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Jun 22 / Springer Healthcare

2021 Cure SMA Annual Conference In-Depth Report

Description

This Cure SMA 2021 in-depth report provides an overview of advances in clinical care, research and management of spinal muscular atrophy

Cure Spinal Muscular Atrophy (SMA)

June 7th – 11th, 2021

In-Depth Report

This year’s annual meeting of Cure SMA - the largest spinal muscular atrophy (SMA) conference in the world - was held virtually from June 7–11th 2021 and brought together leading research and healthcare professionals in the field, together with individual with SMA and their families.

Presidential Plenary Session

The 2021 virtual conference got underway with a welcome address by Cure SMA President Kenneth Hobby, Illinois, USA and Board Chairman, Nick Farrell, Cincinnati, USA, who gave an overview of recent progress in SMA and outlined key goals for the year ahead and beyond. Three drugs are now approved for the treatment of SMA, with many other programmes in ongoing clinical trials and earlier stages of development. The proportion of patients with SMA on active therapy has also been gradually increasing and it is now estimated that ~55% of all individuals with SMA in the USA are on treatment. We want this progress in securing access to therapy to continue, stressed Dr Hobby, and are targeting a figure of 60–70% of patients with SMA on treatment by the end of 2021. A total of 36 states in the USA are currently screening for SMA, equating to 74% of all newborn babies. The goal is to achieve a 95% screening rate by Q4 2021 to ensure SMA is diagnosed presymptomatically and treatment can be started as soon as possible, explained Dr Hobby. Currently, the median time from diagnosis to initiation of treatment stands at around 22 days. The SMA Care Centre Network, consisting of 19 specialist US hospitals, will be important for delivering optimised care and collecting real-world data to improve SMA management moving forward.

“Fantastic progress has been made with three approved treatments - Spinraza, Zolgensma and Evrysdi - that really focus on the underlying causes of SMA - but we have more to do and there is more in the pipeline.”

Kenneth Hobby

Available treatments for SMA act to slow disease development and prevent progression, said Dr Hobby, but the next big step will be to reverse SMA and restore patients’ function to reach a point where SMA can be considered ‘cured’. Current therapies are all survival motor neuron (SMN)-dependent, targeting SMA though the missing SMN1 gene or the backup SMN2 genes to boost levels of the critical SMN protein. A key driver of future therapeutic progress could therefore lie in the combination of different targets and new treatments, in particular SMN-independent approaches. These focus, not on genetics or proteins, but downstream areas of the body impacted by SMA - notably the motor neurons and muscles.

A Therapeutic strategies can be SMN dependent or independent

Therapeutic strategies in SMA

Improving access to treatment and care are one of the many Cure SMA goals

Key Cure SMA goals

Sleep problems seen in SMA

Individuals with all types of SMA are at risk for various sleep disorders. This workshop session discussed the impact of SMA on sleep and reviewed available options to optimise sleep for both patients and their families. There are two key drivers that promote sleep - homeostatic and circadian - and any factor that disrupts one or both of these can lead to insomnia. Richard Kravitz, Durham, USA, explained that the most common behavioural sleep problems in children with SMA are the same as those seen in healthy children and can be addressed with good sleep hygiene practices. However, the disease itself can also have a direct impact on sleep quality, with issues stemming from sleep-disordered breathing, patient discomfort and the need for ongoing night-time therapies.

 

Behavioural sleep problems in SMA

Sleep-disordered breathing is an issue in patients with SMA

Sleep-disordered breathing in SMA

Sleep-disordered breathing and associated ventilatory support pose particular issues in patients with SMA. The need to initiate respiratory support can be triggered by signs or symptoms of impaired sleep which include: restlessness, frequent awakening, sweating, morning headaches, daytime fatigue and afternoon ‘fading’. Breathing support options for patients include both invasive and non-invasive approaches, each of which has its own pros and cons. Non-invasive positive pressure ventilation (NIPPV) with bilevel positive airway pressure (BiPAP) can optimise sleep quality in patients with sleep-disordered breathing and allows for muscle rest and better quality of life. Currently, it remains unclear exactly how the three approved SMA drugs will impact sleep management, acknowledged Dr Kravitz, but the potential now exists for de-escalation of care. For example, weaning off NIPPV/BiPAP may be possible if treated patients remain ‘strong’ and/or asymptomatic. Use of data such as polysomnogram and overnight home pulse oximetry will be critical in guiding decisions and vigilance for potential clinical worsening due to viral illnesses remains important.

