# Innovative treatments of pediatric spinal muscular atrophy: The decision-making process in France

Maelle Biotteau, Juliette Ropars, Brigitte Chabrol, Isabelle Desguerre, Christine Barnéria, Claude Cancès

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Maelle Biotteau, Juliette Ropars, Brigitte Chabrol, Isabelle Desguerre, Christine Barnéria, et al. Innovative treatments of pediatric spinal muscular atrophy: The decision-making process in France. European Journal of Medical Genetics, 2025, 78, pp.105044. 10.1016/j.ejmg.2025.105044. hal-05525123

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# Innovative treatments of pediatric spinal muscular atrophy: The decision-making process in France

## ARTICLE INFO

Handling Editor: A. Verloes

Keywords:

Spinal muscular atrophy

Pediatric population

Treatments

Innovative therapy

Decision-making

Consensus

Multidisciplinary team meeting

## ABSTRACT

Spinal muscular atrophy (SMA) is a devastating early-onset genetic disease characterized by motor neuron degeneration. For several years, an early access program has facilitated the use of three innovative therapies in France. To better define the therapeutic strategy following innovative therapy approval, an online expert committee within the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) evaluates early diagnosed children and treatment-naive SMA cases during pediatric SMA multidisciplinary team meetings (psMTMs). The decision process leading to molecule choice or palliative care encompasses pretreatment data collection, case presentation during psMTMs, decision support, collective decision-making, and consensus, including the place assigned to parents. The process of setting up a nationwide online network of experts seems to be an effective, reactive and useful procedure in choosing the appropriate therapeutic option for newly diagnosed SMA children.

<figure><img src="image_3.png" /></figure>

## What's new

MTM, well-developed in the field of oncology or chronic illness, have goals to provide the best possible recommendation for patients (care, and treatment). Unsystematic in pediatric SMA, we developed MTM in France.

## 1. Introduction

Spinal muscular atrophy (SMA) is a fatal autosomal recessive neuromuscular disorder with an estimated incidence of approximately 1:10,000 live births (Verhaart et al., 2017a, 2017b). The disease is characterized by progressive degeneration of motor neurons, resulting in progressive proximal muscle weakness and atrophy. SMA is divided into five types according to disease severity and age of onset: 1 for the most severe form to 4 for the mildest, and 0 as a prenatal form with decreased in utero movement or a neonatal form. In its most severe form, SMA leads to paralysis and early death if untreated.

SMA symptoms are associated with the degeneration of alpha motor neurons in the anterior horn cells of the spinal cord, caused by the loss or deletion of the survival motor neuron 1 (SMN1) gene located on chromosome 5q13.2. This telomeric gene is responsible for the production of the survival motor neuron (SMN) protein. Homozygous deletion of SMN1 – or more rarely, mutation in another gene or small mutations – abolishes the production of these proteins. SMN2, a paralogous centromeric gene (located on chromosome 5), also produces functional SMN proteins, but at very low levels that cannot fully compensate for the absence of SMN1 and are thus insufficient to prevent disease (Lorson et al., 1999; Wirth et al., 2013). The number of SMN2 copies varies from individual to individual and is inversely related to disease severity. Indeed, having more copies of SMN2 ensures that the amount of produced SMN protein is higher. SMN2 thus acts as a disease modifier:

patients with a higher copy number have milder disease (Wirth et al., 2006; Calucho et al., 2018).

Until recently, SMA was considered incurable. However, treatments for this disease have emerged, with research making remarkable and steady progress in just a few years, changing the disease outcome for many patients. Particular attention has been paid to the introduction of new therapeutic approaches aimed at modifying the splicing of SMN2 or replacing the SMN1 gene. Three disease-modifying treatments have been developed. Two are SMN2 pre-mRNA splicing modifiers that increase SMN protein production (nusinersen, Spinraza® and risdiplam, Évrysdi®). One is a gene therapy (GT) that acts as a SMN1 gene replacement therapy (onasemnogene abeparvovec, Zolgensma®).

A spectrum of positive outcomes was reported with these novel drugs before the end of phase III, leading to early access programs for medicines (EAPs). In 2016-17, Spinraza became the first therapy to be approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), followed by Zolgensma in 2019-20, and Evrysdi in 2020 (Fig. 1). Given the need for a healthcare procedure for dealing with the situation created by this EAP, some French clinician joined together in a pioneering and unique decision-making process to better assess who, when and how treat to SMA children, following Multidisciplinary Team Meetings model.

