The National Academies of Sciences, Engineering, and Medicine recently released a congressionally mandated report on how to make amyotrophic lateral sclerosis — a brutal, always fatal condition — a “livable” disease in the next 10 years. Essentially, the committee was tasked with delivering a plan for a moonshot.
As a health care innovation expert and someone living with ALS, I have to say that the report barely gets off the ground.
ALS is a devastating neurological condition that progressively robs people of their ability to move, speak, eat, and eventually breathe unassisted. Although it’s about as common as multiple sclerosis, because most people with it die within two to five years of diagnosis, only about 30,000 Americans are living with the disease at any one time. There are no effective treatments for 99% of them, and clinical trials keep failing at rates far higher than normal.
To change this bleak outlook, in 2022, Congress commissioned a study and allocated $1 million to identify ways to transform ALS from a fatal condition to a manageable, chronic one “within a decade.” The National Academies of Sciences, Engineering, and Medicine accepted the charge and, to its credit, began studying the issue from a variety of angles. The final report reflects the care that went into the investigation, and includes plenty of good suggestions, such as calls to improve access to high-quality care, eliminate insurance barriers, expand genetic testing, and enhance caregiver support.
But when it comes to the most important problem of all — accelerating treatment development — the report largely punts.
As someone who provided feedback on a draft of the report, I had high hopes that the final report would highlight promising advances at the scientific frontier and recommend a comprehensive R&D strategy to accelerate treatment development. But the final report does no such thing. Instead, it eschews cutting-edge science in favor of tepid recommendations to do more of the same, like develop better biomarkers and run a new natural history study.
It’s hard to disagree with those generic recommendations. But this isn’t a strategy to end deaths from ALS by 2035.
What might a better strategy entail?
As I suggested to the committee, a comprehensive strategy would accept that ALS, like cancer, is a highly heterogeneous disease. Two cases are rarely alike. Think of it almost like a tree: At the roots, more than 50 different genes can independently trigger 15% to 20% of cases. The rest, while seemingly occurring at random, are likely triggered by a range of environmental, lifestyle, and as-yet-unknown genetic factors. At the trunk, despite this multitude of causal pathways, most cases converge on the breakdown of a protein called transactive response DNA binding protein of 43 kDa (TDP43). At the branches, because TDP43 plays an important role in transcribing DNA into RNA and proteins, genetics and epigenetics likely contribute to important differences in terms of how ALS plays out. This means that drugs that work for one person may not work for another — which is exactly what the research suggests.
This biological context might then inform a three-pronged strategy:
Prong 1 would focus on the trunk of the tree — accelerating the development of drugs focused on addressing TDP43 malfunctions and their proximate effects. Specific recommendations here might include funding to parallel process the preclinical tests necessary to move promising drugs into human trials faster, expanding the size of those trials to enable accelerated approval if warranted by the results, and fast-tracking the development of TDP43 biomarkers and tracers so it’s possible to tell how well such drugs work using medical imaging. (This would also be useful in earlier diagnosis).
Prong 2 would focus on the roots and branches — better defining ALS subtypes to enable precision therapies. Here, I’d want to see expanded efforts to develop gene therapies for the most common genetic forms of ALS and to better understand possible epigenetic subtypes of non-genetic forms. In addition, there should also be a big push to develop disease models that better reflect the heterogeneous nature of ALS. Imagine turning a vial of a patient’s blood into ALS neurons, then using these to identify subtype-specific mechanisms and biomarkers to discover targeted drugs, to run better trials, and eventually to tailor treatments for that individual. This may sound like science fiction, but proofs of concept already exist.
Because breakthrough therapies are still a few years away at best, Prong 3 would focus on R&D initiatives designed to rejuvenate the tree — things like accelerating the availability of brain-computer interfaces that facilitate conversation-speed speech, and more basic research on nerve regeneration.
Some might say that many of these technologies are too nascent and unproven. But that is precisely why they warrant additional focus and investment. Others might say that the idea of targeting treatments at ALS subtypes isn’t yet justified by the science. But it’s known from other heterogeneous conditions, such as lung cancer and MS, that subtype-specific therapies are usually the most transformative. Indeed, the most successful ALS drug so far, tofersen, is a precision therapy for 1% of individuals with a rare genetic ALS subtype. And besides, this is why the strategy proposed here also calls for prioritizing the “trunk.” Maybe we’ll get lucky.
What won’t be achieved if the National Academies’ recommendations for ALS research priorities are accepted as the last word, however, is something different from the same old same old, at least not in the coming decade. To make ALS livable, genuine innovations are needed in the approach to drug development and collaboration between the National Institutes of Health, the Advanced Research Projects Agency for Health, ALS nonprofits, and industry players to make it happen.
The National Academies passed the buck. Who accepts the mantle of leadership is now to be seen.
Bernie Zipprich, M.B.A., is a health care innovation expert and founder of Zipprich Ventures LLC, an advisory practice focused on accelerating treatments for ALS and similar conditions. He is also a trustee of the ALS Association and a research ambassador for the Northeast ALS Consortium. The views expressed here are his own.