The European Medicines Agency (EMA) has recommended refusal of marketing authorization for two new drugs, one for Rett syndrome and the other for schizophrenia. In each case, the data presented could not support granting the applications.

Daybue Refused for Rett Syndrome 

Rett syndrome is a rare neurological disorder affecting mainly females, with an incidence of around 1 in 10,000 births. It is believed to be the most common genetic cause of profound intellectual and physical disability in girls.

Daybue (trofinetide, Acadia) was intended to be the first therapy for Rett syndrome to be approved in the European Union. It was designated an orphan medicine in 2015. Preliminary trial evidence suggested that the drug showed a benefit over placebo in increasing patients' ability to communicate. Trofinetide is already approved for Rett syndrome patients aged 2 years and older in the United States and Canada, where it is available as a solution to be drunk twice a day.

However, the EMA recommended not granting marketing authorization because it considered the magnitude of effects observed after 12 weeks of treatment to be too small to be clinically meaningful. In addition, high levels of patient withdrawals complicated conclusions on possible long-term effectiveness.

Although present from conception, Rett syndrome is typically diagnosed between the ages of 1 and 2 years. After a period of near normal development, the child experiences a regression in key skills — usually mobility, speech, and hand use — and may appear very withdrawn. This pattern often leads to a misdiagnosis of autistic spectrum disorder.

Affected girls often also develop repetitive hand movements (wringing, patting, clapping, tapping, mouthing) along with a stiff or clumsy posture and an unsteady wide-based gait due to increasing muscle tone with age. Joint deformities and muscle wasting may occur. 

Typical comorbidities later in the disease trajectory include epilepsy, breathing irregularities (hyperventilation, breath-holding and air swallowing), feeding difficulties (chewing and swallowing problems), irregular heartbeat, scoliosis, and gastrointestinal problems. Affected children have profound and multiple physical and learning disabilities and are usually totally dependent for life, although about 50% develop independent mobility.

The condition is genetic but not usually inherited. It is due to a mutated X chromosome gene called MECP2. Mortality is increased, but more than 70% of patients now survive to age 45. The leading cause of death is cardiorespiratory compromise.

Iloperidone for Schizophrenia and Bipolar I Disorder 

The EMA also gave a negative opinion for Iloperidone (iloperidone, Vanda Pharmaceuticals Netherlands), intended for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Iloperidone is an antipsychotic medicine that attaches to and blocks neurotransmitter receptors for dopamine and 5-hydroxytryptamine (serotonin), which play a role in these disorders. The EMA considered the results of five main studies involving more than 3000 patients with schizophrenia in which iloperidone was compared with ziprasidone, risperidone, haloperidol, or placebo, and a study comparing iloperidone with placebo in 417 patients with bipolar disorder.

The EMA said that, in both conditions, the observed benefits of iloperidone were insufficient to outweigh the risks of the pronounced QT prolongation observed with the drug. Feasible and effective measures to manage and address this risk in clinical practice, such as how to identify and monitor patients at higher risk of potentially fatal arrhythmias, had not been identified. 

The safety and efficacy of iloperidone had therefore not been sufficiently demonstrated, so the agency recommended refusal of the marketing authorization.

Schizophrenia is among the top 10 causes of disability worldwide, with an incidence in central Europe of around 12.6 per 100,000 people and a prevalence of around 244/100,000. Frequent physical comorbidities, unhealthy lifestyles, and multiple cardiovascular risk factors contribute to significant premature mortality.

Bipolar disorders, featuring recurrent episodes of mania and depression, affect around 1% of the population. They also significantly contribute to disability and carry a raised mortality risk particularly due to suicide and cardiovascular disease. 

Dr Sheena Meredith is an established medical writer, editor, and consultant in healthcare communications, with extensive experience writing for medical professionals and the general public. She is qualified in medicine and in law and medical ethics.