The hurdles rare disease patients have to overcome when accessing treatments can seem unending. In this week’s blog, Wan-hin Rex from the University of Hong Kong explores the case of spinal muscular atrophy (SMA) and the first disease-modifying drug to treat it, nusinersen. This piece was originally written for Findacure’s 2017 Student Voice Essay Competition.



Rare diseases are defined as conditions with a prevalence of less than 0.02% (1). Despite its low prevalence, rare diseases have major medical and socio-economic consequences (2,3). Rare disease research is rapidly growing and novel therapies provide hope for patients with previously untreatable diseases. Nonetheless, translating experimental results to the real-world setting remains challenging, and multiple barriers prevent rare disease patients from accessing treatment (4). Using spinal muscular atrophy (SMA) and nusinersen, the first disease-modifying drug for SMA, as an example, this article will review the treatment barriers and propose measures to tackle such hurdles in rare diseases.



SMA is an autosomal recessive disorder caused by motor neuron degeneration in the anterior horn of the spinal cord. Classified into types 1, 2, 3 and 4; SMA-1 constitutes 60% of cases, with patients developing muscle weakness shortly after birth and progressing to death within two years (5). SMA-2 patients start developing symptoms between six to 18 months, and their life expectancy is shortened due to respiratory complications. SMA-3 onsets after 18 months, while SMA-4 onsets in adults, and life expectancy is not affected in these subtypes. SMA is caused by homozygous deletion of the Survival of Motor Neuron-1 (SMN-1) gene, resulting in reduced production of the SMN protein (6). Humans also carry the SMN-2 gene, a gene similar to SMN-1 but with a single nucleotide difference that induces alternative splicing of exon-7. The majority of SMN-2 transcripts lack exon-7 and produce truncated nonfunctional SMN proteins (7).



In the past, there was no treatment for SMA, and only supportive management could be offered (7). Nusinersen, an antisense oligonucleotide, was introduced as a disease-modifying drug for SMA in 2016. Nusinersen binds to the SMN-2 gene, leading to the inclusion of exon-7 and production of functional SMN proteins (6). In 2016, pilot studies demonstrated nusinersen to improve motor function in SMA-18 and SMA-2/39 patients respectively. These promising results led to the ENDEAR trial on 121 SMA-1 patients10 and the CHERISH trial on 126 SMA-2 patients (11). These two trials were both prematurely terminated due to significant improvement in motor function and survival in the treatment groups during interim analyses. Based on these results, nusinersen was approved for SMA treatment in US and Europe in December 2016 and May 2017 respectively (12, 13).



While nusinersen offers hope, multiple barriers prevent SMA patients from accessing this disease-modifying drug.

Drug costs

The key treatment barrier in nusinersen is the drug cost. Priced at 750000 USD in the first year and 375000 USD per year afterwards, nusinersen is one of the most expensive drugs worldwide (14). With SMA patients requiring indefinite treatment, the drug is practically unaffordable without health insurance or government subsidy. Multiple patient groups have voiced out about nusinersen’s price and have called for financial support from their governments (14-16). “It is really tiring to write with two fingers only, but I don’t want other children to experience the hardship I have had growing up,” said Josy, a 23-year-old SMA patient in Hong Kong. With motor function remaining in two fingers only, Josy typed a 22-page proposal, calling for the Hong Kong government to aid SMA patients in acquiring nusinersen (16).

Biogen (Durham, USA), the company that markets nusinersen, commented that the price of nusinersen is in line with other orphan drugs (14). As in all orphan drugs, the development costs for nusinersen has to be earned from a small patient population (17). Nusinersen is also a first-inclass drug with no substitutes. This grants the company with monopolistic power and freedom to set a high price.

A direct method to tackle unaffordable drug costs is for public healthcare systems to subsidise SMA patients. While the price of nusinersen is high, the healthcare resources used by advanced SMA patients should not be ignored (7,16). Advanced SMA patients require repeated admissions with ventilator support, and anecdotal reports have suggested that subsidising nusinersen may be cost-saving when compared with long-term supportive care (16). To guide healthcare policies, studies should be conducted to compare the costs of nusinersen and supportive care to determine which method is more cost-effective.

To overcome the issue of monopoly, further research for novel agents should be encouraged. In SMA, drugs including neuroprotective agents (18,19), SMN-2 splicing modifiers (20,21), and SMN-1 gene therapy (22-24) have shown promise and may be utilised clinically in the future. Should these agents demonstrate comparable efficacy as nusinersen, patients would have more drugs choices and the price of SMA drugs would likely decrease with competition.

