Many of us with slow progression ALS encounter problems of diagnosis and/or re-diagnosis. For some, a definitive diagnosis of ALS can take years because we don’t present with typical ALS progression. Delayed diagnosis is a major complaint among pALS. For others of us, the original diagnosis may be quick, but then our lack of typical disease progression, along with other symptoms that don’t line up with ALS, can lead to a rethink of the original diagnosis. According to the ALS Association website, 10-15% of all ALS diagnoses end up being re-diagnosed as some other disease, typically an “ALS mimic,” of which there are many. This is an excellent reason to get a second opinion if your case isn’t clear-cut.
In my case, I had a speedy initial diagnosis in March 2018. This was despite the fact that my father has had a similar pattern of slow, asymmetric leg muscle weakness for the past 20 years (but not ALS), which raised the possibility that I might have some other nonfatal, inherited neurological condition. When I changed ALS clinics in September 2020, the new team of neurologists were intrigued by the parallel symptoms with my father, and noted enough anomalies in my case – including the very slow and limited disease progression, as well as other symptoms – to propose exploring a re-diagnosis. After running additional tests, the results were inconclusive, so for now, and possibly well into the foreseeable future, I remain diagnosed with “atypical” ALS, with the proviso that the diagnosis will be periodically revisited as more evidence accumulates.
As you can imagine, the possibility of being re-diagnosed with a non-fatal ALS mimic was head-spinning, and then learning that the test results were too inconclusive to warrant a re-diagnosis was a let-down. But the fact that the door to a possible re-diagnosis is still open gives me hope. I keep coming back to that figure of 10-15% of all ALS diagnoses being false positives. That’s a lot of people each year (600 to 900 in the US alone) who were told they have ALS but who later learn they have some other neurological disease or condition (This works both ways — a much larger number of people are originally misdiagnosed with some other condition and then later learn they have ALS). And there must be many people like me, who have an ALS diagnosis but whose symptoms are “atypical” and who live for years with some uncertainty about the diagnosis. This is unavoidable for a disease diagnosed by process of elimination.
Living with uncertainty can be very hard, especially when it involves a diagnosis of a terminal illness. But for now, at least, I feel comfortable with the ambiguity. The uncertainty is a source of hope. Each month without changes in my condition is another small piece of evidence that just maybe I have some other rare but non-fatal neurological disease. Time will tell.
Like many pALS, I had a chest port surgically implanted to facilitate monthly infusions of Radicava, which is a therapy that appears to slow disease progression down for some people with ALS. I had mine implanted in fall of 2018. In March 2020, a topical infection – just a pus pimple – appeared at the injection site of the port during treatment. That happened two more times over the summer. Each time, it was diagnosed as a topical infection, I was given antibiotics, and it quickly cleared up. But the recurrence was troubling, and my neurologist and I agreed that if it happened one more time I should have the port removed. The concern was that if the infection made its way into and past the port, it risked becoming a blood infection, which could lead to sepsis, which is life threatening.
One evening in late September I was watching television when I suddenly began shaking, got very cold, and started having trouble breathing. The shaking was uncontrollable. After ten minutes of this we called 911. Long story short, I ended up in an ambulance, the ER, and then four days in the hospital with a blood infection. I was completely exhausted by the episode, and felt miserable. Luckily the antibiotics worked to clear it up and it never developed into sepsis. The doctors suspected that the chest port was the source, and so we had the chest port surgically removed, and I am now done with Radicava treatments. Time will tell if going off Radicava impacts my ALS progression. For now it hasn’t. The lesson for me was that each person living with ALS has to make a decision about whether the anticipated benefits of Radicava justify the infection risks of a chest port. For me, the risks got too high.
Over the past five months I’ve been schooled on a number of (mostly) ALS-related health issues. Here I share what I’ve experienced and what I’ve learned, for the benefit of others living with ALS who come across this blog. Spoiler alert — this story has a lot of more-or-less happy endings.
Fatigue is very common with ALS, as our muscles are working a lot harder in their weakened state. Sometime in late June or early July, I started experiencing deep, chronic fatigue. I was bone tired, I needed a nap a day, and never felt rested. This was a big drop off from my normal energy levels. And this went on all the way into September. At first we thought it was COVID-19, but I tested negative twice. Then I thought it’s a new phase of ALS, my “new normal,” which was very discouraging. Others asked if I was depressed – in the midst of COVID everyone was feeling blue, so maybe the tiredness was a symptom of mild depression. I also wondered if it was in part caused by the stress I’d gone through in June, when I got caught in the middle of a nasty spat in the ALS community over a house bill (HR7071) proposing to fund expanded access to experimental therapies. Or maybe it was a combination of all of those.
