Advertisement

A multicenter, randomized, phase III study comparing the efficacy and safety of follitropin alpha biosimilar and the original follitropin alpha

      Abstract

      Objective

      The aim of the present study was to investigate the therapeutic equivalence between the follitropin alpha biosimilar and the reference medication in women undergoing assisted reproductive technologies (ART).

      Study design

      This multicenter, randomized (1:1), embryologist-blinded, parallel-group, comparative phase III study involved 110 women aged 20–35 years old with tubal and/or male factors of infertility. All of the subjects underwent controlled ovarian hyperstimulation (COH) using a gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. Over the 5-day fixed-dose regimen, the women received 150 IU/day of follitropin alpha biosimilar (n = 55) or original follitropin alpha (n = 55), followed by dose adaptation. The primary endpoint for assessing the therapeutic equivalence was the number of retrieved oocytes using a pre-determined clinical equivalence margin of ± 3.4 oocytes.

      Results

      Similar numbers of oocytes were retrieved in both groups: 12.16 ± 7.28 in the follitropin alpha biosimilar group and 11.62 ± 6.29 in the original follitropin alpha group, with mean difference of 0.546 ± 1.297 oocytes (95% confidence interval [CI]: -2.026, 3.116), p = 0.002 (intention-to-treat [ITT] population). Additionally, no statistically significant differences were found for secondary endpoints: the onset of biochemical (34.7% and 36.7%, p = 0.883), clinical pregnancy (26.5% and 32.7%, p = 0.507), delivery (26.5% and 24.5%, p = 0.817) and take-home baby rate (28.6% and 26.5%, p = 0.816) for the follitropin biosimilar and original follitropin groups (per-protocol [PP] population). Ovarian hyperstimulation syndrome was observed in subjects with a positive pregnancy test in 0% and 3.64% of cases and after triggering ovulation in 7.27% and 3.64% for the follitropin biosimilar and original follitropin groups, respectively.

      Conclusions

      This study demonstrated similar therapeutic equivalence and safety profiles between the follitropin alpha biosimilar and the reference follitropin in women who underwent COH in GnRH-ant cycles.

      Trial registration number

      1. Name of the registry: ClinicalTrials.gov. Trial registration number: NCT03088137. Date of registration: 02.03.2017, retrospectively registered. Trial conducted between 08.02.2017 and 17.08.2018, the date of enrollment of the first participant – 08.02.2017. 2. Name of the registry: Russian Ministry of Health, grls.rosminzdrav.ru. Trial registration number: RCT 754. Date of registration: 26.10.2016, prospectively registered.

      Abbreviations:

