Pegfilgrastim biosimilars

Filgrastim, a 175-amino-acid non-glycosylated recombinant methionyl human G-CSF produced in Escherichia coli, covalently attached at the N-terminus to a 20 kDa polyethylene glycol chain, giving a total mass of about 39 kDa.

Binds the G-CSF receptor on myeloid progenitors and neutrophils, stimulating their proliferation, differentiation and release from the marrow. The PEG chain reduces renal clearance so that elimination is governed mainly by neutrophil-mediated uptake, which is self-regulating: clearance rises as the neutrophil count recovers.

Subcutaneous injection; peak concentrations at 16 to 120 hours, and a half-life of 15 to 80 hours that lengthens during neutropenia and shortens as the count recovers. A single 6 mg dose covers a chemotherapy cycle, replacing daily filgrastim.

6 mg once per chemotherapy cycle, at least 24 hours after cytotoxic chemotherapy, in a 0.6 mL pre-filled syringe. The reference product also exists as an on-body injector applied on the day of chemotherapy.

• Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignancy (excluding chronic myeloid leukaemia and myelodysplastic syndromes)
• Hematopoietic subsyndrome of acute radiation syndrome (United States)

Antibodies to pegfilgrastim are uncommon and neutralising antibodies rare; the concern with G-CSF products is cross-reactivity with endogenous G-CSF, which has not been observed clinically. Comparative programmes rely on analytical similarity, a pharmacokinetic and pharmacodynamic study in healthy volunteers using absolute neutrophil count and CD34+ cell mobilisation, and usually a comparative study in breast cancer patients receiving docetaxel-based chemotherapy with duration of severe neutropenia in cycle 1 as the endpoint; several recent products were approved on PK/PD data alone.

Neulasta was licensed by FDA on 31 January 2002 (BLA 125031) and authorised in the EU on 22 August 2002 (EMEA/H/C/000420). The EU compound patent expired in 2017 and US patents in 2015, but the manufacturing process proved harder to match than expected, and the first US biosimilar, Fulphila, arrived only in June 2018 after several rejections of earlier applications. In India, Gennova's product was permitted in January 2010 and Dr. Reddy's Peg-grafeel in 2011.

Sources: Purple Book (S016), EMA medicines data (S017), CDSCO lists (S013, S014); patent dates and application history from company and press reports.

Pegfilgrastim is the biosimilar that taught the industry about pegylation: a simple protein made complicated by the conjugation step, with several early applications failing on analytical grounds. It is also one of the most competitive US markets, eight products with Lupin and Accord arriving in 2025 and 2026, and the EU pipeline is still adding names. Six Indian manufacturers hold permissions, and Biocon supplies both the US, EU and UAE (Fulphila, Vivlipeg, Biopegfil) from Bengaluru.