Breakthrough drug from Dame Margaret Brimble's lab

A molecule discovered by Distinguished Professor Dame Margaret Brimble of the University of Auckland is the basis for a breakthrough neurological drug approved by the US Food and Drug Administration on March 10.

Trofinetide will treat Rett syndrome, a condition causing symptoms similar to cerebral palsy or autism in an estimated one in 10,000 girls.

More than 20 years after the molecule was discovered, Trofinetide, to be marketed as Daybue, is the first drug treatment for the condition.

“I’m over the moon for all of the families who need the drug,” says Dame Margaret, Director of Medicinal Chemistry at Waipapa Taumata Rau, University of Auckland. “It’s a horrible disease, and finally there’s a treatment. We've waited so long for this, it's a great day."

Trofinetide is the first New Zealand-discovered neurological drug to win FDA approval.

Rett syndrome almost exclusively affects girls, with motor control and communication skills stagnating or regressing after the first six to 18 months of a child’s life. Successes in clinical trials have included girls walking or talking for the first time.

In children with the condition, mutations in a gene called MECP2 inhibit the formation of a molecule essential to cognitive and motor function. Trofinetide is a synthetic version of that molecule.

The hallmark of Rett syndrome is near-constant repetitive hand movements and levels of disability range from mild to severe, according to the International Rett Syndrome Foundation. Symptoms may include loss of speech, involuntary hand movements, seizures, loss of muscle tone, breathing and sleeping issues.

NNZ-2566, named Trofinetide by the World Health Organisation, was discovered in 2002 when Dame Margaret and three early-career chemists David Callis, Nick Trotter and Paul Harris (now an associate professor in the School of  Biological Sciences) were investigating potential chemical candidates for treating traumatic brain injury.

They were working for University of Auckland spin-out company Neuren Pharmaceuticals (now listed on the Australian Securities Exchange) with biologists including Associate Professor Jian Guan and Professor Mike Dragunow from the Liggins Institute. Sir Peter Gluckman was the chief scientific officer for Neuren.

Dame Margaret’s work built on observations by Sir Peter and his team that a natural peptide called GPE had neuroprotective properties. After the discovery of the key molecule (NNZ-2566), a large team of biomedical scientists, business people, doctors and patients took part in work to develop NNZ-2566 for medical use.

Trofinetide was never adopted for treating brain injuries, but clinical trials began in 2012 in connection with Rett syndrome.

Neuren Pharmaceuticals, established with the help of the University’s research application and commercialisation company UniServices, eventually partnered with Acadia Pharmaceuticals in San Diego to conduct the successful phase-3 trials.

A second neurological drug from Dame Margaret and her team working with Dr Jian Guan, NNZ-2591, also has big potential. NNZ-2591 has FDA approval to enter phase 2 clinical trials for the treatment of Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome and Prader-Willi syndrome.

In 2018, Dame Margaret was the first woman working in New Zealand to be elected a fellow of the Royal Society of London, the world’s oldest scientific organisation, and in 2019 she was honoured with the title Dame for “world-class contributions to research in medicinal chemistry”.