Whatever the case, the fatigue was debilitating. Psychologically it was the worst I’d felt since I first got the diagnosis.
But it turned out to be (we now think) something else entirely – a low grade blood infection that became a full-blown medical emergency in late September. Once the blood infection was cleared up, my energy levels returned to normal and the fatigue problem, thankfully, was gone. The lesson for me was not to assume every health issue I experience is somehow linked to ALS progression.
Today I posted on facebook (which I don’t do often) that I spent my 60th birthday playing golf on a beautiful fall day. I got a lot of nice birthday greetings in response, a couple of which marveled that I was still able to play golf despite having ALS now for four years. The confusion is understandable – our messaging about ALS is that median life expectancy is three years. If, statistically, I shouldn’t even be alive, how am I well enough to play golf?
The answer is that I appear to have a “slow progression” version of ALS. No one knows why, but a fraction of people with ALS (about 10%) live 10 or even 20 years. The fact that my ALS symptoms are still confined to my legs, and my leg strength has not really changed much in 18 months, is a clear indication I have slow progression. That is no guarantee it will continue that way – my condition could change for the worse at any time. But for now it has allowed me to proceed with my life with only minor adjustments. I am still working full time; I can walk a mile or more at a time, slowly, using only an ankle brace (though for long walks I use a roller just to be safe); and I can play golf as well as I could before (which is to say, still not very good). The AFO (foot ankle brace) is a huge help in keeping my weak left foot and ankle stable while I hit and walk In some ways golf is the perfect sport for me now, as it involves walking a lot, but for short distances, and then sitting in the golf cart, which gives my legs a quick rest.
I had my first clinical consultation since January (delays due to COVID-19 disruptions) and the results were excellent. No notable disease progression, and the symptoms remain confined to my feet and legs. The docs were very pleased and intrigued by the very slow progression. I can still walk a mile using a foot ankle brace and either a cane or walker, and I can still play a round of golf. I do tire easily, especially if I have to stand for a long time. But overall the report is very positive. Thanks to all of you who have asked!
Because of COVID restrictions, this fall the NC Chapter of the ALS Association is having to hold a “virtual” Walk to Defeat ALS. Karin, the kids, and I are again sponsoring a fundraising team, “Kens Caucus,” and are reaching out to ask for help, If your family financial situation in this difficult time permits, we would welcome a donation, large or small! And please spread the word to your contacts too.
The link to the site where you can contribute is here:
The answer to this question is, at first glance, blindingly obvious. The patients, of course.
But which patients? The ones who have the condition or disease and know it? Or the many many more who don’t have it yet but will?
There are an estimated 25,000 people in the United States who are currently living with ALS. I’m one of them.
There are an estimated 650,000 or more Americans alive today who don’t have ALS yet but who will get the devastating diagnosis. Maybe in one year, maybe in five, maybe in 40.
Do our US-based ALS organizations have a responsibility to protect and advance the interests of the 650,000 too, or only those of us with the disease now?
It is a fundamental question, laced with moral and policy implications. Each of us volunteering or working in the ALS advocacy, research, and care service space has to answer that question for ourselves as well as demand an answer from our organizations.
If your answer is that our only task is to serve those with ALS now, then policies designed to advance short-term needs and goals should prevail.
If your answer is that we have an obligation both to those of us diagnosed with ALS and the 650,000 Americans who will get the disease, then the calculus changes. Then the difficult challenge is to balance serving the interests of those with ALS now and the interests of the “next gen” of people with ALS. That balance can and must be achieved, but it requires us to be mindful of the many voices we can’t yet hear, all 650,000 of them.
What happened this month in the ALS advocacy space must never happen again. It’s up to those of us living with ALS and our supporters to insist that our ALS organizations do better.
What went wrong? Two of our most active ALS advocacy organizations, the ALS Association and IAMALS, were only partially in sync on two bills introduced in Congress designed to improve early access to experimental therapies. One bill, S3872 (“Promising Pathway Act”), was enthusiastically endorsed by both organizations. But on a second bill, HR7071 (“Accelerating Access to Critical Therapies for ALS Act”), they were not in full agreement. IAMALS fully endorsed HR 7071; the ALS Association expressed reservations about the bill in its current form while expressing hope that discussions can be held with the co-sponsors, IAMALS and other stakeholders to address those concerns and strengthen the bill.
