Anti-GD2 antibody therapy update, March 2017

Unituxin | dinutuximab | ch14.18/SP2/0

Unitixun™, manufactured by United Therapeutics Corporation (UTC) in the United States of America has been completely withdrawn from Europe due to ongoing supply shortages. European marketing authorization has been withdrawn, and the NICE appraisal process suspended indefinitely.

Unituxin is the so-called US anti-GD2 antibody, developed by the National Cancer Institute (NCI) and used in clinical trials conducted by the Children’s Oncology Group (COG). In May 2015, it was approved by the US Food and Drug Administration (FDA), making it only the third drug in history to receive initial approval for treatment of paediatric cancer, and the first immunotherapy drug for children with cancer.

Following Solving Kids’ Cancer’s successful challenge against the decision by The National Institute for Health and Care Excellence (NICE) not to recommend dinutuximab for the treatment of high-risk neuroblastoma, UTC has announced that they are withdrawing from all markets outside of the USA and Canada due to their inability to meet the demand for the product.

During late 2016 the company became aware that commercial demand for dinutuximab was exceeding supply. Our belief is that an increased usage of dinutuximab in combination with chemotherapy in refractory and relapsed patients is mostly responsible for the supply shortage, however this has been neither confirmed nor commented upon by UTC themselves.

The company are not withdrawing from paediatric oncology or abandoning Unituxin. They are planning to increase their production capacity through the building of a new manufacturing facility. However, it will be two to three years before this is up and running; in the meantime, there will be no supply of Unituxin outside of North America.

European Medicine’s Agency (EMA) marketing authorization has been withdrawn at the company’s request, and NICE has suspended the appraisal process. There can be no approval for a drug that isn’t available for clinicians to prescribe. So, despite all the efforts of Solving Kids’ Cancer to try to get dinutuximab approved for children in the UK with neuroblastoma; despite its success in carrying through on a successful appeal against NICE’s decision, there will be no dinutuximab in the UK for the foreseeable future, and there must be a question mark as to whether it will ever now be re-appraised.

Isquette | APN311 | dinutuximab-beta | ch14.18/CHO

Isquette™ was originally developed by APEIRON Biologics and sold to EUSA Pharma, a UK company based in Hemel Hempstead. In March 2017, the Committee for Medicinal Products for Human Use (CHMP), part of the European Medicines Agency (EMA), recommended granting marketing authorization for Isquette. NICE has announced they will appraise Isquette via the Single Technology Appraisal (STA) process.

Isquette is the so-called European anti-GD2 antibody, used in clinical trials conducted by the SIOPEN collaborative research group, which includes the UK.

Towards the end of 2016, EUSA Pharma acquired the global rights to Isquette from APEIRON Biologics, taking on responsibility for regulatory filings, and drug approval processes. In March 2017, the EMA adopted a positive opinion on Isquette, recommending it be granted a marketing authorization for treating both frontline and relapsed or refractory neuroblastoma patients. This is a precursor to an actual marketing authorisation being granted by the EMA, along with detailed recommendations for its use. This is a necessary step towards Isquette being approved by NICE for use on the NHS. NICE will appraise Isquette via the STA route, something Solving Kids’ Cancer argued vehemently against in the case of Unituxin, believing the Highly-Specialised Technology (HST) process to be demonstrably more appropriate. There are currently no established timelines for the appraisal; NICE are awaiting receipt of an evidence submission from EUSA Pharma. A decision by NICE is not expected for at least six months, however our experience with Unituxin suggests actual timescales could be far longer than that.

Impact on high-risk neuroblastoma children in the UK

Children are currently still able to receive anti-GD2 antibody therapy at the appropriate time, but there are no guarantees that this will continue to be the case in future.

Newly diagnosed children being treated on the SIOPEN high-risk neuroblastoma study (HR-NBL1) will continue, subject to eligibility, to receive anti-GD2 antibody therapy (using Isquette) with or without interleukin-2 (IL-2) as part of the maintenance phase of treatment (R4 randomisation). When HR-NBL1 closes to recruitment, sometime in mid-2017, there will no longer be any guaranteed access to anti-GD2 antibody therapy unless and until Isquette becomes NICE-approved. Children diagnosed after this time would normally be receiving antibody at the end of 2017, or beginning of 2018.

Children who become ineligible for the frontline antibody study; slow responders, those who fail to meet protocol requirements, and those who relapse, now have no guaranteed access to anti-GD2 antibody therapy. The SIOPEN LTI study for this cohort of patients closed to recruitment at the end of 2016. These children are treated on an individual basis, dependent on the ability to access antibody supply at the time of need.

Whilst everybody is working very hard to ensure that no child in the UK is refused antibody therapy, the future remains uncertain. This is a deeply unsatisfactory situation for children diagnosed with high-risk neuroblastoma, and for their families.

Solving Kids’ Cancer has been working since 2015 to ensure continued availability of, and access to, antibody therapy for children with high-risk neuroblastoma in the United Kingdom. We are continuing to work to this end and will do so until the future of this important part of high-risk neuroblastoma treatment, considered standard-of-care by leading experts internationally, is secured.