Multidisciplinary Team Meetings (MTM), developed some 25 years ago in the field of oncology (Winters et al., 2021), have goals to provide the best possible recommendation for treatment, care or management of patient, and sometimes when necessary, to homogenize medical care on the scale of a territory. Well-described in Taylor et al. (2013), the core MTM elements are “inclusion of a range of health professionals who can make unique contributions to decision-making about the management of individual patients, and a forum in which they can communicate these contributions”. Based on a full description of UK Department of Health, authors defined multidisciplinary team as “a group of people of different
<figure><img src="image_4.png" /></figure>

TUA: Temporary Use Authorization; nTUA: Nominative TUA; nTUAwp: Nominative TUA without TUP; cTUA: Cohort TUA; AM: Marketing Authorization; ① Phase study on nusineren [11]; ② Phase study on onasemnogene abeparvovec [12]; ③ Phase study on risdiplam [13].

<caption>**Fig. 1. Timeline**</caption>

TUA: Temporary Use Authorization; nTUA: Nominative TUA; nTUAwp: Nominative TUA without TUP; cTUA: Cohort TUA; AM: Marketing Authorization; ① Phase study on nusineren (Finkel et al., 2017); ② Phase study on onasemnogene abeparvovec (Day et al., 2021); ③ Phase study on risdiplam (Darras et al., 2021).

health care disciplines which meets together at a given time (whether physically in one place or by video or teleconferencing) to discuss a given patient and who are each able to contribute independently to the diagnostic and treatment decisions about the patient." Thus, gather experts from various fields and various locations, MTM enable clinicians to discuss patient' clinical observations or tests results, increasing accuracy of the evaluation of the context. The presence of different medical specialty ensures collection of additional clinical opinions, enabling to weigh cooperatively the advantages and disadvantages of each treatment approaches. Patient management and optimal treatment choice may therefore be facilitated by the discussion between different specialties present at the MTM, supporting high-quality decision-making (Lamb et al., 2011; Soukup et al., 2018).

If MTM is frequent and even sometimes mandatory in several care disciplines (oncology, psychiatry, palliative care, chronic disease, etc.), this practice is quite scarce in neuromuscular disease, unsystematic and, to our knowledge, non-existent in pediatric SMA.

## 1.1. Aims and objectives

Practical clinical experience in the French decision on treating pediatric patients with innovative therapies began in 2017 and was generalized to all new SMA patients in the summer of 2019. The effects and impact of these three therapies have remained under investigation, yet no independent clinical trials directly evaluating the short- and long-term efficacy, side effects and safety of these disease-modifying therapies in pediatric SMA have been conducted. However, in response to the EAP, physicians needed to organize quickly, even in the absence of robust scientific data. In our pediatric SMA multidisciplinary team meetings (psMTM), we use a large set of medical data (clinical data, nutritional and respiratory status, motor function scores, multiple biological assessments) and clinical expertise to reach consensus on each newly diagnosed patient. The objective of this consensus is to determine patient care and innovative treatment modalities. In this paper, we describe with precision the decision-making.

## 2. Description of the emergence of French pediatric SMA multidisciplinary team meetings

In France, each of these new therapies became available under an EAP called the Temporary Use Authorization (TUA). The TUA system makes it possible to treat children very early on (Fig. 1), without guidelines that might hinder rapid treatment for several months or years. Yet, from the outset, no independent study or direct head-to-head comparative studies were available. For nusineren, the first study was available in November 2017, 14 months after the TUA was issued (September 12, 2016) (Finkel et al., 2017). For onasemnogene abeparvovec, the first study was published in July 2021, although a TUA was issued on May 21, 2019, 2 years earlier (Day et al., 2021). For risdiplam, a TUA was issued on March 24, 2020, and the first study was conducted in July 2021 (Darras et al., 2021).

During these long periods between TUA issuance and study results, there were distinct phases.

- The first phase was characterized by no guidance.

- The second was characterized by a Therapeutic Use Protocol (TUP) that covered some aspects of patient safety and access to treatment or, on the contrary, ineligibility. However, these TUPs were often incomplete and not very informative.

In both phases, patients were treated on a case-by-case basis (called a Nominative TUA [nTUA]), without a TUP and then with a TUP.

- The third and last phase began when the nTUA grew into a group/ cohort program (Cohort TUA: cTUA), with the TUP sometimes improving a bit, but not systematically.

