Are all GFs equal? How say I?

G‐CSF Filgrastim G‐CSF Lenograstim (Neupogen) (Granocyte) G‐CSF Pegfilgrastim (Neulasta, / Neulastim)

GM‐CSF (Molgramostim) GM‐CSF Sargramostim (Leukine)

Myeloid growth factors BIOSIMILARS

• Copycat versions of a given originator biological product (the “reference product”) that is already authorized on the basis of a full licensing dossier. • Otherwise known as : – “similar biological medicinal products” – “follow‐on proteins” – “subsequent‐entry biologics” – “similar biotherapeutic products” 7 Filgrastim biosimilars currently approved in the EU

•Effectively represent only three distinct products, produced by three manufacturers and marketed under various brand names. •In effect, all multiple brands for a given product share the same marketing authorization dossier. •The most recent guidelines from the EORTC recommend all authorized filgrastim biosimilars, indiscriminately, in patients at increased risk of CIN. • Note the Molecular complexity of recombinant proteins, and the complexity of biological manufacturing processes. • Easy to see that small differences can arise in a recombinant protein product which are hard or impossible to detect with even state‐of‐the‐art analytical techniques. – May have significant impact on the safety and efficacy of the drug. • The European Medicines Agency (EMEA) has taken the lead in issuing guidelines, most of which are still under review.

Need I remind you of the pure red cell aplasia produced by antibodies formed against a biosimilar to EPO? What say I regarding the profusion of biosimilar copycats? • “Beware the Ides of March “ (Shakespeare) • Beware the march of idems!

• Pharmacovigilance is the name of the game since there still has to be some concerns regarding their long‐term evaluation – because of the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity GM‐SCF: More than a hematopoietic growth factor • Apart from stimulating production of granulocytes and monocytes/macrophages • GM‐CSF has also long been used for in vitro generation /survival of dendritic cells (DCs) from monocytes and bone marrow cells • Involved in regulation of the development and function of dendritic cell subsets – promotes inflammation • Plays a role in Immunity against pathogens as well as initiating/mediating immunopathology in chronic inflammation? • Antibodies targeting GM‐CSF or its receptor have been successful in preventing/reducing inflammation in clinical trials(Hamilton, 2008) paradoxical effects on tumor immunity • GM‐CSF‐expressing tumor cells induce potent long‐ lived, systemic anti‐tumor immune responses in mice (Dranoff et al., 1993). – Augmentation of DC differentiation and function has been linked to these beneficial effects of GM‐CSF (Mach et al., 2000). • Has also been associated with tumor growth (Serafini et al., 2004), • Whether the differential influence of GM‐CSF on DC subset differentiation and function reduces the paradoxical effects on tumor immunity is still to be investigated. Sargramostim (rhGM‐CSF)

• Emerging new drugs for wound repair?? Filly, Lenny & Molly Bone Marrow Transplantation (2006) 38, 407–412 • Trend in favor of filgrastim for median number of CD34 cells collected • No difference among treatment arms and subgroups was observed in harvesting CD34 /CD33 cells, CD34 /CD38 cells and CD34 /Thy1 cells. • median number of days until apheresis statistically significant advantage in favor of lenograstim – Lenograstim 12 days – Filgrastim 13 days days in the – Molgramostim 14

Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim CH Weaver, KA Schulman and CD Buckner Bone Marrow Transplantation May 2001, Volume 27, Supplement 2, Pages S23‐S29

• 156 patients with multiple myeloma, breast cancer, or lymphoma received cyclophosphamide with either paclitaxel or etoposide and were randomized to 2 receive G‐CSF 6 g/kg/day s.c., GM‐CSF 250 µg/m /day s.c., or GM‐CSF for 6 days followed by G‐CSF until completion of the stem cell harvest. • patients who received G‐CSF had faster recovery of ANC (median of 11 vs 14 days, P = 0.0001) • fewer patients : – requiring red blood cell transfusions (P= 0.008) – with fever (18% vs 52%, P = 0.001) – hospital admissions (20% vs 42%, P = 0.13) • less intravenous antibiotic therapy (24% vs 59%, P = 0.001). • There were no significant differences in outcomes between G ‐CSF alone and the sequential regimen. Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim CH Weaver, KA Schulman and CD Buckner Bone Marrow Transplantation May 2001, Volume 27, Supplement 2, Pages S23‐S29 • Mobilization with G‐CSF or the sequential regimen – higher numbers of CD34 cells – faster platelet recovery – fewer patients requiring platelet transfusions • In summary, G‐CSF alone is superior to GM‐ CSF alone for the mobilization of CD34+ cells and reduction of toxicities following myelosuppressive chemotherapy. GM‐CSF ≠ GSF

Let’s look at some more data Comparative Effectiveness of Filgrastim, Pegfilgrastim, and Sargramostim as Prophylaxis Against Hospitalization for Neutropenic Complications in Patients With Cancer Receiving Chemotherapy

Derek Weycker, Jennifer Malin, Rich Barron, et al American Journal of Clinical Oncology. 35(3):267‐274, June 2012 • Retrospective cohort design • US healthcare claims data. • Source population included patients with solid tumors receiving filgrastim, pegfilgrastim, or sargramostim during their first observed course of chemotherapy between July 2001 and June 2007. Adjusted ORs for hospitalization. Filled diamonds show ORs for filgrastim versus pegfilgrastim and filled squares show ORs for sargramostim versus pegfilgrastim. Adjusted for patient, cancer, and chemotherapy characteristics—which were selected using a backward elimination method—including sex, comorbidity index, history of anemia neutropenia and infection, cancer type, presence of metastasis, number of myelosuppressive drugs, and year of chemotherapy. **Narrow definition: admission to hospital with a diagnosis (principal or secondary) of neutropenia (ICD‐9‐CM 288.0); broad definition: admission to hospital with a diagnosis (principal or secondary) of neutropenia, fever (ICD‐9‐CM 780.6), or infection • Adjusted odds versus pegfilgrastim of hospitalization were significantly higher for: – Filgrastim (OR :1.58‐1.79; P<0.001] and Filgrastim– Sargramostim vs Peg (OR: 1.89‐2.68; P<0.001) Sargramostim vs Peg

• Fil vsConclusions: Peg Risk of hospitalization for neutropenic complications during cancer chemotherapy is lower Sarg vs Peg with pegfilgrastim prophylaxis than with filgrastim or Fil vssargramostim Peg prophylaxis. Sarg vs Peg Granulocyte colony‐stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta‐ analysis

Katy L Cooper, Jason Madan, Sophie Whyte, et al BMC Cancer 2011, 11:404 http://www.biomedcentral.com/1471‐ 2407/11/404 Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim • Comparisons between different G‐CSFs, – 5 studies compared pegfilgrastim with filgrastim. • FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98) • This is consistent → reduction in FN risk for pegfilgrastim VS no primary G‐CSF was greater than the reduction observed for filgrastim versus no primary GCSF

Are all GFs the same? Perhaps not by a knockout! But certainly on points!! Vive la (Petit?) Difference!