DUBLIN – Apeiron Biologics AG gained formal European Commission approval last week for dinutuximab beta as a treatment for pediatric neuroblastoma, a historic milestone for the Austrian biotech company and one that puts it on a firm financial footing.

The product's imminent rollout, by commercialization partner Eusa Pharma Ltd., of Hemel Hempstead, U.K., is timely, given United Therapeutics Corp.'s recent withdrawal from Europe of a similar product. The European Commission, at the request of the Silver Spring, Md.-based biotech firm, terminated the marketing authorization approval for Unituxin (dinutuximab) on March 20, thus ending a product franchise that had barely begun. Unituxin had only gained European approval on Aug. 17, 2015, but manufacturing problems have forced a retreat to its home market.

The two products share a common history. Ralph Reisfeld, now an emeritus professor at the Scripps Research Institute in La Jolla, Calif., originally raised a murine antibody against the tumor antigen ganglioside GD2 during the 1980s. Unituxin eventually gained FDA approval as a chimeric antibody just over two years ago, while dinutuximab beta languished as an academic project for several decades. Apeiron licensed the rights to the product in 2011. (See BioWorld Today, March 11, 2015.)

"The amino acid sequence is identical between the two antibodies. The glycosylation is not," Hans Loibner, CEO of Vienna-based Apeiron, told BioWorld Today. United Therapeutics makes Unituxin in a murine myeloma (SP2/0) cell line, whereas dinutuximab beta is produced in a more standard CHO background. That leads to a substantial reduction in the risk of anaphylactic shock, Loibner said, as SP2/0 results in the addition of galactose-alpha-1, 3-galactose (alpha-gal) residues, which are immunogenic. "We have a 10-fold difference," he said.

Apeiron's approval was granted under the EMA's "exceptional circumstances" rule, which allows for approvals in the absence of a comprehensive clinical dossier and without the expectation that sufficient data will be generated after authorization. That's because dinutuximab is long established as the standard of care for children with relapsed or refractory neuroblastoma – recruiting subjects onto a placebo-controlled trial is neither clinically feasible nor ethically acceptable. Apeiron's dossier incorporates historical controls instead.

Because of its better safety profile, it was initially on a development track intended to demonstrate its superiority to Unituxin, which would have enabled it to bypass the latter product's orphan exclusivity. Apeiron has also generated data in relapsed or refractory patients, as well as in patients with minimal residual disease. United Therapeutics had only focused on the latter category in its European submission, Loibner said. "We worked very hard to show superiority," he added.

That is no longer necessary in Europe – but it could prove telling in the U.S., where United Therapeutics posted $39.3 million in sales of Unituxin in the first quarter.

CONSIDERING ITS OPTIONS

With a European approval in the bag, Apeiron and Eusa will seek an IND in the U.S. for conducting trials there. The rest of the world would also appear to be there for the taking, given United's U.S. focus. "They did not just withdraw from Europe. They stopped every activity outside of the United States," Loibner said.

Apeiron is not disclosing the financial details of its deal with Eusa, but Loibner said the impact of the deal on the company is "major."

It gained an up-front payment on signing the deal last year. The European approval triggers an initial milestone, and further payments would follow approvals in the U.S. and Japan. Sales royalties will flow throughout the product's life cycle. Given the size of the patient population – more than 1,200 cases are diagnosed between the U.S. and the larger states of the European Union – Loibner forecasts peak annual sales of several hundred million dollars.

United Therapeutics priced the product at $150,000 to $200,000 for a full course of treatment. Eusa Pharma will seek a similar level of reimbursement, he said.

Apeiron is unusual in achieving a product approval as a privately held company – all the more so as it has never taken on venture capital funding. It has raised upward of €40 million (US$43.7 million) from a network of private and corporate investors, including London-based Glaxosmithkline plc, its development partner on APN-01, a recombinant form of human angiotensin converting enzyme 2 (ACE2), which is in phase II trials for treating lung injury. (See BioWorld Today, Feb. 4, 2010.)

The company recently licensed rights from Columbia University to a novel immune checkpoint target, Cbl-b, which forms the basis of an ex vivo cell therapy approach to treating cancer. Company founder Josef Penninger had independently elucidated the role of Cbl-b, an E3 ubiquitin ligase, in attenuating T-cell activation. Apeiron aims to disrupt its expression in patients' T cells using siRNA and then re-introduce them.

"You cannot do it with an antibody, because it's an intracellular protein," Loibner said.

An alliance with Paris-based Sanofi SA and Hamburg, Germany-based Evotec AG has uncovered a low-molecular-weight compound, identified during high-throughput phenotypic screening, which also has potential as an immunotherapy agent.

In terms of its corporate development, the company is considering its strategic options, but not in the usually gloomy sense of the term. It will seek to provide its investors with an exit, but what form that will take is not clear. It could take the form of ongoing cash distributions. An IPO involving all or part of the company is another possibility.