There is no reason that these mixed messages needed to happen after the bill was introduced. This was avoidable, and should have been handled long before the bill saw the light of day. What was missing was communication, coordination, and trust, exacerbated by misperceptions. I have heard enough to believe that there is plenty of blame to go around and both organizations could have done better. I am uninterested in a blame game. What I am interested in is seeing that we do better moving forward.
Doing better means routinizing communication and coordination on public policy ideas, initiatives, and draft legislation; creating publicly accessible forums for debates and discussion about possible advocacy ideas, so proposals get a full airing and a wide range of patient voices can weigh in on their merits or shortcomings; and building trust, without which progress on other fronts is impossible.
The good news is that in my conversations with both leaders and members of these two organizations (including many of us who are members of both!) this desire for improved coordination is widely and deeply shared.And I strongly suspect that leaders in the many other ALS care services, research, and advocacy groups feel the same. Everyone understands that better coordination is essential for success, and is an ethical obligation to the community we serve. I am optimistic that we can make this happen. But we need lots of voices in the ALS community to keep insisting on it. As I settle into the role of Chair of the Association’s Public Policy Committee, I promise you this will be a top priority, and I will hold myself accountable to that goal.
I am also optimistic because, as I have gotten to know both volunteers and staff in our many ALS organizations, I am deeply impressed at how dedicated, smart, and hard-working they all are, and how similar our goals and values are. These are good people. They are having to work in a highly fractious ALS organizational environment, but that is something we can change, if we want to.
All this is not to say that ALS organizations must agree on everything. We have to expect differences in policy preferences, strategies, and principles. In fact, robust exchanges of views on public policy and other matters make for better policies. The key is ensuring that those exchanges occur early and often in the process, and that if organizations end up embracing different positions it can be managed in ways that are respectful and don’t overshadow all the many, many other policies, principles, and positions on which we all agree.
I write this in my own capacity, I am not speaking on behalf of the ALS Association.
A key provision in HR 7071 (“Accelerating Access to Critical Therapies for ALS Act”) authorizes $450 million over four years to underwrite the costs of early access to experimental therapies. This is not a simple ask. It raises fundamental questions of principles and priorities for the ALS community, questions that deserve a full and open discussion – one that has not happened yet, but needs to happen now.
The goal of the $450 million request is straightforward. It seeks to solve one of the most frustrating impediments people with ALS face in their attempts to gain early access to therapies still in clinical trial – namely, cost. Pharmaceutical companies running clinical trials on therapies demand very high fees for access to their experimental therapies, if they agree to allow early access at all. Depending on the type of therapy, the expenses for early access can be prohibitively expensive for all but the very wealthiest patients, some reaching as high as $1 million per treatment – and they typically require recurring treatments. The $450 million request – covering $75 million per year in years one and two, and thereafter $150 million annually in years 3 and 4 – is meant to cover costs of early access for people with ALS.
Several legitimate concerns have been raised about this proposal.
It does not solve the problem it presumably sets out to solve — making early access affordable for all people with ALS. Instead, it would only allow a small fraction of Americans living with ALS to gain early access to experimental therapies. This is the case no matter how one works the math. If the most promising therapy in clinical trial happens to be one which runs close to $1 million per treatment, that would enable only 75 people, out of a US population of 25,000 with ALS, to gain access. That’s 1 in 333 of us – roughly the same odds of being diagnosed with ALS. If the treatments cost less, say $300,000 per round, that would still only cover 250 of us, or 1% of the US population of people with ALS. Even if the cost of early access fell to as little as $10,000 – a figure some argue might be a reasonable estimate for access to a pill-form therapy in a platform trial — that would cover 7,500 people with ALS, or less than one-third of us in the US. And such a low-ball estimate only raises another objection – if the cost of early access drops to $10,000 for some experimental therapies, why are we asking taxpayers to cover that when middle class and wealthy households could find a way to cover the costs and poorer households could be assisted by other means?
It risks creating major rifts within the ALS community. Who will choose what constitutes an eligible “promising therapy” and who decides which people with ALS get covered by the subsidy for early access? How will the vast majority of people with ALS feel when they learn this massive appropriation of funds provides nothing for them? Some who follow ALS research closer than I do suggest that the most promising therapies in the pipeline in coming years are those targeting familial ALS. Will that result in most or all of the $450 million covering the 10% of the ALS population that has familial ALS, and how will the 90% with sporadic ALS react?