When the accelerated approval system was first developed to provide early access to treatments in therapeutic areas with limited therapeutic alternatives, clinicians faced great difficulties. There was a lack of knowledge about safety and tolerability issues and contraindications, a lack of studies supporting the clinical benefits, and little documentation about methods of administration, long-term adverse effects, etc.
<table><caption>**Table 1**
Compulsory minimal clinical dataset in all expert centers.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Age</td><td></td></tr><tr><td>Clinical subtypes of SMA:</td><td>SMA0, SMA1, SMA2, SMA3</td></tr><tr><td>Genetic status:</td><td></td></tr><tr><td>- SMN1 copy number</td><td></td></tr><tr><td>- SMN2 copy number</td><td></td></tr><tr><td>Additional clinical investigations:</td><td></td></tr><tr><td>- Anti-adeno-associated virus serotype 9 antibodies (anti-AAV9 antibodies)</td><td></td></tr><tr><td>- Hematologic profiles</td><td></td></tr><tr><td>- Biological-hepatic balance</td><td></td></tr><tr><td>Medical history:</td><td></td></tr><tr><td>- Patient medical history (pregnancy, birth, illness histories, etc.)</td><td></td></tr><tr><td>- Family history of neurological diseases (family genealogical tree, neurological illness among parents, brothers and/or sisters, etc.)</td><td></td></tr><tr><td>- Patient history of the disease, especially initial motor, respiratory and nutritional symptoms with estimation of onset ages</td><td></td></tr><tr><td>Current clinical examination:</td><td></td></tr><tr><td>- Height</td><td></td></tr><tr><td>- Weight</td><td></td></tr><tr><td>- Head circumference (HC)</td><td></td></tr><tr><td>- Thoracic circumference (TC)</td><td></td></tr><tr><td>- Presence or absence of failure to thrive</td><td></td></tr><tr><td>Respiratory function evaluation:</td><td></td></tr><tr><td>- TC/HC ratio</td><td></td></tr><tr><td>- Night capnography or polysomnographic sleep or non-invasive ventilation</td><td></td></tr><tr><td>- Chest radiograph</td><td></td></tr><tr><td>Bulbar function evaluation:</td><td></td></tr><tr><td>- Weight trend</td><td></td></tr><tr><td>- Impaired/unimpaired swallowing, wrong way and/or nutritional support</td><td></td></tr><tr><td>Both qualitative and quantitative motricity evaluation:</td><td></td></tr><tr><td>- Hammersmith Infant Neurological Examination (HINE2)</td><td></td></tr><tr><td>- Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) or, after 2 years, Hammersmith Functional Motor Scale (HFMS)</td><td></td></tr><tr><td>- Measurement and recording of muscular strength</td><td></td></tr><tr><td>Compound motor action potential (CMAP)</td><td></td></tr><tr><td>Two videos:</td><td></td></tr><tr><td>- During spontaneous movement (movement on an examining table)</td><td></td></tr><tr><td>- In bath, during free movement without gravity</td><td></td></tr></tbody></table>

Each French clinician had the choice to treat or not each child individually or to treat all children without exception. This led to a variable decision-making process depending on the medical team. It thus became urgent to standardize the management and follow-up of the children throughout the territory: to standardize the criteria for deciding whether or not to propose innovative therapies to a family, to choose between curative or palliative care, and to decide which innovative therapies to propose. A common organization had to be found.

Following the first National Plan for Rare Diseases (2005–2008), the second National Plan for Rare Diseases (2011–2016) made it possible to mobilize all the actors in the field of rare diseases to pool their skills by creating 23 networks for rare diseases throughout France. One of them, FILNEMUS, is a healthcare network dedicated exclusively to neuro-muscular diseases. FILNEMUS is made up of about 30 expert centers throughout the country.

All the expert reference centers supported the idea of joining together to form a synergy of skills to better evaluate the medical records of newly diagnosed SMA children during psMTMs. A group of SMA experts from each of the FILNEMUS expert centers was formed to constitute the psMTM consortium (Pediatric neurologist, Neurologist, Specialist of physical and rehabilitation medicine, Geneticist). Approximately 60 members, covering the entire French territory, make up these psMTMs, which are coordinated by a duo (two pediatric neurologists). These two coordinators are elected (usually volunteers) and renewed every three years, in agreement with the FILNEMUS's Executive Committee. They are responsible for circulating requests for advice, managing psMTM, summarizing all proposals and issuing the final written proposal.

The members meet twice a month on a fixed date. Other psMTMs are also organized occasionally in cases of emergency at a member's request. A robust and efficient network exchange by e-mails has also been set up to make collective decisions between psMTMs.

The psMTM takes place through video-conferencing with ROFIM, a secure digital health platform that provides a dedicated space to facilitate the exchange of information between health professionals. A robust authentication system allows practitioners to perform various actions related to the diagnosis and monitoring of patients.