 
“Recently introduced medical therapies in SMA now allow for more flexibility in the management of SMA-related sleep disorders.”

Richard Kravitz, Durham, USA

Respiratory care in SMA

Muscle weakness places individuals with SMA at increased risk for breathing difficulties that may require breathing support during sleep, illness and after surgery. This session outlined respiratory goals in SMA - namely to balance the collapsing forces of the lungs and airways against the expanding drive of the respiratory muscles and chest wall - and reviewed indications to start respiratory support. Peter Schochet, Dallas, USA, emphasised the essential role of BiPAP which, unlike oxygen and continuous positive airway pressure, can achieve the key goal of respiratory muscle rest during sleep. He explained that it is important to synchronise breathing with the machine and allow for good chest wall expansion. High span BiPAP gives maximal support for breathing effort.

 

Orthopaedic management in SMA

Children with SMA often suffer from musculoskeletal impairments that interfere with mobility, function and efficiency and can contribute to restrictive pulmonary disease - a leading cause of morbidity and mortality. This workshop session focused on the optimisation of orthopaedic intervention in SMA, which aims to improve or stabilise these impairments and help prevent further deterioration in function.

Brian Snyder, Boston, USA, outlined the four key musculoskeletal issues encountered in children with SMA: contractures, fragile bones, hip instability and scoliosis. Contractures are loss of joint motion due to compositional and structural changes in the muscles, tendons, ligaments and capsules. Key types include adduction, hip flexure, hamstring, gastroc-soleus muscle and Achilles tendon contractures. Surgical intervention involves tendon lengthening and is indicated for fixed contractures that impair seating, mobility and function.

Osteopenia increases the risk of fragility fractures which are common in SMA, occurring in up to 40% of non-ambulatory patients. Key risk factors include stiff joints and decreased bone mineral density. As osteopenia is silent and progressive, Dr Snyder stressed the important of regular monitoring with dual energy X-ray absorptiometry (DXA). Preventative approaches include physical therapy, notably weight-bearing exercise, and pharmacology with vitamin D, calcium and bisphosphonates. Fractures can be treated with splints or surgical stabilisation, but prolonged cast immobilisation should be avoided.

Hip instability can lead to dysplasia and dislocation and is inextricably linked to both scoliosis and pelvic obliquity. Although normal at birth, SMA hips become unstable due to disease-driven global symmetric weakness and absence of weight bearing. Dr Snyder described surgical intervention as ‘controversial’ in the era of new treatment options for SMA but suggested that children who can stand or walk should still have their hips reconstructed if unstable.

 

Chicken and egg: scoliosis, pelvic obliquity and hip instability in SMA

Scoliosis, hip instability and pelvic olbiquity

Management of spinal deformities in SMA

Samuel Rosenfeld, Irvine, USA, focused on the management of spinal deformities in SMA, notably scoliosis which affects over 50% of type 1 and 2 patients. Surgical intervention in skeletally immature children under 10 years of age consists of growing rod constructs without arthrodesis. Surgical management for older children involves posterior spinal arthrodesis, osteotomies to correct deformity with segmental spinal instrumentation, pelvic fixation and autologous/allograft bone graft. Intrathecal administration of agents like nusinersen in patients with spinal deformities involves guided placement of the intrathecal catheter. Indewelling catheters, reservoirs or infusion pumps are alternatives to deliver medications without repetitive dural puncture. The important thing is to plan long-term intrathecal access at the time of spinal reconstructive procedures, emphasised Dr Rosenfeld.

