All Good Gifts

It is that time of holiday truce between Thanksgiving and Hanukkah and the season of Advent, and I am reflecting on the many gifts I have received since my rebirth in ALS. In my three years since diagnosis, it has been so rare to feel like there was something I could do about my physical regression. I have gotten used to the idea that, as one of its gifts, ALS takes and all I can do is anticipate the loss. This is been borne out by experience, for example my mobility has regressed from walking with the support of a cane to a walker to using a scooter and now spending most of my time in a power wheelchair. The decline of my physical capabilities has been inexorable, and the challenges have become, especially in the past three months, exponentially iterative – one multiplied on top of another on top of another. It should be no surprise that I had come to the point where I despaired that anything I might do in anticipation would be totally palliative in nature, holding off the inevitable and trying to maintain where I was for a few more days or weeks. I had come to despair that nothing would result in my feeling better, that each day would be a little closer toward death, that the best I would ever feel would be right now, because the nature of ALS is to feel worse and worse and worse. Thankfully, in the past month that situation has changed.

In June, I was tested for diaphragmatic strength and phrenic nerve function to see if I might be a candidate for a diaphragmatic pacing system or DPS. Much like a heart pacemaker, only with the power source outside of the body, the diaphragmatic pacing system stimulates the diaphragm causing it to contract and not so gently forces the person to haul in a large breath of air. The DPS was first approved for persons with spinal cord injuries as a way of weaning them off of a ventilator. Aside from the initial surgery to place the electrodes in the diaphragm, the DPS is far less invasive and requires much less maintenance than a ventilator to keep it going. Over a year ago, the Food and Drug Administration approved the DPS on a compassionate care basis for the treatment of ALS. I have been watching with great interest other brothers and sisters in ALS who have had the DPS installed, and I have been doing a great deal of research on the pluses and minuses of the system.

Having passed the June test, it came down to waiting for my breathing to deteriorate into the treatment window that Mayo uses for its protocol, and to file with my insurance to see if they would support the procedure. Those two events came together in mid – October, and I had to decide quickly whether I would do the procedure or not. One reason you might not go through with the procedure is that the surgical team is not sure whether the DPS can be implanted until they have you open and they can stimulate the diaphragm directly. If it contracts, all systems are go; but if it does not, then they close the incision and send you home. I have had enough disappointment already, so even as I scheduled the procedure at Mayo, I steeled myself for the distinct possibility that my diaphragm would be too far gone for the procedure. But it was a rousing success. On November 14, I had surgery to install the diaphragmatic pacing system, and on November 15, I began the process of calibrating its stimulation to the wide smiles of the medical staff.

And here is the first gift.

I feel better. I am breathing more deeply, tolerating the electrical shock to my diaphragm very well, getting used to speaking around the delivery of the shock, and ironically, in spite of fatigue from the surgery, I have more energy. Unlike every single palliative intervention that we have made in the past three years, the DPS has actually helped me experience improvement. I am even sleeping more soundly, though not with the device, and my voice feels stronger than it has in a number of months. What a joy to experience any physical improvement.

Gospel! And there is more.

I have managed to solve some communication problems that I was having before the surgery. With the loss of hand and arm strength, I had lost the ability to use an iPad, to manipulate both the speech to text software I was using, and the smart house technology that I relied upon for basic functions such as turning on and off lights or music or other devices. In the past month I had despaired that I would be totally reliant on another person in order to accomplish such basic tasks. And to be truthful, I am so reliant on those who are with me for such simple things as straightening my fingers, placing my hand on the joystick of my wheelchair, or doing a bit of range of motion just to relieve the physical effects of ALS. But in communication, with a stronger voice and new technology workarounds, I am beginning to find a bit more of that independence that I value so greatly. Using an actual laptop computer instead of an iPad has allowed me to interact totally by voice, and while I am not back to 100% of what I was, the 85 to 90% is highly acceptable. So, even though this is more of a symptom handler, in conjunction with the DPS, I feel like I have voice control over my life again.

But, dis ease insists that the shoe must drop.