The referring clinician who wants to discuss a patient in the psMTM must first inform the parents, who must give consent before the psMTM can discuss their child's records. The clinician then enters the patient's record into the software (ROFIM), which leads to immediate contact with all members of the team to share clinical data. ROFIM provides secure access to all members. The requested files are standardized across the centers and include: (1) a simple form with a minimum of requested data including clinical and non-clinical information, genetics, viral status (anti-AAV9), radiographs, etc. (Table 1); and (2) two videos of the child: one in a spontaneous situation (in daily life or under examination) and another in a bath in order to see the child's residual motor skills without gravity.

Between June 2019 and September 2024, 227 child's medical situation (new diagnoses) have been systematically discussed in psMTM. In fact, this represents all cases from SMA0 to SMA3. The discussion process and adoption of therapeutic decision is detailed below.
### 3. Description of the conduct of the psMTM

During the psMTM, the patient's case is presented by the physician in charge at the local neuromuscular center. The presentation includes the familial context, family and medical history, neurodevelopmental milestones, clinical examination (neurological, nutritional, respiratory, osteoarticular), genetics (SMN1 gene analysis, number of SMN2 copies), and most often a video of the child being bathed. The referring physician also present parents' preferences, collected prior to the psMTM when the diagnosis is announced. These therapeutic preferences are considered during the psMTM.

The experts then discuss the different therapeutic options (onasemnogene abeparvovec, nusinersen, risdiplam or palliative care) based on the patient's characteristics. The members discuss the case until they reach consensus and adopt a therapeutic proposal by collegial decision.

Today, 63 experts are registered to this psMTM, 20 to 25 are regularly connected every 15 days. A minimum quorum is required for decision-making, i.e. 10 experts from at least 10 different centers.

To guide and structure the psMTM discussions, we use a decision-tree (Fig. 2) that presents a clear and structured decision flow. We have developed this decision-tree over time to help us discuss each clinical case on a common objective basis. This decision-tree is the result of experiential knowledge (and not the result of a standardized consensus process; e.g. the Delphi method). It has been (and still is) progressively improved over the years by our feedback on each situation, publication of real data studies and updating government recommendations (Day et al., 2021; Mercuri et al., 2021; Schwartz et al., 2024). It is therefore regularly updated and modified.

This decision tree forms the basis of our discussions. It can also help us reach a consensus. But it does not replace the need for group discussion. The psMTM can deviated from this decision-tree, especially to better takes account of the family's opinion or wishes or to better

responds to the evolution of treatment proposals over time or even to adapts to a specific clinical situation.

The final decision is left to the referring physician, who knows the child. There is no obligation to follow the advice of the psMTM, which is advisory. Decisions are always open-ended but in practice, the referring physician deviate rarely from the opinion of the psMTM (less than 10 %). This deviation is always justified and argued in the context of the child, and greatly respected given the referring physician has the best overview of the family's personal situation as well as on the medical situation of their patient.

The therapeutic proposal is then explained to both parents who decide freely whether or not to follow this recommendation. When the parents do not wish to risk a very negative functional outcome (risk of excessive disability), a discussion and ethical decision may be taken, even if the psMTM initially favored treatment. If the parents want treatment at all costs, despite the unfavorable and severe prognosis of the disease, and even though the psMTM has proposed palliative care, the final decision remains with the referring physician and the family.

A standardized form is progressively completed, first by the referring clinician before the psMTM and second by the coordinators during and after the psMTM. It includes the clinical data and the video, the discussion points put forward by the experts before and during the psMTM, and a conclusion. This conclusion is entered at the end of the form, in a section entitled "psMTM's opinion". The entire form is then uploaded into the patient's medical record by the referring physician. It is thus made available to the medical professionals who follow the child, as well as to the psMTM experts (traceability of the national psMTM decision in the patient's medical record).

Some results of our work, especially for the treatment of children with SMA1, are currently available (Desguerre et al., 2024; Audic et al., 2020, 2024) and show the efficiency of the process.

<figure><img src="image_5.png" /></figure>

PC: palliative care; psMTM: pediatric SMA multidisciplinary team meetings; GTT: gene-targeted therapy; SMT: splicing modulation therapy; Monito.: Monitoring;

* choice of the risdiplam vs nusinersen molecule often depending on the age of the child (parents of an adolescent are more likely to choose risdiplam).