 
 

Goals of orthopaedic management of spinal deformities

Seven goals of orthopaedic management of spinal deformities

Goals of orthopaedic management of spinal deformities

Early scoliosis management in SMA

Early-onset spinal deformity at less than 10 years of age is common in SMA. The major resulting complication is rib collapse which leads to thoracic insufficiency syndrome (TIS) and restrictive lung disease. As new growth and alveolarisation of the lungs cease at around 8 years of age, Dr Snyder stressed the importance of intervening before this age to correct early-onset scoliosis (EOS) and prevent TIS. Thus far, disease-modifying therapy (DMT) with nusinersen has not been shown to mitigate spine pathoanatomy in SMA. A retrospective multicentre cohort study of 87 patients with SMA type II showed no statistical difference in curve progression, parasol rib deformity, need for respiratory assistance or need for surgical intervention in children with initial scoliosis <40 degrees treated with nusinersen versus untreated patients.

Current treatment options for EOS include non-invasive approaches such as the Mehta body cast and thoracic-lumbar-sacral orthosis (TLSO), with Dr Synder specifically recommending use of a semi-rigid (Aliplast) TLSO. However, orthotic management is palliative not preventative, as illustrated by a retrospective review of patients treated with TSLO which found bracing did not slow scoliosis progression. Nevertheless, TSLO was able to maintain or improve functional status - improving postural stability, sitting posture and tolerance and preserving functional motor skills and strength as indicated by a significant change in Hammersmith Functional Motor Scale Expanded (HFMSE) score in braced patients. The alternative approach to treating EOS involves invasive spinal instrumentation with growth friendly devices or spinal fusion. Dr Synder outlined key indications for surgical spinal intervention and emphasised the importance of addressing intra and infra-pelvic deformities before instrumenting the spine.

 

Indications for spinal surgery in EOS

Six indications for spinal surgery in EOS

Indications for spinal surgery in EOS

Dr Rosenfeld then spoke about his 20 plus years’ experience in EOS management using the guided growth segmental sublaminar instrumentation approach. Findings from a review of 20 consecutive patients who underwent segmental spinal instrumentation without fusion from 1998 to 2013, ten of whom had SMA and ten non-SMA, showed that scoliosis correction and sagittal alignment were maintained while allowing for continued growth without the use of external immobilisation. The T1-S1 growth rate in patients with SMA was 1.5 cm/year - similar to the 1.9 cm/year growth rate seen in the non-SMA cohort. None of the treated patients exhibited progressive restrictive pulmonary disease during treatment and all patients remain alive and doing well after average follow up of over 8 years.

“Guided segmental spinal instrumentation without fusion is a well-tolerated and effective surgical technique that avoids the morbidity associated with multiple surgeries in early onset neuromuscular scoliosis.”

Samuel Rosenfeld, Irvine, USA

Pre-symptomatic physical therapy considerations

Physical therapy (PT) considerations for pre-symptomatic individuals with SMA treated early with DMT were discussed by Leslie Nelson, Dallas, USA, and Anne Stratton, Colorado, USA, focusing on monitoring requirements and management strategies.

Dr Stratton stressed that, even with early diagnosis and DMT treatment, PT and input from a multidisciplinary team remain important for ongoing monitoring and care in presymptomatic SMA. She described newborn screening for SMA as a ‘wide-toothed comb’ which detects 90% of affected babies with an SMN1 gene deletion but may miss the 10% with point mutations. As DMTs are not curative, ongoing monitoring should also be carried out for symptoms of decreased endurance and weakness and potential developmental delays. Long-term follow-up of outcomes for presymptomatically treated patients will be critically important, although the data collected so far from clinical studies are encouraging. After 4.8 years of continuous nusinersen treatment in the Nurture study, 100% of children were alive, none required permanent ventilation and all continued to make and maintain progressive gains in motor function, with 96% now able to walk without assistance. Similarly, in the SPR1NT study of onasemnogene abeparvovec survival was 100% without ventilatory or feeding tube support 8–18 months post-treatment and all children achieved a Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score ≥50. Primary analysis of findings from the Rainbowfish study of risdiplam in newborns with presymptomatic SMA are awaited.