Over the past three years, I have worked hard not to be hopeful in my progression. I know that sounds strange, but I have learned that in such hope, particularly with ALS, lies crushing disappointment. I have sought to be realistic and honest and truthful with myself about my prognosis, my life as it continues, my life as it ends. With the installation of the DPS, I find myself having to reconcile this little uptick in how I feel with what ALS hammers home day after day after day. I mustn’t hope for more than is possible. What is possible is that I will feel better for a while, that I will find my voice again for a while, and that my physical body will continue to deteriorate. Reconciling the juxtaposition of deterioration with the tiny flame of hope that the DPS kindles has become a new life task for me. I am by nature a hopeful person, and I have managed to channel my hope into the lives of those for whom I care and that I love. My hope is for humanity, and that through relating my experiences it is helpful to find deeper humanness. And I have learned not to hope for myself except to accomplish this life as best I can within the framework of the circumstances in which I must exist.

My new reality is really just my old reality – I will fulfill body and spirit as designed.

In essence, I am granted the gift of spiritual rationalism. It is in the nature of the human body to wind down until death. It is in the nature of the human being to hold death off for as long as possible. These are facts. One can leave you depressed and morose, the other unrealistic and silly. So I now seek to continue my process of reconciliation, feeling better yet getting worse. I know that none of this is a cure for ALS. Just as Leonard Cohen points out that there is no cure for love, ALS points out that there is no cure for life. But, to have a procedure that results in feeling better almost immediately, coupled with finding a way to bring voice control back over my environment, I have a more positive outlook than I have had in months. I know that ALS continues, but I feel more the possibility of this spiritual and physical and emotional goal I articulated to myself three years ago – to live fully until I die.

And this is no holiday truce – each of us is granted the gift of living in hopeless possibility.

Cytokinetics Part 2

Thank you to everyone who responded either publicly or privately about my letter to Cytokinetics. I want to share with you the following correspondence, because I do believe that people who are working toward new drug therapies for ALS have the best intentions at heart. This letter is from Dr. Jeremy Shefner, the person to whom I sent the original letter describing my experience with tirasemtiv. He also forwarded my letter on to Cytokinetics so that higher ups in the company including the president were aware of its existence. Late yesterday, I received a letter from the Medical Director and Senior Vice President of the company. I will not reprint that letter here, for I have not received permission to do so, but his concern was very similar to Dr. Shefner’s. Below is his letter with my reply.

Dear Dr. Kramer:

Thank you for your extremely thoughtful letter.  I have passed it on to Cytokinetics, and I am sure you will hear from them as well.  As I do not make decisions regarding access to drug outside of the trial, I will defer to them on that issue.  However, I did want to respond with respect to some of your other points.  First, I do truly appreciate the effort that ALS patients expend on participation in clinical trials.  From conversations with people I care for,  I know that, while everyone hopes for personal benefit in any trial, the main motivations are much more altruistic, and involve hopes for better treatment in the future even if they personally may not be directly impacted. 

The commitment of ALS patients to improving future care helps me maintain my own enthusiasm and commitment toward an effort that, in the last 20 years, has seen more than a fair share of disappointment.

I was also very interested in your comments regarding your perceived areas of improvement on drug, and the question of whether the evaluations in the trial will capture these events.  I guess the only real answer is that we will see.  Improvements in sleep should be associated with changes in respiratory function, and neck control hopefully associated with changes in strength of other muscles that we are measuring.  However, your observations highlight a major problem in ALS trial design, which is that patients present with different constellations of disability, and uniform assessments are likely to miss some areas affected.  As you point out, the evaluations that occur in this study are already extensive and potentially fatiguing; its hard to imagine a trial where even more measures were employed.

The issue of open access to drug for patients who successfully complete a trial is complex.  One sobering fact is that, in the last 20 years, patients in placebo groups of ALS trials have fared better than those in the active treatment groups, primarily due to unanticipated adverse events from the experimental agent.  While the early small studies of Tirasemtiv are encouraging, they are by no means definitive, and prolonged open label treatment prior to the analysis of Benefit ALS carries risks as well as potential benefits.  This drug is different than others tested previously in that, if effective, Tirasemtiv is more likely to produce a symptomatic improvement than agents targeting disease progression.  However, I have talked with patients from many previous studies who are absolutely convinced that an agent which has been shown ineffective in general was working on them.

I am extremely enthusiastic about the potential of Tirasemtiv to improve function in patients with ALS, and committed to see the development process move as quickly as possible so that all ALS patients have access to the drug if it proves to be effective.

I know that Cytokinetics shares this commitment.

Best regards,

Jeremy Shefner

And here is my reply:

Dear Dr. Shefner,
Thank you for replying so quickly to my letter. I sent it to you, because you are the principal investigator  for the tirasemtiv  study, and I thought you might  find the observations from one of the participants in the study  to be of interest. I also sent it to you with the idea that any form of communication concerning the difficulties you so rightly point out in measuring response  in persons with ALS might advance the conversation toward more creative and robust methodologies while still controlling for multiple variables. The fact that you would write such a thoughtful and well considered response is indicative of your own care, and I truly appreciate it.