<caption>**Fig. 2.** Decision-making process: the decision tree</caption>

PC: palliative care; psMTM: pediatric SMA multidisciplinary team meetings; GTT: gene-targeted therapy; SMT: splicing modulation therapy; Monito.: monitoring;

* choice of the risdiplam vs nusinersen molecule often depending on the age of the child (parents of an adolescent are more likely to choose risdiplam).
## 3.1. Decision-making process: the decision tree (Fig. 2)

## 4. Conclusion

Seven years ago, it became urgent to specify and standardize a French framework for the introduction of new SMA treatments. To address the complexity and opacity of delivering innovative therapies, the questions that arose about the quality of life achieved with this gain of survival, and the cost of a treatment in relation to its effectiveness, psMTMs made it possible (and still make it possible) to define more precisely which patients were eligible for which innovative treatment, under which circumstances. The psMTMs also led to the standardization of several processes across centers (information to doctors and families, good understanding of the risk-benefit of treatment, discussions of alternative treatment and palliative care, control of risks based on dose administered vs weight, etc.), the specification of treatment options (single treatment or combination of two therapies), and long-term monitoring. It is interesting to note here that with hindsight our decisions would be the same, as a retrospective blinded analysis of our data showed robust reproducibility. Of course, some procedures need to be strengthened and improved. This includes the analysis of the children's movements on video. Their interpretation is currently quite subjective and the use of computer modeling is being investigated. Nevertheless, we believe that this way of working to make decisions about innovative treatments in pediatric SMA has substantial advantages. After almost seven years, it seems that such a strong consensus has emerged among patients, families and physicians that we believe it is in the interest of the international community to extend such methodologies to other countries. Noted however that this decision-tree corresponds to a French expert consensus, guided by French recommendations, guidelines and experiences (for e.g., for the question to untreated children because extremely poor prognosis). It cannot be automatically transferred to other countries or treatment situations.

### CRediT authorship contribution statement

Maelle Biotteau: Writing original draft – Review & editing - Supervision, Investigation, Conceptualization. Juliette Ropars: Review & editing. Brigitte Chabrol: Review & editing. Isabelle Desguerre: Review & editing. Christine Barnéria: Review & editing. Claude Cances: Writing original draft – Review & editing - Supervision, Investigation, Conceptualization.

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

Not applicable.

### Availability of data and materials

Not applicable.

### Funding

This study was partially supported by the FILNEMUS healthcare chain.

### Declaration of interest statement

The authors declare that they have competing interests.

### Acknowledgments

The authors thank the FILNEMUS healthcare chain, Rofim technical support and all the clinicians, past or present, who have participated in the French pediatric SMA multidisciplinary team meetings.

### List of abbreviations

AM Marketing Authorization

Anti-AAV9 Antibodies Anti-adeno-Associated Virus Serotype 9 Antibodies

TUA Temporary Use Authorization

CHOP INTEND Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders

CMAP Compound Motor Action Potential

EAM Early Access Program for Medicines

FDA Food and Drug Administration

FILNEMUS French Rare Health Care for Neuromuscular Diseases Network

GT Gene Therapy

HC Head Circumference

HFMS Hammersmith Functional Motor Scale

HINE2 Hammersmith Infant Neurological Examination

psMTM Pediatric SMA Multidisciplinary Team Meetings

PTU Protocol for Therapeutic Use

SMA Spinal Muscular Atrophy

SMN Survival Motor Neuron

TC Thoracic Circumference

### Data availability

The data that has been used is confidential.

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Maelle Biotteau<sup>a,b,*</sup>, Juliette Ropars<sup>c</sup>, Brigitte Chabrol<sup>d</sup>,
Isabelle Desguerre<sup>e,f</sup>, Christine Barnéria<sup>f</sup>, Claude Cances<sup>a</sup>

<sup>a</sup> *Pediatric Neurology Unit & Reference Center for Neuromuscular Diseases*
*AOC, Children's Hospital, Toulouse University Hospital Center, Toulouse,*
*France*

<sup>b</sup> ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM,
UPS, France

<sup>c</sup> LaTIM INSERM UMR 1101, French Reference Center for Neuromuscular Diseases, Brest University Hospital Center, Hôpital Morvan, Boulevard Tanguy Prigent, Brest, France

<sup>d</sup> Department of Pediatric Neurology, French Reference Center for Neuromuscular Diseases, Hôpital Timone Enfants, 264 rue Saint-Pierre, Marseille, France

<sup>e</sup> IHU Imagine, Paris University, 24 Boulevard du Montparnasse, Paris, France

<sup>f</sup> Department of Pediatric Neurology, French Reference Center for Neuromuscular Diseases, AP-HP, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris, France

<footnote>* Corresponding author. Pediatric Neurology Unit & Reference Center for Neuromuscular Diseases AOC, Children’s Hospital, Toulouse University Hospital Center, Toulouse, France.
E-mail address: biotteau.m@chu-toulouse.fr (M. Biotteau).</footnote>