Osmotic stress, key to Erytech Pharma SA's ability to stash therapeutic enzymes inside red blood cells, was joined by market stress Friday, as investors pushed company shares (NASDAQ:ERYP) more than 30 percent lower on news that a combination of its lead candidate, Graspa (eryaspase), and low-dose cytarabine (LDAC) failed to help people with acute myeloid leukemia (AML) live longer than treatment with LDAC alone. In light of the phase IIb outcome, the company will quit AML development for Graspa, but said it remains committed to developing it for the treatment of acute lymphoblastic leukemia and pancreatic cancer.

Iman El-Hariry, Erytech's chief medical officer, told BioWorld the result in AML was disappointing, but also maybe understandable. Though not drawing on a direct analysis of the study, she suggested that the outcome may have been attributable in part to the enrollment of mostly older, frail patients whose disease could have harbored genetic mutations not fully understood by the broader scientific community when the trial started in 2013, and thus not used in patient selection. Other factors, including co-morbidities and the difficulty of identifying patients most likely to benefit from the treatment in the midst of grappling with aggressive disease may have also affected the outcome, she said.

Graspa consists of an enzyme, L-asparaginase, encapsulated inside donor-derived red blood cells. The enzyme depletes asparagine, a naturally occurring amino acid essential for the survival and proliferation of cancer cells. It has been a standard component of multi-agent chemotherapy for the treatment of acute lymphoblastic leukemia (ALL), but side effects often limit treatment compliance, especially in adults and patients with weak performance status.

The open-label, randomized study, called Enforce 1, sought to evaluate Graspa in newly diagnosed AML patients over the age of 65 and unfit for intensive chemotherapy. It was run in collaboration with Orphan Europe, a subsidiary of Recordati SpA, and Erytech's commercial partner in Europe.

Investigators enrolled 123 patients at 30 European sites with a median age of 78 years. Participants were randomized 2-to-1 to receive Graspa in combination with LDAC or LDAC alone to see what impact the combination would have on overall survival (OS). Key secondary endpoints included progression-free survival, overall response and toxicity.

The median number of months on treatment during the study was less then two months in both arms and the toxicity profile was "acceptable and consistent" with previously reported Graspa data, the company said. The OS hazard ratio (HR) was 1.06 (95 percent CI; 0.70, 1.61). When adjusting for minor imbalances in the main prognostic factors at baseline, the OS HR was 0.98 (95 percent CI; 0.64, 1.50).

Had Erytech's development of Graspa proceeded in AML, it would have been marketed in Europe with support of Orphan Europe and in Israel via Teva Pharmaceutical Industries Ltd. – both partners on the ALL indication, too.

Now, with the discontinuation of the AML program, it faces a mixed blessing. Erytech will miss out on an undisclosed portion of the €37.5 million in clinical, regulatory and commercial milestones Recordati had attached to its deal with the company. But it is also freed from having to expend the resources that program would have demanded as it proceeded to phase III and registration. How much the company currently has in cash was unclear Friday, but it's likely in good shape after having raised €70.4 million (US$74.7 million) in April and closing its first U.S. placement of American depositary shares in November, a financing that raised $144 million in gross proceeds. (See BioWorld, Oct. 10, 2017.)

Asked about any potential for read-through to other tumors, such as relapsed or refractory ALL, El-Hariry said there was absolutely none – a message the company seems likely to underline during a morning conference being held to discuss the AML trial on Monday.

Meanwhile, the Lyon, France-based company will continue to await EMA validation of its recently resubmitted marketing authorization application for Graspa for relapsed or refractory ALL. Furthermore, it's looking forward to meeting with the FDA to gather scientific input and feedback on the same indication (ALL) to determine whether Graspa, which already has FDA orphan status, might also be a candidate for accelerated approval. Progress on the design of a potentially pivotal phase III trial in pancreatic cancer is also underway following the success of a phase IIb study in that indication reported in March. (See BioWorld Today, March 28, 2017, and April 17, 2017.)

In addition to eryaspase, Erytech is developing two other product candidates, erymethionase and eryminase, that focus on using encapsulated enzymes to target cancer metabolism and induce tumor starvation. The company is also exploring the use of its Erycaps encapsulation platform for developing cancer immunotherapies such as Erymmune and enzyme replacement therapies such as Eryzyme.