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

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7 thoughts on “Letter to Cytokinetics

  1. Bruce. I just attended a course at RIC and northwestern medical school. PRO’s are said to now be the FDA’s gold standard. Not in your clinical trial forget the grant. I surely hope the Feds are listening in on your blogs. Human subjects are just that – HUMAN!! Judy

  2. Bruce,
    I read your letter today. Then, I finished my day of work and walked to my car. I knew it was there, so I looked up at the building across the street. I’ve only been working for my new company for 3 weeks, but I knew that the Cytokinetics headquarters was near. The universe reminds me often of how small it is and how inter-connected we all are. It did so again today.

    On Monday, we had a visit at our company from a patient on one of our clinical trials (cancer, not ALS). We asked him (his name was also Bruce), “What can we do to make clinical trials easier on you and on caregivers?” He spoke of the many stresses: the travel (for him, 36 flights in 3 years), the not knowing (drug or placebo?), the uncertainty of what happens at the end of the trial, and the necessity to endure so many tests. At the end, he said, “Just get the drug approved so that others can have easier access to it than I did.”

    We listened. All of us, even those like me who are so early in the process that we are working with numbers or cells or proteins, but not with patients. Our company posts photos of the patients that we do work with in the hallways near our research labs to remind everyone of the importance of moving fast and doing bold science. We try to make new drugs faster and safer and cheaper. The need for better medicines is overwhelming for SO MANY diseases. We agonize over study design and spend hours/days/weeks upfront trying to predict what we should measure. We do not want to be wrong, because we know the costs of being wrong. But, how can you know? We try to evoke change in the system, because as you and others have pointed out, it is an imperfect system. But we do care, and we do sometimes pray – perhaps not all of us, but probably more than some would expect.

    In the end though, today my simple wish is that I had the power to manifest a positive response to your letter.

    The world of science is small world though, so maybe I do.

  3. This is an amazing letter Bruce! So well written and so true. The parameters of study need to be expanded and your observations and contributions can help many. I do so hope you are heard and heeded. Once again, you continue to be an articulate voice for yourself and all people with ALS. What a gift you share with us all! Sigrid

  4. Would it help if we wrote a letter too? Let me know and I will. They need to give you the drug. It is the most humane and decent thing they can do. I honestly don’t know how these researchers can look themselves in the mirror knowing that they yanked a drug that is helping a dying patient live a little bit better. Shame on them.

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