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.

Sincerely,
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.
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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.

Sincerely,

Bruce H. Kramer, PhD and person with ALS

Fear of Failure

Before I start this week’s reflection, I would like to thank all of you for your kind words, thoughts and very considered advice after my last blog. Your willingness to walk with me as I roll along is often the best part of my day.

Last night, we watched the Tony awards. I love musical theater, and I like serious drama, so it should be no surprise that we decided to forgo Game of Thrones and Mad Men in favor of this giant, three-hour advertisement for one of the great joys of New York City. With all the revivals showcased last evening, it was a little bit surprising not to see a show by Stephen Sondheim represented. Of all Broadway composers, I think Sondheim is my favorite, and with the week that I have had, I found myself humming a tune from his show, A Little Night Music – “Every day a little death.” I know this sounds maudlin, but the song actually represents the antithesis of how I have wanted to live since my diagnosis with ALS.

Every day a little death
In the parlor, in the bed,
In the curtains, in the silver,
In the buttons, in the bread.
Every day a little sting
In the heart and in the head,
Every move and every breath
(And you hardly feel a thing)
Brings a perfect little death.

Invariably, you cannot approach ALS without thinking, at least a little bit, about death. When I was first diagnosed, I thought about my death a great deal. Then, as I seemingly worked through each ALS challenge presented, it became less and less apparent that my death would be sooner rather than later. In many ways, I would acknowledge death’s presence, but only begrudgingly and only within the larger context of dis ease. But especially in the past week, as I have dealt with a physical pain that I have not known before, as I have dealt with the emotional pain of saying goodbye to my hand function, as I have dealt with the pain of realization that there really is no going back; death has entered into my conscious space, pushing out the comfort and teaching of dis ease, replacing it with the sparkling clarity only its presence can bring.

Don’t get me wrong, I am not looking to be relieved of life just yet, but the hopeful sense that I can do this and do it well has been replaced with the realistic sense that I will do this and perhaps not with the grace and hope I expect of myself. Such realization causes me to reflect, to ponder, to become introspective on the value of my life as it is now, as it was, and as it will be. And of course when you begin to question value, then you begin to superimpose success and failure into the interpretation of life that is and was. And believe it or not, it calls into question the way you are blessed or graced or forced to die.

How do you fail at death?

In the past, I have chosen to reflect on such questions by turning them aside and asking instead, how does one fail at life? By turning the question to a life question, it seemingly delimits dying’s impact. I think it’s a good way to think – that a good death is based on a good life. But there is a small scratchy voice that asks me if I am avoiding the question entirely by turning it on its ear. After all, unless you choose to take your life, it really does seem that the choices around death are few and far between. So the question of failing at death might seem to be illogical or even silly, yet I find myself asking how that might work.

I have no way of knowing how much time is left between today and the day that I will die, but I am aware that the chances of having one year, a little over one year, a year and a half, less than two years are very good. I know this based on physical symptoms and how quickly they have come on. I know this based on what mitigating factors are available to me and how developing systems for catastrophic disease management are skewed toward profit and not cure. I know this intuitively in the depths of my gut and my soul.

There is nothing like impending death to focus your thinking.

So today, I find myself in a strange position of feeling urgency to bring certain parts of life to fruition while at the same time recognizing a lack of physical strength for the task. Here is an example. From time to time I receive lovely personal comments from friends. Sometimes these comments are soul baring, graceful dances, wisps of ether or shocks of electricity as friends and loved ones struggle in their own versions of dis ease, seeking to share a further understanding of my plight through theirs. They share thinking that perhaps I might have a broader capacity of empathy for what they experience. They share to comfort and question the humanness of living. And the energy that it takes to respond is so great, the physical needs for written response are so beyond me, that I just don’t. This is not the way that I wish to be engaged with my friends. This is not the kind of friend I wish to be. It feels like I am projecting apathy about issues that are truly troubling for my friends. It feels like I am not offering the love and care that I feel. There is urgency to respond, and fatigue in the planning.

It feels like failure.

I suppose that nothing focuses this urgency like the upcoming birth of a granddaughter. What little she may know about me will be in the stories of her parents, of Ev and of course what she discovers on her own. So I have been plotting a presence in her life, yet questioning if it is possible to achieve. For example, I’m beginning to think about digitizing photographs of our family when her dad was just a boy. I’m wondering if I could write stories around these photographs that would help her to know how special her father is through her grandfather’s eyes. Such an offering is a gift that children love. They love to hear stories about their parents when their parents were young. They love to hear of the childhood adventures lived out before their time.

But you can see how the logistics will be tricky. I cannot place pictures or slides on a scanning tray. I will need help putting them in order. I will need to write carefully. Above all, I will need to be mindful of my new granddaughter’s ability to comprehend the stories that are being told. I won’t be there to mediate the scary parts. If I cannot get to this, it will feel like failure. If I do not leave something of myself as a gift for her, it will feel like a purposeless life. It will be the little death I have tried to avoid.

In the end, I suppose it is about the fact that a good death is so tied up in the future beyond the event. It is the translation of one childhood into another, of love projected well beyond the time it was given, of DNA beyond inheritance.

And I suspect there will be no Tony for the performance, although I’m hoping for a long run.