FDA Approves First Therapy for High-Risk Neuroblastoma

Approval of a chimeric, monoclonal antibody, dinutuximab

On 10 March 2015, the US Food and Drug Administration (FDA) approved dinutuximab (Unituxin) as part of first-line therapy for paediatric patients with high-risk neuroblastoma.

Neuroblastoma is a rare cancer that forms from immature nerve cells. It usually begins in the adrenal glands but may also develop in the abdomen, chest or in nerve tissue near the spine. Neuroblastoma typically occurs in children younger than five years of age. Patients with high-risk neuroblastoma have a 40 to 50% chance of long term survival despite aggressive therapy.

Dinutuximab is an antibody that binds to the surface of neuroblastoma cells. Dinutuximab is being approved for use as part of a multimodality regimen, including surgery, chemotherapy and radiation therapy for patients who achieved at least a partial response to prior first-line multiagent, multimodality therapy.

The FDA granted dinutuximab priority review and orphan product designation. Priority review shortens the timeframe for review of drug applications by four months, compared to standard reviews, and is granted to drugs that, if approved, will provide a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.
With this approval, the FDA also issued a rare paediatric disease priority review voucher to United Therapeutics, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. This is the second rare paediatric disease priority review voucher granted by the FDA since inception of the rare paediatric disease review voucher programme, which is designed to encourage development of new therapies for prevention and treatment of certain rare paediatric diseases.

The safety and efficacy of dinutuximab were evaluated in a clinical trial of 226 paediatric participants with high-risk neuroblastoma whose tumours shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Participants were randomly assigned to receive either an oral retinoid drug, isotretinoin (RA), or dinutuximab in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor, which are thought to enhance the activity of dinutuximab by stimulating the immune system, and RA.

Three years after treatment assignment, 63% of participants receiving the dinutuximab combination were alive and free of tumour growth or recurrence, compared to 46% of participants treated with RA alone. In an updated analysis of survival, 73% of participants who received the dinutuximab combination were alive compared with 58% of those receiving RA alone.

Dinutuximab carries a Boxed Warning alerting patients and health care professionals that dinutuximab irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression.

The most common side effects of dinutuximab were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatraemia, elevated liver enzymes, anaemia, vomiting, diarrhoea, hypokalaemia, capillary leak syndrome (which is characterised by a massive leakage of plasma and other blood components from blood vessels into neighboring body cavities and muscles), neutropenia and lymphopenia, hives, and hypocalcaemia.

Unituxin is marketed by Silver Spring, Maryland-based United Therapeutics.