Given the very poor track record of ALS phase three clinical trials to date, the odds of early access resulting in meaningful outcomes for the lucky few who get it are slim, making this a very high cost, high risk of failure gambit for a small number of people with ALS. Of the dozens of ALS therapies that have made it to phase three clinical trials, only two have led to approved therapies, and both have only modest, uneven impact in slowly disease progression. This raises a legitimate cost-benefit question about the fund. Could that $450 million be put to better use than this?
If the ALS community can convince Congress to devote $450 million to our disease, earmarking it for research for a cure would be a far better way to make use of the funding. The bill stipulates that the $450 million be a separate appropriation from research funding, as a way to deflect criticism that this will divert money away from research. But that is a distinction without a difference. The reality is that interest group pressure that is able to secure this kind of funding for early access could certainly be able to do the same for research for a cure. The authorization for early access reflects a choice we as a community are making – that we prioritize gaining subsidized access to experimental therapies for a few of us, now, over seeking a cure for all. Is that what our community wants?
If our priority to to pursue treatments that stop or reverse ALS as speedily as possible for all people with ALS, there are good reasons to question whether the $450 million for early access is a good idea, and good reasons to argue instead for lobbying for more money for research for a cure.
You may disagree with parts or all of the analysis I share above, but these are very reasonable questions and concerns, and they are being raised across the ALS community. Fear of being attacked on social media is preventing some people with ALS from saying this publicly, but make no mistake, they are expressing these concerns in private.
What we need now, and what should have happened well before this bill was introduced, is a full, thoughtful, open discussion and debate in the ALS community about whether this bill in its current form actually reflects our priorities and principles, and if not how we can make calls to modify it to make it stronger and aligned with our principles.
On May 27 2002, the MDA released a statement calling for rapid innovation in the design of ALS clinical trials, and calling on “all stakeholders from across the therapeutic development spectrum to commit to think more creatively on how to address these surmountable challenges, and to heighten the urgency to find solutions.”
The statement was welcomed by the ALS community.
Some individuals on social media used the MDA statement to criticize the ALS Association for its failure to lead on, or even take a position on, this issue.
In reality, the Association has taken public positions on clinical trials. So the question is really whether the Association’s position on clinical trial innovations is lagging behind the thinking among other patient advocacy groups.
That question prompted this short analysis – I wanted to see where the MDA statement and ALS Association’s positions converged and diverged. What follows is a very quick comparison of the May 27 2020 MDA statement on clinical trials and the most recent 2018 Statement of Principles from the ALS Association (from its website) on clinical trials.
I broke down each of the specific topics MDA addressed in its message, drew direct quotes from the MDA statement, and then searched the Association’s 2018 Statement of Principles for positions on each of those issues, taking direct quotes from that document as well. In a few instances the issue in question was discussed in more than one part of a document; in that case I included both quotes. The results are provided in the table below.
issue
MDA
ALSA
1
Date of statement
May 27 2020
Fall/summer 2018
2
Trial inclusion criteria
While trial sponsors may be concerned that expanding the inclusion criteria for the trial may jeopardize findings of efficacy, the use of multiples arms that enroll ALS patients in different stages of progression should be explored
Enrollment criteria should be based on a clear rationale and preclinical data to ensure the correct study population. Simply adopting criteria from previous trials is not acceptable. Many people with ALS want to participate in trials. Every effort should be made to be inclusive while ensuring the trial provides clear answers about treatment efficacy. Adaptive designs and other innovative practices from other disease areas should be used to conduct fast, impactful trials.
3
placebos
We remain hopeful that FDA, working with sponsors, will eliminate the use of placebos in ALS clinical trials, but placebos are clearly still being employed in newly announced clinical trials. We recognize that the use of placebos will not disappear overnight, and the lack of established scientific understanding on the heterogenous progression of the disease poses challenges, but we ask that FDA and sponsors redouble their efforts to avoid placebos wherever possible (Calls for): Collaborative development of innovative clinical trial designs that employ historical controls, Bayesian statistical approaches, and cross-over designs with the FDA, the biopharmaceutical industry, and patient advocacy organizations leading the way.
