Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

Filing 172

MEMORANDUM in Support re #170 MOTION to Compel the Production of Documents filed by F. Hoffmann-LaRoche LTD, Roche Diagnostics GmbH, Hoffmann LaRoche Inc.. (Attachments: #1 Exhibit A#2 Exhibit B#3 Exhibit C#4 Exhibit D#5 Exhibit E (1 of 2)#6 Exhibit E (2 of 2)#7 Exhibit F#8 Exhibit G#9 Exhibit H#10 Exhibit I#11 Exhibit J#12 Exhibit K#13 Exhibit L# 14 Appendix A)(Toms, Keith) Additional attachment(s) added on 12/18/2006 (Paine, Matthew).

Result Content View Case 1:05-cv-12237-WGY

Document 172-13

Filed 12/15/2006

Page 1 of 1 Page 1 of 1

EXHIBIT K
[4364] Cross Lineage Effects of darbepoetin alfa in Normal Mice: A Comparison with Recombinant Human Erythropoietin, darbepoetin alfa and Pegylated-darbepoetin alfa. Session Type: Publication Only Robert Briddell, Julie Argento, Juan del Castillo, David Hill, Cynthia Hartley, Raheem Khaja, Kevin Khonsari, Brian Ring, Ildiko Sarosi, Glenn Begley, Graham Molineux Hematology, Amgen Inc., Thousand Oaks, CA, USA; Pathology, Amgen Inc., Thousand Oaks, CA, USA Darbepoetin alfa is a long-acting hematopoietic cytokine that has known dose-response effects upon the erythropoietic lineage in normal BALB/c mice. The intent of this study was to evaluate the non-erythroid effects of darbepoetin alfa. Darbepoetin alfa transiently induced cross-lineage effects in peripheral white blood cells (WBC) and caused a reversible increase in spleen megakaryocyte numbers. This was evident if administered at doses 10 mg/kg. In an initial doseresponse study, the kinetic changes in hematological parameters between days 1 and 7 after single intraperitoneal (IP) bolus injections of darbepoetin alfa at the doses of 1, 3, 10, 30 or 50 mg/kg or sterile saline were evaluated. On days 1, 2 and 3 after injection, darbepoetin alfa induced a transient increase in WBC counts in a dose-dependent fashion. This was due to a transient lymphocytosis and a mild monocytosis. Additionally, a single IP bolus injection of darbepoetin alfa at doses 10 mg/kg caused a mild but statistically significant splenomegaly in a dose-dependent manner after 5 days. Concurrently, megakaryocyte numbers were increased in spleen sections. A single IP bolus injection of darbepoetin alfa at doses 1 mg/kg and up to 10 mg/kg failed to induce any significant changes from day 1 through 7 in the peripheral blood platelet counts when compared with the controls. An additional study was performed in normal BALB/c mice comparing the kinetics of splenomegaly and the numbers of megakaryocytes in von Willebrand factor (vWF) immunostained spleen sections after single IP bolus injections of either rHu-EPO, darbepoetin alfa or PEG-darb. The change in reticulocyte counts was consistent with the different pharmacokinetics of these erythropoietic molecules. However the reticulocytosis was more marked, sustained and right-shifted in the PEG-darb treated groups of mice. There was a positive correlation between the degree of reticulocytosis in the blood and the degree of splenomegaly after single bolus injections of either rHu-EPO, darbepoetin alfa or PEG-darb. Unexpectedly a mild thrombocytopenia was observed in the PEG-darb-treated mice between days 8 and 14 after injection. There was a direct correlation between the degree of reticulocytosis and splenic mass. The non-erythroid effects of the rHuEPO, darbepoetin alfa and PEG-darb proteins are consistent with each other and with an increased potency of the longer-lasting forms. Abstract #4364 appears in Blood, Volume 102, issue 11, November 16, 2003 Keywords: recombinant human erythropoietin|darbepoetin alfa|pegylated-darbepoetin alfa Publication Only

Close Window

http://www.abstracts2view.com/hem/view.php?nu=HEM3L1_554

12/14/2006