Abstract
The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.
BACKGROUND
Over the last decade, the natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care. Additionally, within the last five years, targeted treatments have been developed based upon a better understanding of the molecular genetics of SMA [1]. Nusinersen was the first drug to be approved for the treatment of SMA patients. The approval of nusinersen is based on well-controlled clinical trial data of a small subgroup of young pediatric patients [2, 3]. Data from early access programs (EAPs) have been published that provide experience with the treatment in a broader cohort of SMA type 1 patients [4–7]. Here, age at initiation of treatment was the most important factor determining the response to treatment regarding improvements in motor function. However, evidence is lacking for the long-term effect of nusinersen treatment and the response to treatment of older or more severely affected patients. Consensus statements for standards of care have been updated recently [8, 9], but they do not yet include recommendations for nusinersen treatment. Therefore, it is still challenging to advice patients and families to what extent they can expect a benefit from nusinersen treatment accepting the burden of a four-monthly intrathecal treatment.
Here, we report the results of a consensus process of child neurologists from Germany, Austria and Switzerland about the indication for nusinersen treatment in children with SMA type 1.
METHODS
We performed a consensus process among child neurologists from Germany, Switzerland and Austria from 03/2019 to 06/2019. All experts were child neurologists who were identified and contacted through the research network SMArtCARE [10]. Thirty-nine physicians were invited to participate in the expert consultation via email. The study was designed as a modified Delphi approach [11]. Thirty physicians confirmed their participation and received a questionnaire by mail to evaluate whether age at start of treatment, motor function, ventilator or nutritional support, or orthopaedic symptoms influence the decision about initiation or continuation of nusinersen treatment in children with SMA type 1. SMA type 1 was defined with onset of symptoms within the first six months of life independent of SMN2 copy numbers. To define the level of motor function, we used the CHOP INTEND [12, 13] and HINE-2 score [14]. We further investigated if difficulties with the intrathecal administration affect the decision about the continuation of nusinersen treatment. The questionnaire was developed and reviewed by members of the SMArtCARE steering committee. Twenty physicians participated in this first survey (response rate 71.4%). All physicians were invited to an expert panel to discuss the results of the first questionnaire. The meeting was attended by 16 physicians and led by members of the SMArtCARE steering committee. As result of the discussion, it was agreed that aspects such as nutritional support, orthopaedic symptoms and difficulties with the intrathecal application of nusinersen were not considered as key factors for a treatment decision. In addition, the HINE-2 score was considered to be too inaccurate to evaluate changes in motor function. Based on this panel discussion, the survey was modified and again forwarded to all participating physicians. Both questionnaires were completed anonymously. A translation of the second survey is provided in the supplement.
For all questions, we used a 7-point Likert scale. In the first part of the questionnaire, answers 1 and 2 on the Likert scale were assessed as agreement to initiate nusinersen treatment, answers 6 and 7 as rejection of treatment. Regarding the continuation of treatment in the second part of the questionnaire, answers 1 and 2 were evaluated as agreement to stop nusinersen treatment, and answers 6 and 7 to continue with treatment. Strong consensus and consensus were defined as percent agreement ≥95% and ≥75%, respectively [15]. A descriptive data analysis was performed by calculation of absolute frequencies and percentages.
RESULTS
Sixteen physicians participated in the second survey (response rate 53.3%). Of these, 73.3% came from Germany, 23.3% from Austria, and 3.3% from Switzerland.
Initiation of treatment
Strong consensus to initiate nusinersen treatment was only reached in children younger than 24 months not requiring ventilator support, having a CHOP INTEND score >10. In children less than 12 months of age, there was consensus to additionally start treatment in children not requiring ventilator support, having a CHOP INTEND score 3–10. In children younger than 24 months using non-invasive ventilation less than 16 hours per day, having a CHOP INTEND score >10, and in children using permanent or invasive ventilation, having a CHOP INTEND score >20 nusinersen treatment was recommended. In children older than 24 months of age, physicians consented to initiate nusinersen treatment in children having a CHOP INTEND score >10 either not requiring ventilator support or using non-invasive ventilation less than 16 hours per day. In children without any visible spontaneous motor function not being able to perform movements against gravity more physicians consented not to initiate nusinersen treatment than to initiate treatment independent of age and ventilator support. Consensus to not initiate treatment was reached for these children using permanent or invasive ventilation. In children older than 24 months of age with a CHOP INTEND score <3 using permanent or invasive ventilation, initiation of treatment was not recommended (see Table 1).
Physicians’ answers if they would recommend treatment with nusinersen in children with SMA type 1 in different stages of the disease
Continuation of treatment
During the panel discussion, there was consensus to continue treatment in all children showing improvements in motor function. In children with no changes in CHOP INTEND score or a worsening in CHOP INTEND score of 1-2 points, consensus was reached to continue treatment in children with a stabilisation or improvement of respiratory function. On the other hand, termination of treatment was recommended in children with a worsening in CHOP INTEND score of >5 points and a concurrent worsening of respiratory function (see Table 2). Further, in children using permanent or invasive ventilation, physicians consented to terminate treatment in children showing a worsening of motor function.
