I haven’t spoken much about the drug research that is taking place in ALS Land, not because I don’t have skin in the game. I am in the open label phase with the Biogen Idec dexpramipexole trial, and although we haven’t been unblinded yet, the rumors are rampant. There are other trials as well, one in Phase 2 that looks pretty interesting, and a seriously hyped stem cell trial in Phase 1. Before ALS, I never thought about drug research. That has changed in the last two years, although I don’t claim deep knowledge. In terms of drug research, I think exploration of intents and unintended consequences is instructive. More specifically, how the larger interests of dis ease research, oversight, investment and profit affect me is something that I take very personally.
In ALS Land, the race is on for anything that will supplement the only drug currently approved for treatment. That drug, Riluzole, was approved in the 90’s with less than stellar effects, but enough to throw us PALS a bone on the drug front. Our reality is that in the 73 years since Lou Gehrig was diagnosed, no other drug has been developed. There is a clear sense that this reality could change. The three specific drugs or treatments mentioned above have us buzzing, and one of the drugs, NP001, has really caused a stir among the PALS community to the point of developing self-treatments.
The methodology adopted by the FDA in coordination with the scientific community for approval of a new drug is designed to keep the public safe and to definitively show that any positive effects are both significant and resultant of the drug. The development of any drug requires hundreds of millions of dollars in resources—gargantuan infrastructures that can only be supplied by Big Pharma or the federal government. This means that the entrepreneurial researcher-developer can only take a new idea so far, usually through Phase 1—determining safety and possible dosage, and perhaps to Phase 2—establishing whether a belief in the drug’s efficacy is well founded. Phase 3—the gold standard randomly assigned, double blind, placebo controlled (meaning neither the researcher nor the participant know who is on the drug and removing the possibility of placebo effect), is almost always beyond the resources of start up or small operation entrepreneurs. It is in Phase 3 that all promising ALS drugs have not been just downed, but crushed. Thus, any drug that makes it to Phase 3 now attracts high interest, even though Phase 3 has not been kind to possible ALS drug treatments.
As an example, Biogen Idec paid 80 millions for the rights to dexpramipexole and took on the cost of a Phase 3 study with 900 international participants at 82 domestic and 10 international sites. I don’t know the cost of the dex study, but I do know that Research and Development costs for Biogen were reported at over 1.25 billion in 2011 for all the trials they were running. That represented over 26% of their revenue. Biogen Idec is into Knopp, the drug’s developer, for up to 265 millions if the drug makes it through the regulatory gauntlet. All these figures illustrate the point that it costs a pile of money to develop treatments; thus introducing two specific considerations to the process–profitability and perseverance.
Clearly, there are two sets of desired outcomes. The first is that we need more research and drug development in ALS. This is the outcome I care most about. It is literally killing me that we have nothing beyond Rilutek, the drug name for the Riluzole compound. And Rilutek is expensive. If it was not covered by insurance, I know I would probably not take on the 4300 dollar per month retail cost. So that brings me to the second outcome that must align for a drug to be made available. It has to show potential for profit. Biogen estimates that their return on dexpramipexole could be as high as a billion dollars per year, representing an additional 20% in revenue over 2011 figures. No wonder they are willing to put out such huge amounts of money. And you can only imagine the costs and returns when you get out of the orphan diseases like ALS and into something like diabetes or breast cancer.
Stay with me; there is a point to all of this.
I need to establish a context for the way things are and why it would be so difficult to construct new ways of seeking effective treatments. The current system is a Holy Alliance of government oversight, scientific rigor and capitalism. Each fulfills a role that, when it works, can be very powerful. We have seen great results of this triad in such areas as space exploration, food production, technology, and healthcare. But as so often can happen, it is easy to emphasize one side over the other two. And right now, it is hard to tell which–science, government or capitalism–has the upper hand. If we overplay the science, then research for the sake of knowledge; brittle in its method, religious in its commitment, closed to further development, oblivious of the human costs its liturgies exact, is the result. Overemphasis on regulation unnecessarily drives up costs and delimits access. Too much attention to the bottom line means that the goal of new and more effective treatments can be lost to the call of profit. When you consider the enormous resources brought to bear, the delicate dance that must be affected in order to bring a new drug to market is breathtaking.
See anything missing?
The Holy Alliance makes it easy to lose sight of the lives most affected by dis ease. What happens if a startup has a good idea, gets it into phase 2, shows some efficacy, not a home run, not enough to attract the deep pockets of Big Pharma, but some? Probably nothing, and that is the point.
An orphan disease like ALS, with the complexity of its manifestations that we are just beginning to understand, is not susceptible to a knockout drug. More likely it will be some drug combination, each compound fulfilling a specific role in a mighty cocktail targeting everything from genetic propensities to the macrophages that are eating axons to the energy needed to keep motor neurons alive. The current model does not encourage the kind of iterative approach that complex dis ease requires. There isn’t enough profit, science does not like so many variables, government is uncomfortable with the regulatory complications a cocktail will require. The current model engages three partners, none of who make dis ease management their primary concern.
Please recognize that for each of us already diagnosed, it is too late. Even though hope is always present, it is not really possible for a drug to develop and then be brought to market in time for us unless we are in a trial. The realities of a system designed for blockbusters combined with the cross purposes of profit, regulation and science, plus the fact that those of us who live in the dis ease milieu have very little voice in actual research decisions, points to the surety that our fates are sealed by such a lack of creativity. It is fundamentalism at its best–the religions of science and regulation and profit unable to conceive of new liturgies through novel methodologies or yet conceived ways to analyze and reanalyze data, because there is no reason except the dis ease to do so.
Which brings me to the title of this essay–“Grudge Match.”
The Google definition of “grudge match” is “A contest or other competitive situation involving personal antipathy between the participants.” I admit my own bad feelings, dare I say grudges, for systems that have calcified with the inevitable drift toward self-service that all bureaucracies experience. And I freely admit that my understanding is incomplete. But I would point to two salient facts that the system is not as robust as the billions of dollars it costs. First, there exists a Phase 4 in the drug approval process in which follow up takes place, and there have been some major clunkers revealed by Phase 4 analysis—hormone replacement therapy comes to mind. Secondly, a system that slaves to market forces will always yield drugs for male erectile dysfunction over orphan disease management. Neither of these bodes well for complex human dis ease conditions.
As a choral artist, I am well aware of the creative possibilities humans can forge together. Perhaps we need to place as much emphasis on researching new, more robust and creative methodologies, achievable with the resources of an entrepreneur. Perhaps we should make it the rule rather than the exception that members of different disease communities have much more to say about the direction of research.
Or the system could work and I swear, all grudges would be forgiven.