Here is an interesting article published by the MDA magazine Quest that details why it takes so long for a drug to go from mouse models to people.

Mouse to Man


Article Highlights:

MDA Director of Translational Research Jane Larkindale, Ph.D., offers a look inside the drug discovery process, and outlines the steps of the preclinical development phase, which takes a significant amount of time.

The pace of research is slow because a treatment that may be effective in a mouse model can't move directly to a human clinical trial.

Although frustrating and long, the drug discovery process helps to ensure that a drug will pass through each testing phase, and ultimately be effective and safe in people with neuromuscular diseases.

For a perspective that is different, and in my opinion much better, check out the following article about Andy Grove and his views on research.

Andy Grove story

Grove is the retired CEO of Intel Corporation and was diagnosed with Parkinson's disease. He became frustrated with slow progress of research and applied his CEO skills to speeding things up. Here's a sample quote:

quote:

In 2001 Grove and a doctor friend at Stanford University sent a letter to NIH director Elias Zerhouni with advice on how to organize NIH research grants around different diseases, including Parkinson's. "I put my heart and soul into that letter and got no answer," says Grove. It was around then he began to get angry about the lack of urgency in Parkinson's research.

Grove spent 35 years in a company that depended entirely on its ability to develop a newer, faster version of its previous product every year. "In my experience people who are getting a chip ready for production are absolutely absorbed in it and driven to meet the deadline." Medical researchers, in his view, lack an urgency to translate basic research into practical tools. The NIH spends $200 million a year on Parkinson's. Yet the mainstay drug, levadopa, which stimulates the brain to produce more dopamine, is 40 years old and provides only symptomatic relief.

As both a person with SBMA and a taxpayer, I share Mr. Grove's outrage about the slow pace of research, the lack of urgency, and the amount of money that is spent with no results.

Thanks for the balancing perspective Dan. It is good to see this issue from multiple perspectives. It is frustrating to see possible drug treatments take several years to get to human trial. Especially when you live with a degenerative condition.

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Thanks Dan for your excellent post. As it is so often, it seems that we have the wrong man in a position of responsibility.
Graham.

This is always an interesting subject ... one that I have written about a couple of times in my "Living with Kennedy's Disease" blog. There are definitely two sides (or more) to the story.

I have quizzed senior researchers on this subject. They, like us, would love to see the process streamlined except for certain needed check points for safety included. In my opinion, the primary reasons for the long testing process are: safety and politics.

Being part of the KDA, I read emails and posts about people with KD that are buying drugs from third world countries and taking them without prescriptions or discussions with their doctors. This concerns me deeply.

I can understand the frustration of not having a treatment ... I have been there and feel that way for my children, grandchildren and great grandchildren. Yes, most of us would do almost anything for a proven treatment.

Patience was something I was not born with nor developed. I am 65 and my hopes are now for future generations. At the same time, I would hate to see patients dying or having other bad side effects because a drug was not thoroughly tested.

As a person with KD, I can understand the frustration that Grove feels with regard to the rate at which treatments for Parkinson’s are (not) produced. As indicated in the article, Andy Grove has a very successful career – with the pinnacle of his success being CEO of Intel. I think that it is this very success that leads to his frustration. As a leader during the computer revolution, his company is known for its innovation with regard to the production of computer chips. He now is trying to bring the organizational lessons he learned at Intel to medical research. From his comments in the referenced article (see an earlier post in this thread) as well as other articles about him, it appears that he believes that the problem with medical research is one of organization and urgency. In my opinion, he grossly underestimates the problems with finding a cure for Parkinson’s Disease (or any other neuronal degeneration malady such as Kennedy’s). What Intel does is make is very, very small transistors (essentially), a technology that was discovered in the middle of the last century. The primary focus of Intel was to make an existing technology much smaller. While this may be a difficult proposition, it is essentially a technical one – they did not have to create ‘new’ science, did not need to discover. The concept of a cpu is essentially the same as 40 years ago, they have simply been made much smaller.
This is not true for medical research on neuromuscular diseases. No one has yet even determined exactly why the cells die in such diseases, much less how to stop the cell death. This is not due to lack of money, effort, organization or urgency, but because it is a very, very difficult problem. Each cell is have thousands of machine-like molecules called proteins and each protein has a specific function in the cell. Of these thousands of proteins, it is not obvious which are important for keeping the cell working properly – or even how they keep the cell working properly. Within the brain alone, there are thousands if not millions of different types of cells, each with their own function and specific set of proteins. KD (or PD or HD or ALS etc.) all cause a small subset (and this subset is different in each disease) of these cells to die. It is not understood what specifically makes each cell type different or why only some neurons die in each of these diseases or, in fact, why any nerve cells die in these disease. It is very difficult to find a cure for KD when it is not even understood why the cells die. One of the first steps to understanding why a cell dies in KD is to understand how the cell works – thus understanding the role of each of the proteins have in the cell. We do know that in KD, the defect is originally in the protein called the Androgen Receptor (AR) and somehow (no one knows how despite extensive research) this leads to some specific nerves cells to die. To figure out the molecular cause, it is necessary to figure out all the possible interactions that AR can have and try to tease out the one that causes the cells to die. The AR interacts with hundreds of other proteins, which of these interactons is relevant for KD? No one yet knows. This is akin to finding a specific hay strand in a haystack – it is a very difficult problem and despite our wishes, it takes time to work this out. I will not even touch on the time it takes to test a treatment in such a slowly developing disease.
There is another issue should be understood. Suppose that someone develops a treatment for KD tomorrow. What would this treatment do? Most likely, it would prevent the nerve cells from dying. It is extremely unlikely, however, that it would regenerate new nerve cells (this is technology that is quite futuristic). Thus, those of us with KD that has progressed will not have our symptoms reversed – we would just stop the current downward progression. While this would be a tremendous development, we would still have KD symptoms. (sorry for the long post)