      ART (assisted reproductive technology), IVF (in vitro fertilization), r-hFSH (recombinant human follicle-stimulating hormone), IU (International Units), OPU (ultrasound-guided follicular aspiration), AFC (antral follicle count), GnRH-ant (gonadotropin-releasing hormone antagonist), GnRH-a (gonadotropin-releasing hormone agonist), FSH (follicle-stimulating hormone), LH (luteinizing hormone), NIBSC (The National Institute for Biological Standards and Control), AMH (anti-Müllerian hormone), ITT (intent-to-treat), PP (per-protocol), CI (confidence interval), BMI (body mass index), ELISA (enzyme-linked immunosorbent assay), COH (controlled ovarian hyperstimulation), SC (subcutaneous), OHSS (ovarian hyperstimulation syndrome), ET (embryo transfer), PCOS (polycystic ovary syndrome), hCG (human chorionic gonadotropin), ICSI (intracytoplasmic sperm injection), PN (pronucleus), EMA (European Medicinal Agency), Neu5Gc (N-glycolyl neuraminic acid), CHO (Chinese hamster ovary)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Orvieto R.
        • Seifer D.B.
        Biosimilar FSH preparations - are they identical twins or just siblings?.
        Reprod Biol Endocrinol. 2016; 14: 32
        • Committee for Medicinal Products for Human Use
        Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human follicle stimulating hormone (r-hFSH).
        EMA. 2012; 2013: 597110
        • Vorob’ev I.I.
        • Proskurina O.V.
        • Khodak Y.A.
        • Gosudarev A.I.
        • Semikhin A.S.
        • Byrikhina D.V.
        • et al.
        Physicochemical properties, toxicity, and specific activity of a follitropin alpha biosimilar.
        Pharm Chem J. 2017; 50: 753-760https://doi.org/10.1007/s11094-017-1525-3
        • Orlova N.A.
        • Kovnir S.V.
        • Khodak Y.A.
        • Polzikov M.A.
        • Nikitina V.A.
        • Skryabin K.G.
        • et al.
        High-level expression of biologically active human follicle stimulating hormone in the Chinese hamster ovary cell line by a pair of tricistronic and monocistronic vectors.
        PLoS One. 2019; 14: e0219434https://doi.org/10.1371/journal.pone.0219434
        • Tyul’kina E.E.
        • Gordeev I.G.
        • DYu Grebenkin
        • Kazei V.A.
        • Tsikarishvili M.M.
        • Luchinkina E.E.
        • et al.
        Randomized crossover comparative study of safety, tolerance and pharmacokinetics of primapur vs. Gonal-f upon single-dose subcutaneous administration in healthy volunteers.
        Eksperimental’naya i Klinicheskaya Farmakologiya. 2017; 80 (in Russian): 13-17https://doi.org/10.30906/0869-2092-2017-80-4-13-17
        • Drakopoulos P.
        • Blockeel C.
        • Stoop D.
        • Camus M.
        • de Vos M.
        • Tournaye H.
        • et al.
        Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos?.
        Hum Reprod. 2016; 31: 370-376
        • Venetis C.A.
        • Tilia L.
        • Panlilio E.
        • Kan A.
        Is more better? A higher oocyte yield is independently associated with more day-3 euploid embryos after ICSI.
        Hum Reprod. 2019; 34: 79-83
        • Abramson J.H.
        WINPEPI updated: computer programs for epidemiologists, and their teaching potential.
        Epidemiol Perspect Innov. 2011; 8: 1
        • Humaidan P.
        • Nelson S.M.
        • Devroey P.
        • Coddington C.C.
        • Schwartz L.B.
        • Gordon K.
        • et al.
        Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.
        Hum Reprod. 2016; 31: 1997-2004
        • Mohammadi Yeganeh M.L.
        • Moini A.
        • Hemmat M.
        • Salman Yazdi R.
        • Bagheri Lankarani N.
        • Khodabakhshi S.
        • et al.
        The association of different auto-antibodies against ovarian tissues and gonadotropins and poor ovarian response in intracytoplasmic sperm injection cycles.
        Hum Fertil (Camb). 2017; 20: 126-131
        • Lofgren J.A.
        • Dhandapani S.
        • Pennucci J.J.
        • Abbott C.M.
        • Mytych D.T.
        • Kaliyaperumal A.
        • et al.
        Comparing ELISA and surface plasmon resonance for assessing clinical immunogenicity of panitumumab.
        J Immunol. 2007; 178: 7467-7472
        • Rettenbacher M.
        • Andersen A.N.
        • Garcia-Velasco J.A.
        • Sator M.