As you probably saw, I carbon copied a number of politicians and persons with some influence in the ALS research community. This was not done to put you or Cytokinetics on the hot seat, but to acknowledge the complexity of ALS drug trials. There are so many players and so many priorities that must be met in order for a drug to actually be brought to market that the possibility of more responsive testing can be difficult to comprehend. My own work as an educational leader  has showed me that until we put all of the facts and all of the feelings, at least as much as possible, onto the table, with all of the players present – government, industry, researchers, advocacy organizations, study participants – we really have only an incomplete picture of the complexity, and therefore less possibility of constructing more  responsive and creative methods to account for the complexity.

As you also can tell, I only know enough about research design to be a little dangerous. Most of my own research has been qualitative in nature, a methodology that is not understood in the hard sciences but might have much to offer in humanizing and accounting for the complexities presented by a disease such as ALS. I do not know how much time I have (most of us don’t), but I do know that helping the science to become more responsive, better able to account for the multiple presentations that my disease offers, is one of my final priorities. Thus, I would offer that if there is anything that you think I might do to advance such a dialogue, if there is anything that I might do that could help you in your role as an ALS researcher, please do not hesitate to ask. It would be a privilege.

Finally, I have a request. As you may or may not recognize, I have been blogging my experiences with ALS for over a year and a half. My blog, the Dis Ease Diary is not followed by thousands, but it does reach out to several hundreds. As you may have guessed, my blog entry for this week was my letter to you. Your kind and considered response would be most welcome on the blog, and I would ask if you might grant permission for me to share it along with this email back to you. As you can imagine, the responses have ranged from sadness to realism to a sense of wanting to do something. My greatest hesitation in writing my letter in the first place was that some would see it as demonizing the research and the methods. Nothing could be further from the truth.

Dr. Shefner, your response was most welcome, and I do have great hopes for this particular trial. Thank you for taking away a little bit of the isolation of ALS. I wish you only the best.

Bruce H. Kramer, PhD and person with ALS

I am waiting to see what happens next, but at least a dialogue is now opened. I don’t believe that this is all about profit, nor do I believe that we have arrived at the best system.  But I do know that it is the system that we have, and to change it fully would be like turning the Empire State building in the middle of the ocean, if you will pardon the mixed metaphor.

Thank you again for your support and loving expressions. It’s been a remarkable two days.

Letter to Cytokinetics

To: Cytokinetics, c/o Jeremy M. Shefner, MD, PhD, Principal Investigator BENEFIT – ALS

Dear Dr. Shefner,

I am a person with ALS, and I have recently completed the 13-week protocol for the study, BENEFIT – ALS, a Phase IIb clinical trial to evaluate the safety, tolerability and potential efficacy of tirasemtiv. I am writing to you to share my experience of the trial, one that required enormous commitment on my part as well as my caregivers. I am also writing you to make a request regarding how Cytokinetics, as well as other corporations engaged in drug research, might reframe their efforts as they seek novel treatments for orphan diseases such as ALS. Even though I was lucky enough to work with the Minneapolis site staff for the study, and they sought to lessen the logistical impact that the protocol required, the demands visited upon subjects such as me are significant. As of next week, I will have completed all the visits as required by the study, and I believe that my experiences might be informative on both a scientific and humanitarian level.

As you are aware, the protocol for the BENEFIT – ALS requires weekly visits that could range from one to over three hours. For a person with ALS, the planning it takes to get to the study site, securing a driver and a caregiver to help negotiate the way, and then the energy expended in the measurements and examinations is significant. ALS is a disease that results in great fatigue, and often, after an evaluation, I would find myself nearly catatonic with how tired I was. I tell you this not so much that you would change the protocol but so that you will understand the commitment that participation in such protocols requires. It is not as if I get in the car and drive to the site in a normal, able-bodied way. The preparation of getting dressed and cleaned up to come in to the Berman Center where the evaluations are held is only the beginning, and the actual protocol – particularly in the strength and pulmonary testing – is quite exhausting. Yet, I was happy to do it if it might push forward our understanding of a novel treatment for ALS.

