Gene therapy trial leads to life-changing treatment for children

Clinical trials conducted by the Sydney Children’s Hospitals Network (SCHN) have led to a life-changing treatment for children with Spinal Muscular Atrophy (SMA).

The treatment involves using gene therapy to deliver the missing gene that causes SMA into an infant’s cells. SCHN was the only Australian site selected for the global trial. The results have been extremely encouraging: all 29 patients in the global trial are alive and meeting developmental milestones. Without the treatment, they were unlikely to survive to their first birthday.

At the same time as the trial, the Australian team launched a program that screened newborns for SMA. Today there are three approved therapies for SMA and newborn screening programs in multiple jurisdictions around the world. Five years ago, these were just beginning.

‘Australia was one of the first places in the world to screen for SMA in newborns, coupled with gene therapy to treat infants with the condition,’ says Associate Professor Michelle Farrar, a paediatric neurologist and the leader of the Australian trial. ‘It shows how quickly things can change.’

Finding a treatment for SMA

SMA is a genetic condition that affects the motor nerve cells in the spinal cord. It causes progressive muscle weakness, preventing infants from sitting up, crawling, walking, swallowing and eventually breathing. Left untreated in the most common and serious form, infants typically don’t live to see their first birthday.

Although SMA affects one in 10,000 births, not much Australian research was being done on the condition. Farrar knew the genetic underpinnings of SMA could provide a pathway to developing a therapy. Her PhD examined the steps involved in setting up clinical trials, assembling cohorts and assessing data.

By the time she completed her PhD, she had the skills, expertise and cohorts ready for clinical trials. In 2015, she led an Australian site conducting Phase III trials for a new investigational drug for SMA. Those trials resulted in SprinrazaTM becoming the first approved treatment for SMA.

Australian expertise in clinical trials and gene therapy

This groundbreaking, multicentre international study was published in the New England Journal of Medicine. Also in the same issue was a study by a US biotech called AveXis. It was trialling the use of a viral vector to deliver a single Survival Motor Neurone (SMN) gene. The SMN1 gene is missing from children with SMA. AveXis was looking to do Phase III trials for its proposed therapy.

Farrar was keen to bring the study to Australia. Her colleague Professor Ian Alexander was also interested. Alexander is Head of the Gene Therapy Research Unit at SCHN (a joint initiative with the Children’s Medical Research Institute at Westmead). His team was the first in Australia to treat a genetic disease (SCID-X1) using gene therapy.

‘Together we approached AveXis,’ says Farrar. ‘We had the clinical expertise, the clinical trial readiness and the cohorts. We also had experience in gene therapy through Ian’s work. These elements were successful in us bringing the trial to Australia.’

Australia is a great place to conduct clinical trials, according to Farrar.

‘We have the combination of clinicians, scientists, cohorts and infrastructure. We have dedicated teams and a deep knowledge of the science. Our ability to collect Phase IV data is also valuable. It adds real-world data to trial data, which is important for companies aiming for product registration.’

Newborn screening key to optimal treatment

AveXis wanted to trial its therapy in pre-symptomatic patients. Farrar says: ‘For several years I’d been trying to develop newborn screening readiness for SMA. It made sense that the best results are likely to be achieved through early treatment. It’s like the stars aligned and now we needed to put all of the pieces into place.’

The opportunity to participate in a pre-symptomatic trial meant Farrar’s team could undertake multiple studies at once. They could show newborn screening was essential to optimise therapy and look at implementing the screening process in parallel with the clinical trial.

Farrar worked with the state-wide newborn screening laboratory over 10 months to set up the newborn screening process and the clinical research team to initiate the clinical trial. The newborn screening program and the clinical trial went live in August 2018. In three weeks, SCHN had identified its first patient.

‘We enrolled one of the first participants in the worldwide trial and the first outside North America,’ says Farrar. ‘It was a huge achievement that was the result of working well as a team across multiple stakeholders.’

A life-changing treatment

The global trial, called SPR1NT, enrolled 29 children in the US, Asia-Pacific and Europe. SCHN was the only Australian site in the trial.

SCHN screened infants for SMA and enrolled four aged under six weeks old in the trial. They were given a single dose of Zolgensma®, the novel viral vector-based gene replacement therapy. The study reported results for two cohorts, defined by the number of SMN2 genes. SMN2 copy number inversely correlates with the severity of SMA. Infants in Cohort 1 were followed for 18 months. Infants in Cohort 2 were followed for 24 months.

The final results of the SPR1NT trial were presented at international congresses. All 29 patients are alive and do not need breathing or feeding support. 

AveXis (acquired by Novartis in 2018 and renamed Novartis Gene Therapies) received US FDA approval for Zolgensma in May 2019.

‘By identifying infants with SMA before the onset of symptoms, early results suggest we may have taken what was considered a lethal disease, and turned that around with a one-time, single therapy,’ says Farrar. ‘It is giving life to these babies and hope to their families.

‘It’s a career highlight, based on science, but sounds like fiction,’ she adds. ‘I feel very privileged to have played a role, and to have the trust of the families and support of my team. It’s so gratifying to see the children celebrating birthdays, starting preschool, swimming lessons and soccer classes. I’m just blown away.’

Gene therapy the future of treatments for rare diseases

SCHN has become a national centre for gene therapy. It receives patient referrals from every state. But Farrar says the work is only just beginning.

‘Gene therapy has given hope to many people with a rare disease,’ she says. ‘We have to look at how we can safely translate this technology to develop treatments for other conditions and to a broader population. We also have to work out how to deliver the therapy into the healthcare system.’

Find out more about Australia's clinical trials capabilities.

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