Dr Nelson described how physical therapists are ‘now swimming in new waters’ with the advent of effective therapies used presymptomatically. Traditional outcome measures developed to monitor changes in motor function in SMA specifically such as CHOP INTEND and HFMSE may require supplementation with non-SMA specific tools like Test of Infant Motor Performance (TIMP), Alberta Infant Motor Scale (AIMS), Bayley III or IV and Peabody. These measures are used to assess developmental milestone attainment and are being increasingly used in SMA in the anticipation that child treated presymptomatically will follow a similar developmental trajectory. With all SMA children, it remains important to follow standard of care guidelines for PT and adhere to prescribed activity and exercise recommendations.

Six exercise and activity recommendations in SMA

Exercise and activity recommendations in SMA

“Infants identified and treated early with DMT tend to do very well and achieve developmental milestones that we would never expect based on disease natural history”

Anne Stratton, Colorado, USA

Rehabilitation of speech and swallowing deficits in SMA

Deficits in speech, voice, chewing and swallowing are frequently reported by older children and adults with SMA and stem from multifaceted sources. In this lecture, Katlyn MGrattan, Minnesota, USA, and Kristen Allison, Evanston, USA, reviewed the evidence and theoretical models from SMA and other populations which may guide treatment of disease-related speech and swallowing deficits. Treatment falls into two broad categories - restoration aimed at improving the underlying impairment and compensation which seems to maximise participation and function.

 

Multifaceted source for speech and swallowing deficits in SMA

Speech and swallowing deficits in SMA

Multifaceted source for speech and swallowing deficits

In the area of speech restoration, preliminary evidence exists for a subsystems approach, the Lee Silverman voice treatment and speech intelligibility treatment. Compensatory approaches may include speech modification strategies, prosthetics and saliva management/positioning - although none of these strategies have been studied in SMA specifically. Alternative/augmentative communication (AAC) is another compensatory approach which has been tested in SMA type I patients and can be used to supplement or replace speech.

In the area of swallowing/chewing, the Therabite device has been studied in SMA type II and works by stretching the jaw in controlled increments. To help stop choking and food sticking, the ‘chin tuck against resistance’ technique can be employed while the IOPI device may help with messy eating and fatigue (neither have been evaluated in SMA specifically). Compensatory interventions proven to work in SMA type II involves postural support with chair, neck support and head strap. Overall, there remains a lot still to learn about which speech and swallowing treatments are most beneficial for patients with SMA, Dr McGrattan concluded.

 
 

Reproductive options for SMA families

Harvey Stern, Fairfax, USA, reviewed reproductive options open to SMA families which include limiting family size (the most common choice), adoption, use of a gamete donor pretested for SMA or prenatal testing of a naturally conceived pregnancy by chorionic villus sampling (CVS) or amniocentesis. Another important option is preimplantation genetic diagnosis (PGD) with in vitro fertilisation (IVF), which provides an alternative method of prenatal diagnosis.

Unlike CVS or amniocentesis, which Dr Stern described as ‘a trial with an n of 1’ PGD allows for creation of multiple embryos therefore increasing the chances that at least one will be unaffected by SMA. Preimplantation genetic testing for monogenic single-gene disorders like SMA involves whole genome amplification with multiplex polymerase chain reaction (PCR) amplification of the mutation along with 3–4 linked polymorphic markers which generate a chromosomal haplotype. Embryos are simultaneously analysed by chromosomal microarray for other abnormalities (e.g. Down’s syndrome) that can lead to failed implantation or pregnancy loss. Overall, PGD shows high accuracy (98–99%), although contamination with external DNA can be a major concern. In terms of success rates, findings from a large series of patients showed that around 60% became pregnant per IVF/PGD cycle in cases where a chromosomally normal embryo could be identified. Specific issues associated with PGD/IVF include patient discomfort (as medications require subcutaneous administration), abdominal discomfort, distension, nausea and potential risks of ovarian hyperstimulation syndrome. Egg retrieval must also be carried out under general anaesthesia.