Reduce the size and ratio of placebo groups and consider eliminating them completely when efficacy is not a trial outcome, and/or when additional natural history progression models, crossover studies, or other approaches provide informative comparative data.
4
Continued access to therapy post -trial (open label extensions)
Sponsors of ALS therapies to commit to considering expanded access and open label extensions at the outset of their clinical studies. Sponsors should meet with patients, their loved ones, and their advocates before clinical trials commence to ensure the approach is supported by the patient community.
Access: Trial sponsors need to increase access to experimental treatments. Trial participants originally on placebo or who believe the treatment impacted their disease should have access receive the experimental treatment, through open-label extensions or expanded access options, provided that the additional access does not slow or reduce the impact of the trial itself.
5
Funding to cover costs of expanded access programs and open label extensions
Innovative financing mechanisms to overcome the financial disincentives associated with including expanded access programs and open label extensions within ALS clinical trials, including ongoing late-stage or Phase III clinical trials. Congressional consideration of legislative interventions that would lower financial and logistical barriers to employing scientifically sound, but also patient-centric, approaches in ALS clinical studies.
People with ALS and caregivers should be consulted on trial design to minimize the risks, discomfort, loss of control, hassles, financial barriers and logistical challenges of trial participation. IRBs, the FDA, funders and other oversight groups should favorably consider trial features designed to reduce burden on people with ALS and their caregivers. We appreciate the ethical challenges of spending resources on access to experimental treatments, when many families with ALS are already overwhelmed with the financial burden of ALS (loss of income, home modifications, copays, etc.). Providing financial support for access to experimental treatments could draw resources away from the broader community to the handful of people willing and able to take experimental treatment outside of a clinical trial. Additionally, there is the potential that trial sponsors may profit from experimental treatments by exploiting people with ALS. The Association will continue to explore this issue, while honoring the rights and wishes of people with ALS.
6
Biomarker development
Greater effort and urgency behind ALS biomarker development that can hopefully inform surrogate endpoint development (clinical trial endpoints that likely predict effective clinical outcomes) and eventual qualification to facilitate use of FDA’s accelerated approval pathway.
Experimental treatments need testing to determine their effectiveness and safety using the fewest possible participants, shortest length of follow-up, and least burden on participants. Approaches include: Developing and using valid surrogate endpoints and biomarkers when possible to measure impacts quickly and precisely.
7
Expanded/early access
FDA consideration of the utilization of innovative approaches towards expanded access, such as the Oncology Center of Excellence Project Facilitate, in progressive neurological diseases without satisfactory therapeutic alternatives, including ALS. –
Trial sponsors should strongly consider companion studies where patients ineligible for clinical trials assessing efficacy can still participate to provide safety and tolerability information. The entire ALS community should have access to experimental therapies under clinical supervision, provided that the additional access does not slow or reduce the impact of the trial itself.
Assessment: For the most part, the 2020 MDA statement aligns very closely with the Association 2018 Statement of Principles.
In addition, both documents use qualifying language like “should consider,” “should be explored,” “when possible” or “provided that” to express preferences without locking themselves into unconditional positions on complex issues. This diplomatic language has the virtue of allowing readers with opposing views to feel that their position was supported, without actually committing to that position in full.
The one real divergence is on the question of funding to cover costs of expanded access programs and open label extensions (item #5). The new MDA position embraces the creation of a government fund to cover costs associated with extended access to therapies still in clinical trials (though the MDA does soften this position a bit by asking legislators to “consider” this option). By contrast, Association takes a more cautionary tone, arguing that funds diverted for experimental therapy for a few could come at the cost of research on other promising therapies.
This latter issue is especially relevant now, as legislation has been introduced in the House (“Accelerating Access to Critical Therapies for ALS Act”) that would, if passed, establish a $75 million fund to cover fees charged by pharmaceutical companies to people seeking early access to therapies still in clinical trial. The efficacy, ethics, and other aspects of this kind of government funding of expanded access to therapies still in clinical trial are complex and deserve a careful, thoughtful discussion and debate in the ALS community.
(NOTE: There are currently two bills pending in Congress on expanded/early access to ALS therapies. The House bill described above includes the $75 million fund proposal. The Senate bill, proposed by Senator Braun, focuses on creating a new pathway for expedited access to therapies still in clinical trial, does not include a government funding mechanism, but apparently creates other incentives for therapy developers to participate. More on all this soon; stay tuned!).
Ken's Caucus 