Ed, thanks for the information. I marvel at the complexity of even a single cell, never mind an entire organism such as a human... my high school bio teacher did not do it justice!

About nerve regeneration... can't nerves regenerate on their own? A few years ago I had bells palsy (a condition where a nerve controlling facial muscles was damaged and incapacitated 1/2 my face). The nerve did recover and I have my natural KD smile back! :-\ Also, what about the news of Peyton Mannings neck and shoulder nerve cells needing to regenerate after his surgery. Are these both cases of nerves simply repairing themselves?

The long cell processes from nerve cells (called axons) have some ability to repair themselves - this ability is generally restricted to axons outside the brain and spinal cord. Both of your examples are of like this.

In the brain/spinal cord, the ability to regenerate is greatly diminished - damaged spinal cords do not regenerate, as an example.

In KD, there are a couple possibilities with regard to 'fixing' what is broken. If the nerve cell has died (and this occurs in the brain and spinal cord in KD), there is no natural way for that cell to be replaced. It is possible that stem cells could replace these cells but this is not likely to be possible in the near future. If could also be true that nerve cells get "sick" prior to dying - in this case, it may be possible to cure them. If such a treatment is found, then it may be possible to get some functionality back but it is likely to be minimal (I expect we would appreciate any improvement!).

Bruce wrote:

quote:

In my opinion, the primary reasons for the long testing process are: safety and politics.

He is exactly right, but I'd add: bureaucracy and fear of lawsuits.

The real Catch-22 of medical research is that the FDA approval process is enormously long and expensive, therefore only newly-invented, patentable substances can be approved. If an existing, natually-occurring substance has a beneficial effect, it is very difficult to get news of this to physicians and the public.

A classic example is the naturally-occurring, inexpensive melatonin, which is helpful for insomnia and jet lag. Yet if you go to your doctor for insomnia, you will get Ambien, Lunesta or Rozerem, which are expensive and have numerous side effects. The latter three have been pushed through the expensive FDA approval process by pharma companies, but melatonin hasn't.

Apply this same notion to our disease. Suppose, just hypothetically, that high-absorption curcumin had a benefit for SBMA. (Not a cure, but perhaps it helps to degrade androgen receptors and therefore postpone the process of neuron death.) The problem is, you will never hear about it, because there is no one to push it through the FDA approval process; and your doctor will never recommend it, because it's not FDA-approved.

As I said, that's really the Catch-22 of medical research.

There's another good story about Jack Dreyfus, a retired CEO who got relief from debilitating depression by taking an older, non-approved drug. He spent years trying to get the attention of the FDA and the maker, but they completely ignored him. The story is documented in his book, entitled "A Remarkable Medicine Has Been Overlooked". Here's a quotation:

quote:

For forty years, Jack Dreyfus has dedicated himself to disseminating information to the public about phenytoin, which has been found useful for over eighty symptoms and disorders, and is currently being used for a wide variety of conditions in nearly thirty countries around the world. However, because of a flaw in the way the government brings medicines to the attention of the public, the drug is still listed for only one use in the United States.

It's sad that the talents of people like Grove and Dreyfus can't be applied to the problems of developing medicines.