PGD shows high accuracy

Fertility, pregnancy and SMA

This workshop examined the unique obstetric issues confronted by patients with SMA and provided recommendations to improve maternal and foetal outcomes. Snigdha Alur-Gupta, Rochester, USA, explained how the prognosis of SMA has changed over the last few decades with many patients now able to maintain independent living - bringing issues like fertility and pregnancy to the fore. Available data do not indicate any impact of SMA on female fertility, however there is some evidence to suggest a potential link to infertility in males, including impaired sperm production and abnormal testicular anatomy in mice models. Dr Alur-Gupta stressed that genetic counselling is an essential component of preconception care and should involve confirmation of the SMA diagnosis, review of understanding of heritability and confirmation of the partner’s carrier status. Carrier screening is a simple DNA blood test that detects 95% of carriers in the general population.

Dr Ahmed Ahmed, Rochester, USA, discussed care of patients with SMA during preconception, pregnancy, delivery and during the post-partum period. Potential effects of pregnancy on SMA include worsening of cardiac and pulmonary disease as pregnancy is a significant respiratory stressor; this may in turn increase the risk of adverse foetal outcomes. Currently, data on obstetric complications remain limited although the likelihood of preterm and assistive/Cesarean delivery is known to be increased in SMA. Dr Ahmed stressed the importance of MDT care throughout pregnancy and the involvement of anaesthesia teams prior to labour and delivery. Early epidural anaesthesia is recommended but may be difficult to site due to spinal deformities. Moving forward, contraception with menstrual suppression avoids unplanned pregnancies and associated risks and can be helpful with issues such as hygiene, anaemia and nutrition, noted Dr Ahmed.

 

Effects of SMA on pregnancy

Pregnancy and SMA

Effects of SMA on pregnancy

The issues of mobility and cardiopulmonary care during pregnancy were explored by Debra Guntrum, Rochester, USA. Pregnancy worsens respiratory functional status and reduces functional lung capacity, although there is no ‘absolute number’ on pulmonary function tests that contraindicates pregnancy. The highest-risk groups include those with diaphragm involvement, low peak cough flow (PCF), low forced vital capacity (FVC) and/or severe scoliosis with pulmonary restriction. There is also an increased risk for weakness and fatigue in the thoracic wall during pregnancy. A baseline respiratory review is recommended with serial measurements in each trimester. Above all it is important to plan ahead said Dr Guntrum, mobility and ADLs will be affected and assistive devices may be needed to assist with care of the infant.

 
 

Clinical care and research updates

Jill Jarecki, Cure SMA Chief Scientific Officer, provided a research update for 2021, highlighting the $80 million in total research funding that CureSMA has provided since its inception. Significant progress has been achieved in SMA over the past three decades and the landscape is continuing to evolve. FDA approval of three new therapies has revolutionised and dramatically altered the natural history of SMA, with early identification and treatment able to dramatically improve long-term outcomes, most strikingly in presympomatic patients. However, 40% of all patients with SMA still remain untreated, Dr Jarecki pointed out.

Reviewing the burgeoning SMA drug pipeline, Dr Jarecki asserted her hope that different therapeutic approaches and ways to treat SMA would lead to combination therapies with maximum effectiveness for all ages and stages of SMA. Clinical data from the phase 2 proof-of-concept TOPAZ study of the Scholar Rock drug candidate apitegromab (SRK-015; NCT03921528) in 55 type 2 or 3 SMA patients aged 2–21 years have recently been released. This agent targets myostatin by specifically blocking its activation in the muscle, leading to muscle bulking. The study was split into three cohorts by age/SMA type with all patients receiving apitegromab intravenously every 4 weeks either as monotherapy or in conjunction with nusinersen over a 12-month treatment period. Dr Jarecki explained that, although only modest effects were seen in cohorts 1 and 2, cohort 3 (patients age ≥2 years of age with type 2 SMA who had initiated nusinersen at <5 years of age) had ‘very impressive’ improvements in the HFMSE of 7.1 and 5.3 points at 20 mg/kg and 2 mg/kg dose arms of apitegromab. These changes were more pronounced than those seen in the pivotal CHERISH trial (NCT02292537) that formed the basis of approval for nusinersen in type 2 SMA, noted Dr Jarecki. A phase 3 trial of apitegromab is planned for initiation by the end of this year.

