According to the Lancet study, neonatal screening for SMA results in more kids being able to walk two years after diagnosis. In this article, physicians will get comprehensive information on this topic.

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Spinal muscular atrophy (SMA), an inherited neuromuscular disease causes muscles to become weak and waste away. According to the National Institute of Neurological Disorders and Stroke, USA, “some forms of SMA are fatal without treatment. People with SMA may appear to be stable for long periods, but improvement should not be expected without treatment.” SMA is the leading genetic cause of infant deaths

About one in every 40 to 60 people carries the main gene that causes SMA and an estimated one in 10,000 babies will be born with the absence of two essential genes, leading to disease.

“The age when symptoms appear is variable, but they may not be seen until the baby is several months old, and many individuals with SMA experience a delay in diagnosis. Although no cure for SMA exists currently, there are treatment options which can improve symptoms, especially when the child starts treatment prior to the development of clinical symptoms.”

-A press release from the journal cautioned

Newborn screening (NBS), a public health program of screening infants shortly after birth for conditions that are treatable, but not always evident in the newborn is very crucial. In Australia, all newborns—not just those with a family history of the disease—undergo NBS programmes with parental agreement.

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The study

The researchers from Australia compared the health of 15 newborn babies diagnosed with SMA following a positive screening result between 1st August 2018 - 1st August 2020 (the first two years of the Australian pilot NBS for SMA program) with that of 18 infants and children with SMA diagnosed following clinical referral with symptoms of disease in the two years prior to the start of the pilot NBS for SMA programme (1st August 2016 - 31st July 2018).

NBS diagnosed that out of the 15 children, nine did not show any symptoms of SMA within the first few weeks of life and so were considered pre-symptomatic when they started treatment.

Evaluation

Health care providers evaluated the children's capacity to sit, crawl, stand, and walk at two years after diagnosis, along with some other measures of movement ability. Three children (one diagnosed with NBS and two by symptom onset) in the trial entered palliative care during the two years post-diagnosis.

Findings

1. The researchers found that 11/14 of the children diagnosed with NBS were walking independently or with assistance at two years after diagnosis compared with only 1/16 of children diagnosed prior to the NBS pilot programme.
2. The children diagnosed with NBS scored better on average in other measures of movement ability and independence in everyday tasks than the children diagnosed by symptoms.
3. This is true even though the NBS-diagnosed youngsters are uniformly younger than the other group.

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Early screening essential

In the press release from the journal, a co-author Dr Didu Kariyawasam, University of South Wales stated that newborn screening for SMA reduces the current delays in children being diagnosed and treated for SMA.

“Early screening and diagnosis are essential to giving children with SMA better health outcomes and quality of life. It’s extremely promising that the majority of children diagnosed via newborn screening in our study were able to walk after two years, compared to those children diagnosed through symptoms who were mostly only able to sit unassisted,”

 -Dr Didu Kariyawasam.

She also added:

“Although we are seeing pilot programmes rolled out, only a small number of countries have fully introduced newborn screening for SMA, with fewer than 2% of newborns across the world currently screened for the condition. Our study offers further evidence of the value of newborn screening for SMA and encourages wider implementation of this effective intervention.”

 

While completing a literature review from Jan 1, 2016, to Aug 1, 2022, on the status of the field, the authors found that nine countries had implemented newborn screening for spinal muscular atrophy (SMA) by 2022. They realised that the papers cited a paucity of real-world data on long-term efficacy as a rate-limiting factor for wider dissemination.

The researchers found that the clinical trials for the three disease-modifying agents (nusinersen, risdiplam, and onasemnogene aberparvovec) described motor function, survival, and co-morbidity outcomes for pre-symptomatic and symptomatic infants. They noted that the enforcement of strict inclusion criteria within these trials precluded generalisability to a real-world incident population of children.

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SMA modifying agents

A fact sheet from the National Institute of Neurological Disorders and Stroke

1. “In December 2016 the U.S. first medication recognised by the Food and Drug Administration for the treatment of both children and adults with SMA is nusinersen (Spinraza). The medication is injected into the spinal cord's protective fluid. It is designed to increase the production of the full-length SMN protein, and it is critical for the maintenance of motor neurons. Infants and children, especially when initiated at a young age, have the most established benefits. Other treatments are in the final phases of development and could soon be made available to those who need them.

2. In May 2019, the FDA approved onasemnogene abeparovec-xioi (Zolgensma) gene therapy for children less than 2 years old who have infantile-onset SMA. A safe virus delivers a fully functional human SMN gene to the targeted motor neurons, which in turn enhances muscle movement and function, and also improves survival. Risdiplam (Evrysdi), an oral medication, was given FDA approval in August 2020 to treat SMA in patients two months of age and older.

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Newborn screening, the way forward

In the Lancet press release, a co-author, Dr Arlene D’Silva, University of New South Wales acknowledged that newborn screening (NBS) has been proposed as the gateway to early diagnosis and more-timely access to treatment for SMA. However, before now, there was a lack of evidence on the impact of newborn screening for SMA beyond the non-diverse populations in clinical trials.

“Our study is the first to look at real-world data on how children with SMA diagnosed via newborn screening fare compared to children diagnosed after symptoms develop. We believe our findings justify the broader implementation of newborn screening for SMA,” Dr Arlene D’Silva clarified.

