Impact case study database

Research at UCL has identified antisense oligonucleotides (ASOs) that restore function of genes associated with the most common neurodegenerative diseases affecting children (DMD and SMA). This work has been instrumental in developing effective novel interventions that are the first to be licenced to treat these life-limiting conditions which affect over 2 million children worldwide. The medicines are transforming the lives of thousands of affected children, allowing them to live active lives for longer; maintaining the ability to walk and avoiding respiratory failure. The medicines have also had significant economic benefits for the companies manufacturing them.

New antisense oligonucleotide therapies for Duchenne Muscular Dystrophy (DMD)

As a direct result of Muntoni’s research to identify effective ASOs that allow production of dystrophin protein in affected children, Sarepta Therapeutics Inc has brought the first genetic treatments to market, which in total can treat one in five boys with DMD. Exondys 51® (eteplirsen) was granted approval by the FDA in December 2016. As part of the approval process, Muntoni presented a dossier to the FDA panel that included the data from the original UCL-led phase 1 and 2 trials in the UK. The Sarepta FDA document states, “Based on promising results observed in the Phase 1 proof of concept study (Study 33) and a 12 week dose-ranging study (Study 28) conducted in the United Kingdom from 2007 to 2010, Sarepta conducted a 28-week double-blind, placebo-controlled Phase 2 study (Study 201) in July 2011” ( S1). Exondys 51® is applicable to 13% of the male DMD population and is now regularly given to some 1500 DMD patients in the US, significantly delaying the onset of disability. Trials showed that the group treated with eteplirsen showed no increase in the proportion of patients losing the ability to walk (as measured by a 6 minute walking test) over 4 years (17%) while the percentage of those who lost the ability to walk in the untreated group increased exponentially over the same period ( S2). This benefit, and the subsequent reduction of respiratory decline ( S3) is now felt by over 1500 DMD patients who are regularly receiving EXONDYS 51®, as well as their families and carers.

In December 2019, Vyondys 53™ (golodirsen) became Sarepta’s second RNA therapy when it was approved by the FDA and made commercially available immediately. This drug can be used in a further 8% of the male DMD population (a further 18,000 patients worldwide). Long term follow-up of children in the original SKIP NMD EU trial showed that golodirsen also reduced the risk of loss of ambulation, and improved respiratory outcomes, in treated patients. In particular, patients treated for 3 years showed a less severe annual decline in walking abilities and of respiratory function compared to untreated patients ( S4) .

New Antisense oligonucleotide therapy for Spinal Muscular Atrophy

Research from UCL to identify an effective ASO for SMA contributed to the development of Spinraza® (nusinersen) by Biogen, which was granted approval in December 2016 by the FDA and May 2017 by the EMA. By the end of 2018, it had been used to treat more than 2600 people in the US alone, with >95% of those remaining on treatment and >80% reaching the maintenance dosing phase. The efficacy of Nusinersen was demonstrated in SMA1 children and in less severe variants and led to rapid EMA and FDA approval. The impact of Spinraza on the lives of affected families has been dramatic. A couple, whose daughter was diagnosed with SMA Type 3 at three years old and treated with nusinersen said, “She loves painting, and each one of those minor movements has been monumental… we still have challenges to face, but we now have this tool to fight back with” ( S5). A recent Phase 2 trial involving 25 children with SMA1 or SMA2 treated with nusinersen found that over 80% of the children were able to sit, stand and walk independently at three year follow up ( S6). Biogen then initiated an extended access program (EAP) for all infants affected by SMA1.

Ensuring access to nusinersen treatment for SMA in the UK

Nusinersen (Spinraza) received NICE approval in June 2019 ( S7) and the NHS adopted it for use in infants with SMA. Since then, the UCL team has played a key role in developing a co-ordinated approach and the up-skilling necessary to deliver this treatment throughout the UK and 300 patients are already receiving treatment.

In the UK, the SMA Research and Clinical Hub UK consortium (SMA REACH UK), led by Muntoni, is collecting data on all the SMA1 children recruited nationally on the EAP. These children can expect to enjoy significantly longer life. Clinical studies show that only around 15% of untreated SMA sufferers were still alive after 24 months of a study, while 50% of patients treated after onset of symptoms could still be alive after 36 months if treatment began early enough. All patients who received nusinersen before symptoms appeared were still alive after 36 months ( S8).

Muntoni is a member of the International Standard of Care group for SMA. He and others in the SMA REACH UK consortium are training medical and treatment staff to ensure optimal care is delivered, including respiratory care, such as physiotherapy and supportive ventilation ( S9). More than 200 health care professionals attended training workshops in 2019. The clinical and research network is collecting high quality longitudinal data on SMA that is providing a robust national database to ensure a standardised approach to the assessment of SMA is implemented to help improve the standards of care for people with SMA in the UK ( S10).

SMA REACH UK links all paediatric centres involved in delivery of clinical care for SMA and is funded by advocacy groups and Biogen. NICE has designated SMA REACH UK as the group to manage the access program for nusinersen in England and monitor patient progress, with Muntoni representing the group on the NICE clinical panel which oversees the access programme ( S11).

Economic impact of novel treatments for DMD and SMA

Exondys 51®, marketed by Sarepta, has registered a rapid rise in demand, with revenues rising from USD155,600,000 in 2017 to USD301,000,000 in 2018 and USD381,000,000 in 2019. Based on the success of Exondys and Vyondys 53, Sarepta continues to invest in further therapies for the treatment of DMD. In the case of Spinraza,(sold by Biogen), sales have shown rapid growth from USD884,000,000 in 2017 to USD1,700,000,000 in 2018 and USD2,097,000,000 in 2019. Revenues for the first half of 2020 were USD1,060,000,000 ( S12).