LONDON – Erytech Pharma SA has provided definitive phase III evidence that its technique for encapsulating L-asparaginase in red blood cells prevents allergic reactions and the generation of neutralizing antibodies, while keeping the enzyme in circulation and active for longer, in the treatment of acute lymphoblastic leukemia (ALL).

In the first arm of the phase III trial, patients known to be allergic to standard L-asparaginase were treated with Erytech's encapsulated formulation, called Graspa. Only two of the 26 patients exhibited allergic reactions, and those were mild and manageable.

In the second arm of the trial, patients who had not shown any allergic response during first-line treatment for ALL were randomized to receive Graspa or standard L-asparaginase. In all, 43 percent of those receiving the standard enzyme suffered an allergic response, while none of the Graspa-treated group had an allergic reaction.

"Both primary endpoints of superior safety and noninferior asparaginase activity were met with high statistical significance," said Gil Beyen, CEO of Lyon, France-based Erytech. "This is an important validation of our encapsulation technology and brings us to the registration phase," Beyen said in a conference call.

In addition to preventing allergic reactions, the encapsulated L-asparaginase in Graspa remained in circulation and active for 20.5 days vs. 9.2 days for the standard enzyme. Across the two arms of the trial; 71.4 percent of Graspa-treated patients achieved complete remission, against 42.3 percent in the control arm.

"Graspa showed a significantly increased therapeutic index and tolerability, whilst maintaining its activity," Beyen said.

Graspa was licensed to Orphan Europe, part of the Recordati Group, in November 2012 in a deal with a total value of €50 million (US$63 million). In addition to ALL, the agreement covers use of Graspa in treating acute myeloid leukemia, and a phase IIb trial in that indication is ongoing.

A phase Ib study of Graspa in ALL is under way in the U.S, where the product is known as Eryasp. Beyen said that in the light of the phase III European data, the company plans to talk to the FDA to see if development can be speeded up, enlarging the study.

Asparaginase destroys asparagine, an amino acid that is essential for leukemic cells to grow. It has also been shown to have an effect in solid tumors, and Erytech has started a phase Ib in pancreatic cancer. The company also is considering trials in other solid tumors and said it believes data from the phase III ALL trial will allow it to go straight into phase II development.

"We have a clear strategy for broadening the franchise," Beyen said. "These phase III ALL data provide the basis for leveraging the technology to other indications and other products."

Erytech's technology for encapsulating asparaginase in red blood cells both protects against neutralizing antibodies and keeps the enzymes in circulation within the body for about three weeks from a single infusion. That reduces the number of injections that are required and minimizes the side-effect profile.

While the erythrocytes provide a vehicle, Erytech's technology is not what is conventionally regarded as drug delivery. The enzyme is not released but rather retained within the circulating erythrocytes, which act as pumps, sponging up the target amino acid. After the usual three weeks in circulation, the modified red blood cells are removed from the body naturally.

Although L-asparaginase has been used to treat ALL for more than 30 years, it has significant side effects, sparking allergic reactions and causing organ damage. In addition, neutralizing antibodies can limit its efficacy.

In the phase II European trial of Graspa in ALL, a single injection of encapsulated L-asparaginase led to sustained depletion of asparagine that was equivalent to the effect of eight separate injections of regular L-asparaginase. The reduction in levels of asparagine continued for an average of 18.6 days following a single infusion of Graspa.

The phase II trial not only confirmed the utility of Erytech's platform technology, but also allowed the company to validate its manufacturing and the logistics for delivering the product from its manufacturing facility in Lyon. Red blood cells are placed in a hypotonic medium that makes them swell and opens up the pores, allowing therapeutic molecules to enter. The erythrocytes are then put into an isosmotic medium that returns them to their normal shapes, encapsulating the drug product.

Erytech sources erythrocytes from blood banks. The process of loading the enzyme takes two hours, and the product can then be handled and administered in the same way as ordinary blood for transfusion.

In the U.S., Erytech has an agreement with the American Red Cross in Philadelphia, giving it access to blood supplies and a GMP manufacturing facility.

Beyen said he is expecting to hold a pre-submission meeting with the EMA shortly and to submit the file in ALL in the first half of 2015.

Shares of Erytech (PARIS:ERYP) gained €3.33, or 12.7 percent, to close Wednesday at €29.50.