The authors acknowledge that their study has some limitations;

1. As the trial was non-randomised, it could be prone to selection bias. They argued that the chronological enrolment of children as they were referred to the service mitigated the bias.
2. It was not possible to match the two groups by age, due to the inherent diagnostic delays associated with a clinically based diagnosis.
3. The researchers designed the Australian NBS for the SMA pilot study to speed up and enable equitable access to diagnosis and treatment.
4. Therefore, these findings may not be generalisable to areas where there are delays in the screening to the treatment process, including challenges in accessing appropriate health services and treatment.

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Other highlights

While describing the value of their study, the researchers highlighted the following;

1. Their study is the first to provide evidence for the clinical effectiveness of newborn screening for SMA as a means to identify patients who could benefit from earlier treatment, directly compared with traditional pathways of diagnosis and management (ie, clinical referral).
2. Their study population represents the heterogeneous, genotypic and phenotypic spectrum of children with SMA encountered in a real-world setting.
3. This study uniquely incorporates a broad range of outcome measures, such as patient-centred endpoints that determine the level of future functional independence for affected children, which are directly relevant to their everyday lives. Their incident, newborn screening population consisted of six children with symptom onset within the newborn period. With only seven children described with pheno-conversion within the neonatal period in previous studies, our findings add to a limited pool of data for the emergence of a new phenotype.
4. The clinical, genetic, and electrophysiological factors that affect a child's prognosis and response to treatment for SMA, which is discovered by newborn screening, are for the first time identified in this study.

Implications of all the available evidence

Newborn screening for SMA coupled with access to disease-modifying therapies is clinically effective as an intervention to promote motor skill attainment, improve functional independence, and reduce co-morbidities associated with SMA. Optimisation of health outcomes through this model is observed for a genotypic and phenotypic spectrum of children presenting within the real-world practice. “, they added

“This study provides an evidence base and impetus to refigure pre-existing pathways of diagnosis and management, that are currently based on clinical referral. Newborn screening for SMA facilitates a precision medicine approach to prognostication and management, based on a child’s individual clinical, genetic, and electrophysiological characteristics”, the researchers concluded.

In a Linked comment, after reviewing the new study, Professor Hisahide Nishio, Kobe Gakuin University, Japan, who was not involved in the study, says:

“Importantly, newborn screening needs to be coupled with access to treatments with new drugs, including nusinersen and onasemnogene abeparvovec. However, these drugs are extremely expensive, hampering the implementation of newborn screening for SMA in many countries because screening without treatment is illogical. In a survey of experts in 152 countries and 87 responses, newborn screening programmes for SMA were reported only in Australia, Belgium, Canada, Germany, Italy, Japan, Russia, Taiwan, and the USA”

“Cost–benefit data of newborn screening for SMA will help to inform countries who wish to implement a newborn screening programme for SMA. However, it will take some time for patients with SMA due to the high expense of new medicines and the varied situations in different countries (such as different economies and insurance systems).worldwide to benefit equally from advances in medicine” he concluded.

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Status in India and cost of drugs

If India has to benefit from the finding of the new study, it must address several issues.

While reviewing the information on the cost of the three SMA modifying agents globally, this author was tempted to search for their cost and availability in India.

In a review titled “Spinal Muscular Atrophy Therapeutics in India: Parental Hopes and Despair!” in Annals of Neurosciences (July 2021), Drs Renu Suthar and Amol N.Patil stated that the cost of Nusinersen injection is 92, 51,875 INR per injection, with a total price of 6,20,78,700.00 INR in the first year and 3,10,39,350.00 INR in the subsequent years. Novartis is marketing Onasemnogene abeparvovac under the trade name of Zolgensma. It costs approximately 140 million (14 crores INR).

Drs Suthar and Patil rightly concluded thus: “Recent approval of three SMA disease-modifying therapies offered a ray of hope to parents and children globally. However, mammoth challenges include drug pricing regulation, authorisation, availability, and a sustainable funding model.”

The New York Times (April 6, 2022) reported that the only drug approved for the condition in India is Evrysdi, manufactured by Roche. It’s the cheapest among the three treatments, but it still costs $53,000 to $80,000 a year, and that’s a discounted price for India, negotiated with Roche by the government.

The NYT listed a few instances in which the Indian public assisted their compatriots by contributing to crowdfunding.

The NYT reported that since May 2019, when Zolgensma was introduced, the parents of at least 10 children have succeeded in raising $2.1 million through crowdfunding. Such solutions are not permanent.

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The way forward

Drs. Suthar and Patil are hoping that a few historical precedents will serve as a guide to bringing these currently unavailable drugs to Indian patients with SMA. They even suggest that the “Indian patent controller has the right to break the patent monopoly and grant compulsory license when drug cost is not affordable to many, similar to classical Bayer and Natco dispute Sorafenib case”.

In that instance, the Intellectual Property Appellate Board (IPAB) dismissed Bayer Corporation's appeal and confirmed Natco Pharma Ltd.'s compulsory license to manufacture Bayer's patented kidney cancer drug Nexavar. (Mukesh Kumar, Research Associate at Anovip, linkedin.com 5 Aug 2021).

The author noted the way the Indian judiciary has made it clear in a slew of patent cases that the public interest is paramount, and that the country will not accept drug companies exploiting its people for financial gain. The cost-benefit analysis of such medical treatment may excite raw emotions. The eternal conflict between the pharmaceutical sector and intellectual property rights needs urgent resolution.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and is a medical physicist with a specialisation in radiation safety and regulatory matters.