Muscle Atrophy and a New DMD Drug: From Sarcopenia Management to Updated Evidence on eteplirsen

Muscle Atrophy and a New DMD Drug: Treatment, Surrogate Endpoints, and Subsequent Evidence

Bottom line

Resistance exercise and adequate nutrition should be the foundation of care for sarcopenia in older adults. Eteplirsen for DMD is restricted to patients amenable to exon 51 skipping; although biomarker findings and subsequent observational signals are available, stronger evidence is still needed to clarify its clinical benefit. (PMID: 41923567; PMID: 41934514; PMID: 42324661; PMID: 41961051)

First, clarify what “muscle atrophy” means

In everyday language, muscle atrophy may refer to age-related losses in muscle mass and strength, or it may refer to Duchenne muscular dystrophy, or DMD, which has a defined genetic mechanism. Both affect muscle function, but their causes, clinical courses, and treatment questions differ. In sarcopenia among older adults, the central issue is how exercise and nutrition can maintain or restore function. In DMD, the issues include defects in the dystrophin gene, progressive deterioration of muscles throughout the body, and whether a particular genetic subtype is eligible for targeted treatment. Conflating the two can create the mistaken impression that a supplement can treat a genetic disease, or that a drug indicated only for a specific DMD subtype is a general treatment for muscle loss.

Sarcopenia in older adults: exercise and nutrition remain central

Professor Lin expressed reservations about the claim that approximately 3 g of HMB daily is necessary to maintain or restore muscle mass and strength in older adults, because sufficient evidence had not established such necessity. A more recent meta-analysis still does not support positioning HMB as a necessary, routine supplement for increasing muscle mass and strength in older people. The more accurate conclusion is not that HMB could never have an effect under any circumstances, but that current evidence is insufficient to support strong claims such as “routine use for everyone” or “indispensable.” (PMID: 41934514)

By contrast, a consensus-oriented review places resistance training and adequate nutrition at the center of sarcopenia management. This is consistent with Professor Lin’s core message, drawn from information provided by multiple institutions, that exercise is the best way to slow or reverse sarcopenia. In practice, readers should first determine whether physical activity, training, and overall nutrition have been properly addressed, rather than expect a single supplement or drug with supposedly established clinical benefit to replace these foundational strategies. (PMID: 41923567)

The genetics and disease mechanism of DMD

DMD is an X-linked recessive genetic disorder that occurs almost exclusively in males. Its fundamental cause is a defect in the dystrophin gene, which prevents muscle from producing dystrophin protein normally and leads to progressive muscle degeneration. The disease affects not only limb muscles but also muscles involved in breathing and cardiac function, and it can therefore be life-threatening. Professor Lin’s original account of the inheritance pattern, protein deficiency, and systemic disease course is consistent with the subsequent literature. (PMID: 42324661; PMID: 41892993; PMID: 40831143)

Statements about survival age should respect the medical context at the time the article was published while also recognizing that science and care have advanced. Updated evidence included in the ECU indicates that survival has increased with modern care. Fixed ages taken from older textbook descriptions therefore should not be treated as the inevitable outcome for every patient today. This reflects an updated literature and improvements in care; it does not rewrite the evidence environment in which Professor Lin was working. His core assessment—that the disease affects breathing and the heart and poses a risk to life—remains valid. (PMID: 41892993; PMID: 40831143)

Who is eligible for eteplirsen, and how does it work?

Eteplirsen, also known as Exondys 51, is an antisense oligonucleotide therapy designed for exon 51 skipping and was the first DMD drug of its kind to receive FDA approval. It applies only to genetic variants amenable to exon 51 skipping, which account for approximately 13% of DMD, and cannot be used by every patient with DMD. Eligibility depends on whether the patient’s genetic variant matches the drug’s skipping mechanism, not merely on the presence of a DMD diagnosis. (PMID: 42324661; PMID: 41961051; PMID: 40831143)

The objective of this mechanism is entirely different from that of ordinary nutritional supplementation. It targets a specific exon-skipping condition so that muscle cells can produce dystrophin. Precisely because eligibility is defined by genetic subtype, findings on eteplirsen cannot be extrapolated to sarcopenia in older adults or to patients with DMD whose variants are not amenable to exon 51 skipping. (PMID: 42324661; PMID: 41961051)

Accelerated approval does not mean that clinical function has been proven

The FDA granted eteplirsen accelerated approval on the basis of dystrophin production after treatment as a biomarker or surrogate endpoint, not on confirmed improvement in muscle function. Professor Lin’s key concern at the time was that “cells can produce the protein” could not be directly equated with “the patient’s muscle function has shown a clinically confirmed improvement.” Subsequent reviews continue to note that approvals of this kind rest on limited clinical data, that gaps exist between preclinical and clinical results, that confirmatory trials remain underway, and that debate continues. (PMID: 41961051; PMID: 42324661; PMID: 40547866)

A surrogate endpoint is not without value. For a severe disease with few treatment options, it can allow a therapy with a reasonable mechanism to reach clinical use sooner. The tradeoff is that post-approval evidence must still answer the questions patients genuinely care about: whether function, cardiac health, breathing, and the long-term course of disease improve. By evaluating the biomarker separately from clinical efficacy, Professor Lin’s original article preserved an essential evidentiary boundary for understanding accelerated approval. (PMID: 41961051; PMID: 42324661)

The literature has been updated: positive signals, but no final resolution

In 2016, Professor Lin was confronting an evidence landscape in which a surrogate endpoint had supported approval while clinical benefit remained uncertain. His strong skepticism about whether the drug offered meaningful benefit and whether its approval would persist had a legitimate basis in the evidence available at that time. By 2026, eteplirsen had not had its approval withdrawn, remained in use, and continued to be studied in confirmatory trials and long-term follow-up. This should be clearly identified as an update in the literature, rather than projecting later data backward as information Professor Lin already knew or as an update he personally made. (PMID: 42324661)

Subsequent evidence has produced several more positive signals. Nonrandomized real-world data suggest that left ventricular ejection fraction declined more slowly among people receiving eteplirsen and that they had a lower risk of reaching a lower ejection-fraction threshold. EVOLVE data also indicate long-term safety and high treatment continuation. These results mean that a strong implication of “almost no benefit” should be adjusted as the science evolves. Nevertheless, observational findings and treatment continuation cannot replace randomized trials that can establish clinical causal effects more reliably. The most balanced conclusion is that the drug’s approval has not been withdrawn and its subsequent signals deserve attention, but the central controversy over clinical benefit has not been definitively settled. (PMID: 40831143; PMID: 41961051; PMID: 42324661)

Principles for patients and families evaluating the evidence

When reading about treatments related to muscle atrophy, first ask which disease is being discussed, then ask who is eligible for the treatment, and finally ask whether the study measured a biomarker or patient function. Advertising for supplements should not distract people with sarcopenia from resistance exercise and adequate nutrition. For DMD, genetic testing must establish whether the variant is amenable to exon 51 skipping. When encountering the phrase “FDA approved,” readers should also determine whether approval followed full confirmation of clinical benefit or was accelerated on the basis of a surrogate endpoint. These questions preserve hope while preventing promotional language from filling gaps that the evidence has not yet closed. (PMID: 41923567; PMID: 41934514; PMID: 42324661; PMID: 41961051)