Neuren Pharma granted orphan drug status for treatment of Phelan-McDermid, Pitt Hopkins and Angelman syndromes

A drug developed by Neuren Pharmaceuticals (ASX: NEU) to treat debilitating childhood neurodevelopmental disorders has been granted orphan drug designation by the US Food and Drug Administration.

Drug candidate NNZ-2591 has previously demonstrated positive results in separate mouse models of Phelan-McDermid, Pitt Hopkins and Angelman syndromes.

Currently there are no drug therapies approved for these conditions and there are few in clinical development.

While each disorder is caused by a mutation or deletion in a different gene, they share an underlying impairment in the connections and signalling between brain cells, which is the target for treatment with NNZ-2591.

Treating rare conditions

Orphan drug designation is a special status which may be granted to drugs developed to treat rare diseases or conditions.

Under the terms of a designation, drug sponsors can qualify for seven years of marketing exclusivity – plus six months if the drug is approved for paediatric use – as well as a waiver of the prescription drug user fee for a marketing application.

Neuren executive chairman Richard Treagus said the designation was an important commercial milestone which adds significant value and momentum to the development of NNZ-2591.

“It validates our encouraging preclinical data as well as our plans to develop NNZ-2591 for the treatment of debilitating childhood disorders with an urgent unmet need,” he said.

“We look forward to working with the FDA as we execute our development plans to move NNZ-2591 into clinical trials next year.”

Autism link

Phelan-McDermid syndrome is caused by a deletion or mutation in the 22q13 region of chromosome 22, which includes the shank3 gene responsible for providing instructions for making a protein found in many of the body’s tissues and most abundantly in the brain.

The shank3 protein plays a role in the functioning of synapses, which are the connections between nerve cells (or neurons) where cell-to-cell communication occurs.

Disruption of the gene is also thought to be associated with autism spectrum disorder.

Phelan-McDermid syndrome is characterised by intellectual disability, delayed or absent speech, symptoms of autism, low muscle tone, motor delays and epilepsy.

Neuren’s research estimates that 1% of people with autism also have Phelan-McDermid, which implies that between 1 in 8,000 and 1 in 15,000 people have the syndrome.

NNZ-2591 was tested in the shank3 knockout mouse model of Phelan-McDermid syndrome, with treatment for three weeks.

The study compared normal mice (wild type) and mice with a disrupted shank3 gene (knockout).

In the knockout mice, deficits in anxiety, repetitive behaviour, motor performance and social interaction were restored to the wild type.

Treated knockout mice also showed a 60% reduction in susceptibility to seizures.

Gene mutation

Pitt Hopkins syndrome affects males and females, and is caused by the loss of one copy or a mutation of the tcf4 gene on chromosome 18.

While exact incidence figures are not known, it has been estimated that 1 in 11,000 people are affected.

The syndrome is characterised by developmental delays with moderate-to-severe intellectual disability and behavioural differences, seizures, gastrointestinal issues, lack of speech, sleep disturbance and distinctive facial features.

Some patients are also diagnosed with autism.

NNZ-2591 was tested in the tcf4 mutation mouse model, which exhibits features of Pitt Hopkins in humans, comparing normal mice and mice with a disrupted tcf4 gene.

In the mice with a disrupted gene, treatment with NNZ-2591 for six weeks normalised the deficits in hyperactivity, daily living, learning and memory, sociability, motor performance and stereotypy tests.

Gene deletion

Angelman syndrome is estimated to affect 1 in 15,000 people and is caused by a deletion or mutation in the ubiquitin protein ligase E3A (ube3a) gene on chromosome 15.

It is characterised by delayed development, intellectual disability, anxiety and hyperactivity, severe speech impairment, problems with movement and balance, seizures and sleep disorders.

It is often misdiagnosed as autism.

NNZ-2591 was tested in the ube3a knockout mouse model, which resembles features of Angelman syndrome in humans and includes motor deficits, learning problems and alterations in synaptic connectivity and plasticity.

The study compared normal mice and knockout mice with a disrupted gene.

In the knockout mice, treatment with NNZ-2591 for six weeks normalised the deficits in anxiety, daily living, sociability, motor performance and cognition tests and eliminated seizures.

At midday, shares in Neuren were trading 2.08% higher at $2.45.