Reply: A new diagnostic entity must enable earlier treatment in gene carriers

In their Letter to the Editor, ‘A new diagnostic entity must enable earlier treatment in gene carriers’, Swidler et al.¹ highlight the recent description of prodromal clinical states that precede amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)^2,3 and call to attention many important issues that are worthy of public discourse. While we agree with most of their arguments, we wish to provide some context and clarifications related to these points in their letter: that presymptomatic gene mutation carriers are patients with significant clinical care needs; that those who are susceptible to ALS based on genetic risk or have developed prodromal disease ‘deserve access to efficacious interventions or interventional clinical trials as they desire’; and ‘whether it is past time to move from observation to intervention’ in this population.

 

Distinction between research and clinical care

Broadly put, the goals of clinical care are to improve the health and wellbeing of people seeking medical attention from healthcare professionals. The goals of research, by contrast, are to advance scientific understanding that can one day translate into the advancement of clinical care. Clinical trials, for example, are—at their core—scientific experiments. Importantly, in research (and indeed in clinical care), all appropriate measures must be taken to minimize harm and to protect the wellbeing of research participants. Parenthetically, although the federal regulations that govern human research are replete with the term ‘human subjects’, we prefer to describe those who volunteer for research as ‘participants’ rather than ‘subjects’, given that they participate in research rather than being the subject of research.⁴

An area where the distinction between research and clinical practice is crucial is the social and legal consequences that may result from disclosure of information generated in these different arenas. Healthcare data, for example, may be accessible to commercial entities such as insurance companies, with implications for patient eligibility for disability and life insurance. By contrast, research studies may ensure strict separation between research and medical records, with tools such as a Certificate of Confidentiality to shield sensitive research data (e.g. genetic risk for disease) from access by insurance companies. Presymptomatic mutation carriers should therefore take this into consideration if seeking clinical care related to their genetic risk.

Distinction between susceptibility and disease

Susceptibility implies a state of being ‘at risk’ for a disease that one does not yet have. Susceptibility and disease are not one and the same. Smoking, for example, is a risk factor for lung cancer. However, the fact that someone smokes does not mean that they have lung cancer. We do, however, recognize that the boundaries between susceptibility and disease are currently hard to define in ALS. For example, an elevation in neurofilament levels, which is a marker of axonal degeneration, may indicate that disease has begun—but not when it began. In addition to the scientific rationale for not conflating susceptibility and disease,⁴ there are also compelling sociolegal factors to consider. For example, the Genetic Nondiscrimination Act (GINA) affords protection in the context of genetic risk for disease, but only so long as disease has not yet manifested. Conflating susceptibility to disease with disease itself would undermine such protection.³

Importantly, regardless of the distinction between susceptibility and disease, we recognize the healthcare needs of those at genetic risk for ALS/FTD. We also agree that the infrastructure to effectively support such care is still in its infancy, with frequent reliance on support (e.g. genetic testing and counselling) available through natural history studies such as Pre-Symptomatic Familial ALS (Pre-fALS).⁵ We (M.B., J.W.) also note, based on interactions with Pre-fALS participants, that not all presymptomatic mutation carriers view themselves as patients, underscoring the importance of recognizing the diversity of perspectives embraced by this community.

Access to efficacious interventions or interventional trials

We agree with—and indeed have been longstanding proponents of—earlier, even preventative, treatment, as this is likely to be the most effective. The simplicity of this idea, however, belies a much greater complexity.

The FDA has approved four drugs for treating patients diagnosed with ALS (riluzole, edaravone, sodium phenylbutyrate/taurursodiol, and tofersen). Nevertheless, the evidence supporting the therapeutic value of these agents varies, as does the potential for adverse effects. For example, the efficacy of sodium phenylbutyrate/taurursodiol (sold in the USA as Relyvrio) in treating ALS patients is far from established and pending the results of the ongoing PHOENIX phase 3 trial. Similarly, the ongoing phase 3 ADORE trial in Europe will impact our view of the efficacy of edaravone. With the efficacy of these drugs in presymptomatic disease entirely unknown, as well as their prohibitive cost and the accompanying practice by insurance payers of restricting coverage to those meeting eligibility criteria of pivotal studies, the cost-benefit ratio in presymptomatic mutation carriers is difficult to determine. On the other hand, tofersen, an intrathecally administered SOD1 antisense oligonucleotide, may be associated with significant side effects. Its risk-benefit ratio therefore varies enormously from person to person, depending on, for example, whether the SOD1 mutation carrier is 1–2 years or 40 years from developing clinically manifest disease (or may never do, given that some SOD1 mutations have incomplete penetrance).