Healthcare resource requirement associated with drug administration

Nusinersen is administered intrathecally since it cannot cross the blood-brain barrier. It also requires four injections in the first seven weeks, followed by one injection every four months afterwards. Intrathecal injection requires trained personnel to perform, and given that the majority of SMA patients are children or infants, immobilisation or sedation may be required to facilitate drug administration (25). Specific patients may need additional care. For example, severe scoliosis patients require interventional radiologists to perform X-ray guided injection (26) while patients with respiratory distress require ventilator support and monitoring pre- and postinjection. Due to the extensive resource requirement, the number of patients that can receive follow-up and nusinersen administration at each institution is limited (26).

To enable more patients to access therapy, regional specialised SMA centers should be set up (27). Specialised institutions will provide high-quality care from experts and will also facilitate efficient utility of human resources and medical equipment. With streamlining of clinical services, more SMA patients will be able to receive nusinersen.

While nusinersen has rapidly become the standard treatment for SMA, the evidence on the drug is still preliminary and many research questions remain unanswered. Further studies should aim to optimise the dosing regimen of nusinersen. If a less rigorous treatment regimen with fewer injections can be identified, the healthcare resource demand will correspondingly decrease.

As stated in the prior section, other promising SMA drugs are in the production pipeline. Olesoxime, a neuroprotective agent (18,19), and SMN-2 splicing modifiers (20,21), are both oral drugs, whereas SMN-1 gene therapy is administered in a single intravenous dose (24). None of these agents require intrathecal injections as nusinersen does. Hence, should these agents be available on the market, they will bypass the need for invasive lumbar punctures, provide patients with convenience and alleviate the healthcare resource demand.

Delayed diagnosis

Early treatment is critical in SMA, as delayed nusinersen initiation impacts motor and respiratory function recovery (6,10). The studies on SMA-1 included infants younger than seven months and without respiratory impairment (8,28). Similarly, the studies on SMA-2/3 included stable patients without major scoliosis and contractures (9,11). Therefore, there is only evidence for nusinersen treatment in patients at earlier stages of SMA without major omplications. Due to the paucity of evidence in advanced SMA patients or in patients older than the age-limit in trials, experts generally recommend treatment decisions to be made on a case-by-case basis in these patients (6,29).

Given the narrow treatment window for SMA, prompt diagnosis and referral to specialists is paramount. Unfortunately, as in most rare diseases, delayed diagnosis of SMA is common and poses as a potentially avoidable treatment barrier. In a 2015 systematic review, the mean diagnostic delay (time from symptom onset to diagnosis) in SMA-1, 2 and 3 were 3.6, 14.3 and 43.6 months respectively (30). In particular, the mean diagnostic age of SMA-1 was 6.3 months. This is exceedingly close to the seven-month limit in clinical trials and makes it unlikely that infants can receive treatment before the ideal seven-month cutoff.

A major cause of diagnostic delay is the lack of awareness by primary care providers, leading to misdiagnoses, unnecessary tests and multiple referrals (30-32). While the final diagnosis of SMA is usually made by neurologists (32), timely referral by primary care physicians would shorten the time to diagnosis and prevent diagnostic odysseys. Enhancement of medical education to increase all doctors’ awareness towards SMA and other rare diseases would be essential.

Newborn screening, which will ameliorate the issue of delayed diagnosis, is another potential area of development for SMA. The benefit of screening was debatable before the availability of treatment (33,34), but with the treatment paradigm shifted by nusinersen, universal screening for SMA should be implemented (6,35). The NURTURE trial is an on-going study on 17 presymptomatic infants with genetically diagnosed SMA. The interim analysis at 29 months demonstrated 100% survival with no patients requiring ventilator support (36). These encouraging results support the potential of universal SMA screening coupled with presymptomatic treatment.



SMA illustrates several treatment barriers in rare diseases, namely 1) unaffordable drug costs; 2) healthcare resource demand associated with drug administration; and 3) delayed diagnosis leading to missed treatment opportunities. Research in cost-effectiveness, optimal drug regimen and alternative novel agents are critical in guiding health policies and increasing drug affordability. Enhancing medical education and developing specialised centers will guarantee high quality care at both the primary and tertiary levels. Finally, universal screening may reduce diagnostic delay and enable presymptomatic treatment. Treatment barriers in rare diseases should not be overlooked and collaborative efforts between patients, doctors, researchers and policy-makers will be required to overcome these hurdles.



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