Physicians’ answers if they would recommend to continue treatment with nusinersen in children with SMA type 1 showing different responses to treatment regarding motor and respiratory function
Observation period
Regarding an adequate observation period to evaluate the response to treatment, 43.8% of physicians recommended an observation period of 12 months, 6.3% of 18 months, and 43.8% of physicians of 24 months.
DISCUSSION
The transfer of well-controlled clinical trial data into a real-life environment is challenging. Approval of nusinersen was based on clinical trial phase III data of a small pediatric patient cohort, but was nevertheless approved for all types of SMA patients. The cohort of infants with SMA type 1 within the clinical trial phase III was defined as having 2 SMN2 copies, aged less than 7 months and not requiring ventilator support, among other parameters. Recently published data on nusinersen treatment from different EAPs provide experience in a much broader cohort of patients with SMA type 1 including older and more severely affected children. In all of these studies, response to treatment regarding motor function significantly correlated with age at treatment onset having the most promising effect of treatment in children younger than 7 months of age. Bulbar function and the need for continuous or permanent ventilation was not significantly altered by nusinersen treatment [4–7]. Pane et al. evaluated their data subdivided into the different subtypes of SMA type 1. Here, children with the most severe phenotype SMA type 1.1 [16, 17] did not show significant changes in CHOP INTEND score in a 12-months follow up [18]. Based on these results, strong consensus to initiate nusinersen treatment was only reached in children younger than 24 months not requiring ventilator support, having a CHOP INTEND score >10. In children with very limited motor function, nusinersen treatment was not advised in children requiring permanent or invasive ventilation because it was not considered to have a significant effect on the severity of the disease.
Consensus was reached to continue treatment with nusinersen in case of an improvement or stabilization of motor function. Termination of treatment was only recommended in children with a worsening in CHOP INTEND score >5 points and a concurrent worsening in respiratory function. However, despite the positive effect of nusinersen treatment on motor function, the burden of recurrent lumbar punctures, the risk of analgosedation or general anesthesia or the exposure to radiation due to image-guided lumbar punctures have to be considered in the indication for nusinersen treatment. Therefore, it is crucial to objectively inform parents and patients before initiation of treatment to avoid unrealistic expectations and to explain to parents that treatment will probably not obviate the need for ventilator support or tube feeding. Situations such as worsening of respiratory or motor function that could lead to discontinuation of treatment should be discussed initially.
The main limitation of our consensus process is the lack of long-term follow-up data. Therefore, we focused on SMA type 1 patients having both clinical trial data and data from EAPs. In our study, physicians recommended an observation period of 12–24 months to evaluate the response to treatment as defined by an improvement of motor function. A longer observation period is required to assess a stabilization of the course of the disease. Further, symptomatic multidisciplinary treatment has improved significantly during the last decade, and therefore additionally influences the course of the disease. To provide recommendations for nusinersen treatment for patients of all stages of the disease, monitoring of long-term follow-up data in a real world environment is needed as we aim for within the SMArtCARE project [10]. In addition, treatment decisions are influenced by wishes of the families and ethical considerations.
Thus, any decision to initiate or stop nusinersen treatment for patients with SMA type 1 should be based on an individual informed consent process between caregivers and treating physicians and also depends on local availability and reimbursement policies. This consensus might help to guide this process.
CONFLICT OF INTEREST
AP received research funding and compensations for presentations and training activities from Biogen. MB received compensations for presentations from Biogen and AveXis. MvdH received compensations for presentations and taking part in advisory boards from Biogen, Avexis, PTC and Sarepta. JJ received travel support and registration fees from PTC Therapeutics, Biogen GmbH and consultancy fees from Sarepta Therapeutics, Biogen GmbH, PTC Therapeutics, and AveXis. AK received travel expenses and training activities from Biogen. BP received compensations for attending the Austrian Advisory board for SMN1 gene therapy by Avexis. OS received compensations for presentations from Biogen and consultancy from Avexis. MS received compensations for presentations and training activities for Biogen. CR received travel expenses from Biogen. CW received compensations for advisory board meetings and training attendance from Biogen. GW obtained honoraria for speaking engagements from Desitin (Hamburg, Germany) and Novartis (Nürnberg, Germany). He gave scientific advice for PTC Therapeutics (Frankfurt, Germany). EW received compensations for presentations from Biogen. BW received compensations for presentations and training activities from Biogen. US was/is site PI for the SMA studies by ISIS/Biogen, Novartis, Roche, Trophos/Roche. She was/is member of advisory boards from Biogen, Roche, Avexis/Novartis and received honoraria for oral presentations and adboards from Biogen, Avexis/Novartis, and Roche. JK received research funding and/or compensations for presentations and consultancy from Avexis, Biogen, Ionis Pharmaceuticals, Novartis, and Roche.
