Experts Agree Ventilated SMA Patients Deserve Access to Disease-Modifying Therapies

People living with spinal muscular atrophy who depend on permanent ventilation should not be excluded from disease-modifying therapies simply because they breathe with mechanical support, according to a new UK expert consensus. A modified Delphi process involving 19 multidisciplinary specialists has produced 22 consensus statements defining how treatment benefit should be assessed, monitored and judged in this severely affected and historically overlooked patient group. The process ran from 8 April to 9 June 2025 and reached agreement after just two voting rounds, with every one of the 18 voting participants taking part in both.

Spinal muscular atrophy is a rare inherited neuromuscular disorder affecting an estimated 1.14 to 1.78 individuals per 100,000. In most cases it is caused by mutations in the SMN1 gene, which reduce production of survival motor neuron (SMN) protein, driving progressive muscle weakness and atrophy. Disease severity depends largely on age at onset and the number of SMN2 gene copies, which partially compensate by producing a limited amount of functional protein. Types range from the most severe Type 0, with prenatal onset, to the mildest Type 4, with adult onset.

Respiratory failure is the critical complication. Weakened respiratory muscles impair secretion clearance and cough, leading to recurrent infections and eventual ventilatory dependence, while scoliosis and chest wall deformities compound the burden. Permanent ventilation is defined as invasive ventilation via tracheostomy, or at least 16 hours of non-invasive ventilation per day for 21 consecutive days. Three disease-modifying therapies are approved for SMA: risdiplam, nusinersen and onasemnogene abeparvovec, which raise functional SMN protein through different mechanisms. Yet until recently, UK access pathways under National Institute for Health and Care Excellence managed access agreements excluded patients already on permanent ventilation, leaving their management limited to supportive or palliative care and compassionate use programmes.

The consensus effort was designed to break a circular problem: sparse clinical evidence restricts treatment access, and restricted access prevents the generation of real-world evidence. A targeted literature review of MEDLINE and Embase from database inception to October 2024, supplemented by grey literature, identified 91 relevant articles. It confirmed that clinical trials rarely include patients already on permanent ventilation at baseline, that post-ventilation outcome data are limited to small observational studies, and that standard SMA outcome measures are often infeasible or insufficiently sensitive in this population. No prior consensus or published guidance existed on how treatment benefit should be defined or monitored.

The Delphi panel comprised a non-voting Chair, three additional voting steering committee members and 15 voting panellists, spanning paediatric and adult neurology, neuromuscular medicine, respiratory medicine and physiotherapy, with individual experience ranging from 8 to 29 years. Recruitment achieved an 83 percent response rate. Alongside the voting process, a five-member patient advisory panel of adults with SMA on permanent ventilation, caregivers and an advocacy representative reviewed every draft statement and provided anonymised feedback, though it did not vote. Voting used a six-point Likert scale, with consensus predefined as at least 75 percent agreement, and a maximum of three rounds.

The results were striking. Twenty-two draft statements across seven themes entered the process, and 21 of them, 96 percent, achieved consensus in the first round. The single statement falling short, on cost and access, reached 72 percent agreement and was revised to acknowledge that resource-benefit analyses are essential for reimbursement decisions while maintaining that cost alone should not bar access. A second statement was revised after patient advisory feedback to emphasise maintaining the highest perceived quality of life possible. Both revised statements passed in round two, eliminating the need for a third vote.

The headline recommendations are pragmatic. Permanent ventilation alone should not preclude disease-modifying therapy, and access should incorporate a trial period of at least six months to determine benefit, irrespective of prior gene replacement therapy. Candidacy should be judged case by case against local guidelines, weighing age, disease stage, ventilator dependency, potential to wean and route of administration, with patients and caregivers agreeing realistic, individualised treatment goals. Ongoing care should follow international standards of care, with biannual multidisciplinary reviews, reducible to annual reviews in adults with stable respiratory and bulbar function.

Crucially, the panel redefined what counts as clinical benefit. Because conventional motor scales such as the Hammersmith Infant Neurological Examination module 2 may be impossible to perform or too insensitive, the experts endorsed broader outcome domains: patient- and caregiver-reported changes validated by the care team, diary records of subtle functional shifts, and fine motor indicators such as eye movement, facial expression and finger dexterity, including interaction with touchscreens and communication aids. Respiratory benefit may appear indirectly as more hours off ventilation, stronger cough or speech, and fewer infections, hospitalisations or suctioning needs. Quality of life should be assessed through validated instruments, including the SMA-QoL, Severe Respiratory Insufficiency Questionnaire, PedsQL and SF-36 or SF-12, combined with direct observation.

Supporting real-world evidence remains small and uncontrolled. One study of patients on invasive ventilation reported reduced daytime non-invasive ventilation use and fewer pulmonary infections over 12 months of SMN2-targeted therapy; another recorded a median increase in daily hours off ventilation from 8 to 10.5 over roughly 7.6 months on onasemnogene abeparvovec; and a separate study found reduced hospitalisations in four of 12 patients after two years of nusinersen. The authors caution, however, that patients with tracheostomy differ from those on non-invasive ventilation even without therapy, so attributing outcomes to any single intervention in uncontrolled settings is difficult.

The panel also flagged future priorities: harmonising patient-reported outcome measures in national registries, quantifying caregiver burden and healthcare resource use, and developing a validated functional assessment tool using remote video recording and wearable biometric data. Limitations include the UK-specific panel composition, the use of a targeted rather than systematic literature review, the advisory and non-voting role of patient representatives, and industry funding from Roche Products Ltd, which the authors state had no role in developing, voting on or interpreting the statements. The recommended six-month trial period is a minimum reassessment interval, not a validated threshold, and absence of measurable motor improvement at six months should not be read as absence of benefit. For a population long excluded from trials and treatment pathways, the consensus offers clinicians and policymakers a concrete framework for more inclusive, personalised care.

Subject of Research: Expert consensus recommendations on disease-modifying therapy use and benefit assessment in ventilated spinal muscular atrophy patients

Article Title: Defining the clinical benefits of disease-modifying therapy in people living with spinal muscular atrophy who require permanent ventilation: a UK-based modified Delphi consensus process

Article References: Scoto, M., Marini-Bettolo, C., Chan, E., Simonds, A. K., Baranello, G., Childs, A.-M., Edel, L., Edwards, C., Illingworth, M. A., Kulshrestha, R., Ong, M. T., Pabary, R., Parton, M., Ramdas, S., Sedehizadeh, S., Tan, H.-L., Wilkinson, S., Willis, T., Wraige, E., & Raslan, Z. (2026). Defining the clinical benefits of disease-modifying therapy in people living with spinal muscular atrophy who require permanent ventilation: a UK-based modified Delphi consensus process. eClinicalMedicine, 101, Article 104278. https://doi.org/10.1016/j.eclinm.2026.104278

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104278

Keywords: spinal muscular atrophy, permanent ventilation, Delphi consensus, disease-modifying therapy, risdiplam, nusinersen, onasemnogene abeparvovec, clinical benefit, quality of life, respiratory monitoring, patient-reported outcomes, UK healthcare