ERYtech Pharma, the specialty pharmaceuticals company developing red cell-based medicinal products, announces the results of its phase II clinical trial.

GRASPALL 2005-1 was presented orally on the 8^th December 2008 at the 50^th Annual Meeting of the American Society of Hematology in San Francisco (USA).

 

This study aimed to assess the efficacy and the safety of 3 doses of GRASPA^®, a new formulation of L-asparaginase, given in frontline treatment for children and adults with relapsed acute lymphoblastic leukemia (ALL).

 

L-asparaginase is a critical and irreplaceable component of combination chemotherapy for ALL and has been used in the clinic for over 30 years. The enzyme destroys the plasmatic amino acid asparagine, which leukemia cells require to continue their rapid, malignant growth. Infusion of L-asparaginase suppresses the plasmatic source of asparagine, which starves leukemic cells of this amino acid and leads to cellular death.

Despite its highly effective anti-tumor properties and its availability in different forms, clinicians still remain wary, due to its high toxicity profile (allergic reactions and toxicity to organs). In addition, the appearance of neutralising antibodies often inhibits the efficacy of L-asparaginase.

 

GRASPA^® is L-asparaginase encapsulated inside homologous red blood cells provided by the blood bank. The loading of L-asparaginase into the red cells is very reproducible and can be completed within 2 hours, thanks to ERYtech Pharma’s proprietary technology, in a fully safe environment. The red cell membrane protects the enzyme against antibodies, allowing it to remain in circulation within the body for several weeks, as opposed to just a few days, as is the case with injection of the free form. Consequently, the number of injections is significantly reduced, leading to an equivalent reduction in side effects, and particularly the allergic reactions.

 

This new L-asparaginase formulation, considered a new medicinal product, received the Orphan Drug Designation by the European Medicines Agency (EMEA).

 

GRASPALL-2005 was a randomized and active-controlled study. Twenty-four patients from 13 centers were grouped by age (1-18 and 18-55 year olds) and enrolled. All patients received the backbone chemotherapy based on the COOPRALL protocol recommended by the European Organization for Research and Treatment of Cancer (EORTC).

For the first month of treatment, the patients randomly received either the free or encapsulated L-asparaginase form. One group of 6 patients received the free form of the native E. Coli L-asparaginase with the usual posology, i.e. 8x10,000 IU/m² injections every 3 days. Three groups of 6 patients received one single injection of GRASPA^® (50, 100 or 150 IU/kg, at random). For the second month of treatment, the patients had the option of continuing with the same treatment, thus 10 patients received a second injection of GRASPA^®.

 

As expected, a depletion of asparagine was observed after the GRASPA^® injection, regardless of the dose. One single injection of 150 IU/kg achieved a sustained asparagine depletion equivalent to the effects of eight free L-asparaginase injections, but with a better safety profile, especially in terms of the occurrence of allergic reactions and coagulation factor disorders. The biological efficacy of GRASPA^® is long-lasting: the average duration of asparagine depletion is 18.6 days (range between 14.6 and 22.5 days) after a single injection of 150 IU/kg.

Analysis of tolerability did not give rise to any unexpected safety issues among this high risk population. In terms of L-asparaginase adverse events, 3/6 patients receiving the native E. Coli L-asparaginase suffered allergic reactions (50%), including one life-threatening case, while among the 18 patients receiving GRASPA^® for the second time, only one had a minor allergic reaction (5.6%).

Regarding coagulation and hemostasis, only 2/18 patients experienced a biological coagulation factor decrease (11.1%) in the GRASPA^® group, as opposed to 4/6 from the native E. Coli L-asparaginase group (66.7%). Other adverse events were roughly equal between the two groups. Interestingly, the incidence of the known side effects showed no correlation to either the GRASPA^® dosage or the asparagine depletion duration.

 

ERYtech Pharma also presented further data in a poster session, demonstrating that, in mice, when asparaginase is encapsulated in red cells, the enzyme activity is maintained and the asparagine depletion is effective even in presence of neutralizing antibodies. In the same study, when the mice were treated with free L-asparaginase, the activity was destroyed within 6 hours, and no asparagine depletion was recorded.

 

Professor Yves Bertrand, Head of the Institut d’Hematologie et d’Oncologie Pediatrique in Lyons (France), Chairman of the Children’s Leukemia Group at European Organization for Research and Treatment of Cancer, main investigator and presenter of the results at the ASH said: “We sensed a great deal of interest in GRASPA^® from other researchers, and a lot of interesting questions were asked. We all wait for the next clinical steps”.

 

“These results confirm that encapsulation of medicinal products inside red blood cells can be useful for patients, as it increases efficacy while decreasing the side effects. This trial was also an opportunity for us to validate our industrial process, its very good reproducibility and the logistic aspects involved in treating patients throughout France”, underlined Dr Yann Godfrin, Chief Executive Officer and co-founder of the company. In terms of the logistics, patients received GRASPA^® no later than one day after its manufacture. Dr Godfrin added: “I would like to take this opportunity to say a big thank you to the Leon Berard Center and its highly motivated team for their help in providing air controlled rooms for manufacturing”.

 

Pierre-Olivier Goineau, COO, co-founder in charge of Business development added: “further studies are due to start in 2009 to confirm the efficacy/safety profile of GRASPA^® in specific sub-populations such as allergic and elderly patients. There is also a good rationale for developing GRASPA^® for treatment of certain solid organ tumors such as in pancreatic, ovarian or head and neck cancers. We hope to soon be able to develop a comprehensive range using this product”.

 

 

ERYtech Pharma is a specialty pharma company developing a new generation of drugs.

A pioneer in the encapsulation of therapeutic molecules into red blood cells, ERYtech Pharma is developing a pipeline of innovative therapeutic solutions based on its proprietary technology and expertise in the physiological properties of erythrocytes. The company addresses serious pathologies, orphan indications or sub-populations of patients, particularly in the fields of haematology, cancer and metabolic diseases.