Other ongoing studies which are currently recruiting patients include: DEVOTE, a 152-patient study evaluating higher doses of nuinersen (NCT04089566); RESPOND which is assessing nusinersen among patients who have previously received onasemnogene abeparvovec (NCT04488133) and Rainbowfish, an open-label US study of risdiplam in ~25 infants aged up to 6 weeks with genetically diagnosed and presymptomatic SMA (NCT03779334).

Trials which aim to start recruiting soon include SMART, an open-label efficacy and safety study of intravenous onasemnogene abeparvovec in patients weighing ≥8.5 kg and ≤21 kg, which is heavier that the current label indication for onasemnogene abeparvovec.

Dr Jarecki also highlighted the importance of surveys in SMA, which have helped to uncover unmet needs in the adult community that it is hoped future therapies will address. Since the introduction of DMTs, almost half of those with type 1 SMA currently sit without support making it more relevant to think about SMA in terms of SMN2 copy number rather than type, emphasised Dr Jarecki.

 

Unmet needs in adult SMA

Seven unmet needs in adult SMA

Unmet needs in adult SMA

Mary Schroth, Cure SMA Chief Medical Offer then reviewed work in SMA clinical care, which includes the Cure SMA Clinical Data Registry. This Registry aims to enroll 25% of all patients with SMA by 2024, with the goal of collecting real-world evidence to establish standard-of-care, evaluate the impact of new therapies and combination approaches, and provide evidence for payors to increase access to treatment. Dr Schroth also presented results from a survey of 814 individuals with SMA, caregivers and family members carried out between November 2020 and January 2021 highlighting the impact of COVID-19 on the SMA community.

Clinical care of SMA considerations

SMA clinical care

“We recommend that you don’t wait for a future treatment or clinical trial if other options are available now. Early treatment results in the best outcomes - time is neurons!”

Mary Schroth, Cure SMA Chief Medical Officer

Decision making in SMA

This session explored the key principles that underpin decision-making in SMA. Robert Graham, Boston, USA, explained how the availability of effective therapies has reshaped the way SMA is conceptualised as a disease, creating a new landscape for care, treatment and research. Complicating factors include type overlap, maintaining therapies after trial completion and limited population sizes for future research. All speakers emphasised the importance of shared decision-making which is individualised and tailored to family’s own values and perspectives. It is vital to accurately convey risks and benefits to enable optimal decision-making based on the available data, while acknowledging what remains unknown - such as long term impact of DMTs and the effects of switching between therapies. Overall, decision-making in SMA is a dynamic process which must balance goals of care with available options for treatment and intervention.

Subjective and objective considerations for breathing support

When to start breathing support in SMA

Optimising telehealth

This session provided practical tips for patients on optimising different kinds of telehealth visits, from neuromuscular appointments to PT and nutrition. Although in-person visits are expected to resume in the near future, telehealth may occasionally still be required in specific situations. Uptake may vary state to state due to logistical and insurance issues.

“With neuromuscular telemedicine it’s important to go through every system - from head to toe. These are complex patients and we’re not just checking on their muscles or their nerves, we’re checking on the patient as a whole.”

Diana Castro, Dallas, USA

Closing remarks

Looking ahead to next year, the 2022 SMA Conference is planned to be an in-person event which will take place between June 15th-June 19th at Disneyland in Anaheim, California. This is expected to be a large-scale congress, said Dr Hobby, which will condense 3 years of SMA knowledge into one live meeting with over 3000 attendees expected.

 

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