Lonquex

Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC code: L03AA14 Mechanism of action Lipegfilgrastim is a covalent conjugate of filgrastim with a single methoxy polyethylene glycol (PEG) molecule via a carbohydrate linker consisting of glycine, N -acetylneuraminic acid and N -acetylgalactosamine.‍‍‍‍‍‍​​​‍​​​​​​ The average molecular mass is approximately 39 kDa of which the protein moiety constitutes approximately 48 %. Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Filgrastim is an un-glycosylated recombinant methionyl human G-CSF. Lipegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Lipegfilgrastim binds to human the G-CSF receptor like filgrastim and pegfilgrastim. Pharmacodynamic effects Lipegfilgrastim and filgrastim induced a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. These results suggest that the G-CSF moiety of lipegfilgrastim confers the expected activity of this growth factor: stimulation of proliferation of haematopoietic progenitor cells, differentiation into mature cells and release into the peripheral blood. This effect includes not only the neutrophil lineage but extends to other single lineage and multilineage progenitors and pluripotent haematopoietic stem cells. G-CSF also increases the antibacterial activities of neutrophils including the phagocytosis. Clinical efficacy and safety Once-per-cycle dosing of lipegfilgrastim was investigated in two pivotal randomised, double-blind clinical studies in patients undergoing myelosuppressive chemotherapy. The first pivotal (phase III) clinical study XM22-03 was an active-controlled study in 202 patients with stage II-IV breast cancer receiving up to 4 cycles of chemotherapy consisting of doxorubicin and docetaxel. Patients were randomised 1:1 to receive 6 mg lipegfilgrastim or 6 mg pegfilgrastim. The study showed non-inferiority of 6 mg lipegfilgrastim to 6 mg pegfilgrastim for the primary endpoint, duration of severe neutropenia (DSN) in the first cycle of chemotherapy (see table 2). Table 2: DSN, severe neutropenia (SN) and febrile neutropenia (FN) in cycle 1 of study XM22-03 (ITT) Pegfilgrastim 6 mg (n = 101) Lipegfilgrastim 6 mg (n = 101) DSN Mean ± SD (d) 0.9 ± 0.9 0.7 ± 1.0 Δ LS mean -0.186 95 % CI -0.461 to 0.089 SN Incidence (%) 51.5 43.6 FN Incidence (%) 3.0 1.0 ITT = Intent-to-treat population (all randomised patients) SD = standard deviation d = days CI = confidence interval Δ LS mean (least square mean difference lipegfilgrastim – pegfilgrastim) and CI out of multivariate Poisson regression analysis The second pivotal (phase III) clinical study XM22-04 was a placebo-controlled study in 375 patients with non-small cell lung cancer receiving up to 4 cycles of chemotherapy consisting of cisplatin and etoposide. Patients were randomised 2:1 to receive either 6 mg lipegfilgrastim or placebo. The results of the study are presented in table 3. When the main study was finalised, the incidence of death was 7.2 % (placebo) and 12.5 % (6 mg lipegfilgrastim) although after the 360-day follow-up period the overall incidence of death was similar between placebo and lipegfilgrastim (44.8 % and 44.0 %; safety population). Table 3: DSN, SN and FN in cycle 1 of study XM22-04 (ITT) Placebo (n = 125) Lipegfilgrastim 6 mg (n = 250) FN Incidence (%) 5.6 2.4 95 % CI 0.121 to 1.260 p-value 0.1151 DSN Mean ± SD (d) 2.3 ± 2.5 0.6 ± 1.1 Δ LS mean -1.661 95 % CI -2.089 to -1.232 p-value < 0.0001 SN Incidence (%) 59.2 32.1 Odds ratio 0.325 95 % CI 0.206 to 0.512 p-value < 0.0001 Δ LS mean (least square mean difference lipegfilgrastim – placebo), CI and p-value out of multivariate Poisson regression analysis Odds ratio (lipegfilgrastim / placebo), CI and p-value out of multivariate logistic regression analysis A post-authorisation safety study XM22-ONC-40041 was conducted to collect data of disease progression and mortality in patients with advanced squamous or non-squamous cell lung cancer receiving lipegfilgrastim in addition to the platinum-based chemotherapy. Increased risk of disease progression or death was not observed with lipegfilgrastim. Immunogenicity An analysis of anti-drug antibodies of 579 patients and healthy volunteers treated with lipegfilgrastim, 188 patients and healthy volunteers treated with pegfilgrastim and 121 patients treated with placebo was performed. Drug-specific antibodies emerging after start of treatment were detected in 0.86 % of the subjects receiving lipegfilgrastim, in 1.06 % of the subjects receiving pegfilgrastim and in 1.65 % of the subjects receiving placebo. No neutralising antibodies against lipegfilgrastim were observed. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Lonquex in all subsets of the paediatric population in the treatment of chemotherapy-induced neutropenia and prevention of chemotherapy-induced febrile neutropenia (see section 4.2 for information on paediatric use). In a phase 1 study of 21 children aged between 2 and 16 years with Ewing family of tumours or rhabdomyosarcoma, lipegfilgrastim was administered as a single subcutaneous dose of 100 μg/kg (up to a maximum of 6 mg, which is the fixed dose for adults) 24 hours after the end of the last chemotherapy treatment in week 1 of the regimen. The incidence of FN varied according to age (from 14.3 % to 71.4 %), with the highest frequency in the oldest age group. The use of three different chemotherapy regimens, with varying myelosuppressive effects and age distributions, complicated the comparison of efficacy across age groups (see section 4.2).