        • Barri P.
        • Lindenberg S.
        • et al.
        A multi-centre phase 3 study comparing efficacy and safety of bemfola® versus gonal-f® in women undergoing ovarian stimulation for IVF.
        Reprod Biomed Online. 2015; 30: 504-513
        • Strowitzki T.
        • Kuczynski W.
        • Mueller A.
        • Bias P.
        Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of ovaleap® (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART).
        Reprod Biol Endocrinol. 2016; 14: 1
        • van Wely M.
        • Kwan I.
        • Burt A.L.
        • Thomas J.
        • Vail A.
        • Van der Veen F.
        • et al.
        Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles.
        Cochrane Database Syst Rev. 2011; 2: CD005354
        • La Marca A.
        • Papaleo E.
        • Grisendi V.
        • Argento C.
        • Giulini S.
        • Volpe A.
        Development of a nomogram based on markers of ovarian reserve for the individualisation of the follicle-stimulating hormone starting dose in in vitro fertilisation cycles.
        BJOG. 2012; 119: 1171-1179
        • Julious S.A.
        Sample sizes for clinical trials with normal data.
        Stat Med. 2004; 23: 1921-1986
        • Marci R.
        • Caserta D.
        • Lisi F.
        • Graziano A.
        • Soave I.
        • Lo Monte G.
        • et al.
        In vitro fertilization stimulation protocol for normal responder patients.
        Gynecol Endocrinol. 2013; 29: 109-112
        • Hamdine O.
        • Eijkemans M.J.
        • Lentjes E.W.
        • Torrance H.L.
        • Macklon N.S.
        • Fauser B.C.
        • et al.
        Ovarian response prediction in GnRH antagonist treatment for IVF using anti-müllerian hormone.
        Hum Reprod. 2015; 30: 170-178
        • Rombauts L.
        Is there a recommended maximum starting dose of FSH in IVF?.
        J Assist Reprod Genet. 2007; 24: 343-349
        • Nohr E.A.
        • Olsen J.
        • Bech B.H.
        • Bodnar L.M.
        • Olsen S.F.
        • Catov J.M.
        Periconceptional intake of vitamins and fetal death: a cohort study on multivitamins and folate.
        Int J Epidemiol. 2014; 43: 174-184
        • Shuvalova M.P.
        • Yarotskaya E.L.
        • Pismenskaya T.V.
        • Dolgushina N.V.
        • Baibarina E.N.
        • Sukhikh G.T.
        Maternity care in russia: issues, achievements, and potential.
        J Obstet Gynaecol Can. 2015; 37: 865-871
        • Goddijn M.
        • Leschot N.J.
        Genetic aspects of miscarriage.
        Best Pract Res Clin Obstet Gynaecol. 2000; 14: 855-865
        • Steward R.G.
        • Lan L.
        • Shah A.A.
        • Yeh J.S.
        • Price T.M.
        • Goldfarb J.M.
        • et al.
        Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.
        Fertil Steril. 2014; 101: 967-973
        • Baker M.P.
        • Jones T.D.
        • Chamberlain P.
        Immunogenicity of biologics.
        in: Methods and principles in medicinal chemistry; Protein therapeutics. Vol. 71. Willey, 2017: 387-423
        • Ghaderi D.
        • Zhang M.
        • Hurtado-Ziola N.
        • Varki A.
        Production platforms for biotherapeutic glycoproteins. Occurrence, impact, and challenges of non-human sialylation.
        Biotechnol Genet Eng Rev. 2012; 28: 147-175
        • Chamberlain P.D.
        Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learnt and open questions based on 10 years’ experience of the European Union regulatory pathway.
        Biosimilars. 2014; 4: 23-43
        • Ulloa-Aguirre A.
        • Midgley Jr, A.R.
        • Beitins I.Z.
        • Padmanabhan V.
        Follicle-stimulating isohormones: characterization and physiological relevance.
        Endocrine Review. 1995; 16: 765-787
        • Zambrano E.
        • Olivares A.
        • Mendez J.P.
        • Guerrero L.
        • Díaz-Cueto L.
        • Veldhuis J.D.
        • et al.
        Dynamics of basal and GnRH-releasable serum follicle-stimulating hormone charge isoform distribution throughout the human menstrual cycle.
        J Clin Endocrinol Metab. 1995; 80 (1647–165)
        • Jean-Claude Emperaire
        Ovulation stimulation with gonadotropins.
        Springer: Cham Print, 2015https://doi.org/10.1007/978-3-319-18654-2