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Here's another story, this one about a person with ALS who was frustrated by the slow pace of medical research. Here's a quotation:

quote:

It is an accepted part of scientific lore that scientists sometimes use themselves in experiments, and cancer patients and others with life-threatening illnesses are known to self-medicate using concoctions of vitamins, special teas, and off-label medications. But the efforts of patients with ALS to come up with a home-brewed version of a drug still in early-stage clinical trials and not approved by the FDA is one of the most dramatic examples of how far the phenomenon of do-it-yourself science has gone.

I emphasize that I do not suggest trying to develop and inject your own drugs as Eric Valor did in the story when facing death. However, I wouldn't discourage anyone from reading up on oral high-absorption curcumin either.

From Dan: Apply this same notion to our disease. Suppose, just hypothetically, that high-absorption curcumin had a benefit for SBMA. (Not a cure, but perhaps it helps to degrade androgen receptors and therefore postpone the process of neuron death.) The problem is, you will never hear about it, because there is no one to push it through the FDA approval process; and your doctor will never recommend it, because it's not FDA-approved.

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I am not sure this would be true. I am no economist but I do know that it is quite expensive to get a drug to market. While there may some actions that can streamline the process (and drug companies may be evil), it is still going to cost money to develop as well as test the efficacy and the safety of any drug and this money has to come from somewhere. The way I see it, money for drug development comes primarily from two major sources, drug company profits and the government (there is also money that comes from private foundations – I will group these monies with the government source). In order for a drug company to invest in the development of a drug, the drug must have the ability to make money. Otherwise, the drug company will not make a profit and the company will go bankrupt – this is good for no one. What this means, I think, is that a drug for a rare, non-fatal disease such as KD is not a likely candidate for development by a drug company as it would not be able to sell enough of it to economically justify the money spent in developing it. If this were the only method of subsidizing pharmaceutical research, those of us with KD would be out of luck and be even more bitter than we currently are. However, the government (along with various private foundations) also fund drug development and their motive is not profit driven. NIH (for example) does not care if the development of a particular treatment is economically viable, thus they are willing to invest in disease treatments that a ‘for profit’ company would not. KD is an example of such a disease. There are an estimated 5000 men in the US who have KD (if that many). Despite the low numbers of those with KD, the KD research community is well funded (imo).
There are presently several clinical trials sponsored by NIH that do not involve costly pharmaceuticals. For KD, there is currently a clinical trial examining the effect of exercise – not sure one can get cheaper than that;-). For Huntington’s disease, NIH has several trials running, one using coenzyme Q and another using creatine, both of which are inexpensive, over the counter chemicals. I would suspect that the reason that curcumin is not studied has more to do with the fact that it did not show any interaction with the androgen receptor as ASC-J9, a chemical derived from curcumin, did and ASC-J9 but not curcumin was shown to be effective at treating KD in mice.

From Yang, Z., Chang, Y.-J., Yu, I.-C., Yeh, S., Wu, C.-C., Miyamoto, H., Merry, D. E., et al. (2007). ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nature medicine, 13(3), 348-53.
“Collectively, the results demonstrated that ASC-J9, but not 17-AAG, classic antiandrogen hydroxyflutamide (HF) or curcumin , can selectively promote AR degradation, which might be secondary to disrupting the interaction between AR and AR coregulators, which results in the suppression of AR transactivation.”

Regeneration of neuronal cells is not as futuristic as it might appear. They are regenerating brain neurons in England using stem cells.
I do agree that the biological problems tend to be more complex than an isolated physics or engineering problem. However, that's not to say that the biological research might not be enhanced by a different approach.
As far as "hundreds of proteins" interacting with the AR cells, it seems like this is a research problem made for a microarray investigation -- where many interactions can be tested simultaneously.

Here is another good drug research story, which gives an optimstic slant on the following issues:

quote:

The clinical trials for rare disease drugs are shorter and have fewer patients, so the cost is lower.... There are a number of other advantages enjoyed by the rare-disease space. The Orphan Drug Act in the U.S. provides a 50 percent tax credit for the development of drugs that treat diseases affecting fewer than 200,000 patients. Drugs for rare diseases also enjoy an easier road to U.S. Food and Drug Administration approval....over the past five years, 22 percent of orphan drugs submitted to the FDA gained approval, versus 16 percent of drugs overall. There is also a large swath of unexplored territory....there are 7.000 rare diseases and only about 200 drugs on the market.

All of that sounds like good news for research into rare diseases including ours.

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