My first visit for trial eligibility evaluation resulted in disqualification due to my ALS Functional Rating Scale (ALS FRS) lacking the requisite number of “2’s” and “3’s.” However, after attending the Mayo ALS Clinic, where I receive my treatment, and retaking the ALS FRS both at Mayo and at the study site, I was approved for the study.  I mention the Mayo Clinic because while I was there I was prescribed a neck brace in order to support my head and neck in the evenings. I was having great difficulty keeping my head up and the neck brace was designed to alleviate that symptom.

Since the study protocol required participants to take the drug for a week in order to blind us to the possible side effect of dizziness, I know I was on the drug for at least one week. Although I never experienced dizziness, I did experience another side effect that was actually positive. I did not need the neck brace again throughout the 13 weeks of the trial. In essence, I noticed a strengthening of my neck and shoulders so that it was unnecessary to wear the brace.

A second notable response for me was in sleeping. As you probably know, persons with ALS often suffer from different types of sleep difficulty. Some of this is due to the physical discomfort we experience. Some of this is due to breathing difficulty.  For some, anxiety interferes with sleep. Until the trial, I was rarely able to sleep more than two hours at a time, and I required constant readjustment due to physical discomfort. Unlike an able-bodied person, I have no ability to turn or change my posture, and my experience of sleeping was uncomfortable at the least and sometimes quite painful. My inability to sleep had other side effects, most notably on my principal caregiver and wife Evelyn. Not only is she my principal caregiver, but she also supports us by teaching in an elementary school. Trying to teach during the day after night upon night of interrupted sleep is very difficult for her.

Within the first week of being in the BENEFIT – ALS study, my sleep became much less interrupted and much more comfortable. I was able to put together 7 to 8 hours of sleep in three and four hour chunks. This was a remarkable development, and it resulted in less fatigue, a better mental outlook, and most importantly a rested wife.

On May 30th, I took my last dose of tirasemativ. The following day, I awoke feeling as though I had recently been in a street fight, receiving much more punishment than I meted out. I ached from head to toe, and it is only in the last two days (today is June 18th) that I have begun to lose a headache and bodily aches and pains that started over two weeks ago. In the meantime, I have consulted with an ENT over heightened ringing in my ears and perceived loss of hearing. Of course, I have also documented all of this with the research center, and they have moved to support me through prescriptions of potassium and magnesium and well–considered advice about water intake.

The bottom line is that where I felt the greatest effects of tirasemativ, study protocols did not measure. The measurement of sleep quality for persons with ALS is significant, and protocols need to take sleep into account. In addition, it would not be difficult to measure strength in other places besides pulmonary, leg, arm and hand. As I can no longer walk, you have received no measurements of my lower body strength. As I can barely hold up my arms, you have received less consistency, particularly from my left side. But were there to be some way in the protocol to measure an area where strength is noted when strength did not exist before, you would have data supporting muscle strengthening that could be analyzed through statistical meta-aggregation.

Please understand that I share with you these observations not just to tweak the science, but because I am a human being. I am not number XYZ out of the 30,000 or less people who currently have ALS in this country. I continue to hope for effective treatments, even though I know that drug trials will not result in treatments quickly enough that I might enjoy their benefit. I continue to hope that somewhere the human factors of how we do scientific research will be given as much consideration as the actual double-blind, placebo-controlled protocols that have resulted in one approved drug for ALS in the last 160 years.

I continue to hope that people like you will begin to recognize the futility of gold standard drug trials and push for more creative approaches that control independent variables, and minimize the objectification of subjects.

You have received a great service from the nearly 300 subjects who have enrolled in BENEFIT – ALS thus far. To cut even one of us off from the drug at completion of protocol – especially when some clear benefit has been experienced – saying that you have met your legal obligations and scientific responsibilities, is inhuman and a squandered opportunity. The humanity is in offering something that might make us feel a little bit better. The opportunity is in a readily available and committed population in which you could continue to study drug effect.

I do not know for a fact that I was on the drug, but the effects of going on and going off were certainly profound. If the drug is found to be well tolerated, why would we not offer it to those who have given their bodies for scientific research if they want it? Were you to offer tirasemtiv to me today, I would happily go back on the drug. Did it create strength in my legs or arms? I don’t think so. But a good night’s sleep and a stronger neck were meaningful results of my participation in the protocol.

Therefore I am requesting access to the drug tirasemtiv. I request this for myself and for others who find similar experiences within the trial. I offer to remain a study subject if that will advance the science forward.

Thank you for your kind consideration, and I look forward to hearing from you very soon.


Bruce H. Kramer, PhD and person with ALS

Grudge Match

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.