known enzyme, but if you have an unknown protein, it will (by definition) have no function assigned to it. In that case you must use physical-chemical methods of characterization. With the aid of mass spectrometry and other tools, there are a number of special properties that will reveal the folded state of the protein. One can also determine if the protein is too large, as an indication of an aggregated, and therefore denatured condition.

You can check these techniques out in my report for Insight Pharma on mass spectrometry (listed in resources on my website).