Access to interventional trials for presymptomatic mutation carriers requires that such trials exist—and they are currently few and far between, in large part because of critical gaps in our knowledge. For example, if efficacy is to be measured based on a clinical end point such as phenoconversion to clinically manifest disease, then it will be necessary to identify and enrol those at greatest risk of developing clinically manifest ALS within the timeframe of a trial—and our tools for identifying this subset of the population are currently quite limited. If efficacy is to be measured based on a surrogate end point, then significant work still needs to be done to validate biomarkers to fit this purpose. As explained below, observational studies, including natural history studies, are critical to filling these knowledge gaps.

Transitioning from observation to intervention

While we have indeed entered an era of ALS prevention trials, and some presymptomatic mutation carriers have successfully availed themselves of therapies FDA-approved for use in ALS patients, we would venture that observational studies remain essential and should continue in parallel to clinical trials. In the same way that the discovery of blood neurofilament light (NfL) elevation in a subset of SOD1 mutation carriers before phenoconversion⁶ was instrumental to the design of the ATLAS trial,⁷ other biomarkers (alone or in combination) will be crucial to the successful implementation of disease prevention trials in carriers of other gene mutations. In addition, the optimal eligibility criteria (e.g. definitions of prodromal clinical states) and outcome measures (e.g. phenoconversion to ALS and/or FTD) to employ in these trials are as yet unclear. As such, the feasibility and success of future prevention trials critically depends on the quality of data generated from carefully designed and rigorously conducted observational studies.

While we should not conflate the off-label use of an FDA-approved drug with evidence of efficacy, it would not be unreasonable for individual presymptomatic mutation carriers to discuss with their physician the pros and cons of such off-label use. This is an individualized discussion best suited to the confines of a patient-doctor relationship. Incidentally, a nascent effort is underway to develop a guidance document to support the clinical care of presymptomatic mutation carriers. An additional consideration is the logistical complexity of securing insurance approval and the operational burden that this places on physician and office staff, which is time away from direct patient care.

Conclusion

We recognize and appreciate the sense of urgency articulated in this Letter to the Editor. For perspective, we have gone from the idea of disease prevention, which was ridiculed when first proposed by the Pre-fALS investigators, to the first-ever ALS prevention trial (ATLAS) in <15 years. [Parenthetically, our (M.B., J.W.) first attempt at initiating an ALS prevention trial was back in 2010, but we were unsuccessful in securing the funding for a randomized placebo-controlled trial to study riluzole in presymptomatic mutation carriers.] While this pace is not fast enough, significant progress has been made. Given how much we have learned about presymptomatic disease and prevention strategies from studies such as Pre-fALS, what we anticipate will be learned from ATLAS, and the increased interest in and funding for presymptomatic research, we can expect the rate of progress to accelerate.

Ultimately, we agree with the central premise that delineation of prodromal ALS as a new clinical entity should enable earlier treatment of presymptomatic mutation carriers. We would, however, go even further, and venture that a better understanding of mild motor impairment (MMI), which is not specific to mutation carriers, should empower early intervention of those with a high likelihood of developing genetic as well as non-genetic (‘sporadic’) forms of ALS. But some caution is needed. MMI was only described relatively recently^2,3 and significant work remains to develop a formal operational definition of this clinical syndrome so that it can be better understood. This in turn, should empower earlier diagnosis and earlier therapeutic intervention for all patients with ALS—as well as those at genetic or non-genetic risk for ALS.^2,8

Data availability

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Competing interests

M.B. reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study. M.B. also serves as the global principal investigator for the ATLAS study. A.A.-C. reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, Sanofi, and Wave Pharmaceuticals, and the following patent currently being reviewed: Use of CSF-Neurofilament determinations and CSF-Neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases. A.C. reports no conflicts. J.W. reports grants from the National Institutes of Health and the ALS Association.