Safety and efficacy of Ovaleap® (recombinant human follicle-stimulating hormone) for up to 3 cycles in infertile women using assisted reproductive technology: a phase 3 open-label follow-up to Main Study

Abstract

BackgroundOvaleap® (follitropin alfa), a recombinant human follicle-stimulating hormone intended for use in controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART), showed therapeutic equivalence to Gonal-f® in a multinational, multicenter, randomized, controlled, assessor-blind phase 3 Main Study. The current study examined safety, including immunogenicity, and efficacy of Ovaleap® in an open-label, uncontrolled, follow-up treatment period of up to 2 additional treatment cycles in patients who did not become pregnant in the phase 3 Main Study.MethodsPatients with negative biochemical or clinical pregnancy in the phase 3 Main Study, regardless of treatment group (ie, Ovaleap® or Gonal-f®), were eligible to participate. Patients received Ovaleap® (Merckle Biotec GmbH, Ulm, Germany) for up to 2 additional cycles, administered using a reusable semi-automated pen device. The primary objective was the assessment of safety, including adverse events (AEs), ovarian hyperstimulation syndrome (OHSS), and anti-drug antibodies. Tolerability, patient satisfaction with the Ovaleap® pen device, and efficacy outcomes (as evaluated in the Main Study) were also assessed.ResultsOne hundred forty-seven patients were included in cycle 2, and 61 patients were included in cycle 3. In cycles 2 and 3, 10.9 % (16/147) and 6.6 % (4/61) of patients experienced treatment-emergent AEs (TEAEs), respectively. Three serious TEAEs (ie, appendicitis, OHSS, and borderline ovarian tumor) were reported and successfully resolved. The OHSS TEAE was the only OHSS reported in the study (0.7 % [1/147]). Positive findings on anti-drug antibody assays in 6 serum samples did not show neutralizing activity or clinical relevance in biochemical pregnancy rate. No hypersensitivity reaction occurred. Most patients reported “very good”/“good” local tolerability. All patients were “very confident”/“confident” about dose accuracy and correctness of the injection. They all found use of the pen “very convenient”/“convenient” and were all “very satisfied”/“satisfied” with the pen device. Efficacy outcomes were consistent with the phase 3 Main Study.ConclusionsThese findings further support the safety, including immunogenicity, and efficacy of Ovaleap® for stimulation of follicular development in infertile women undergoing ART. The findings support continued use of Ovaleap® for multiple cycles or a switch to Ovaleap® if pregnancy is initially not achieved with Gonal-f®.Trial registrationEudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901.

Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review

“…Of the 23 clinical, non-medical switching studies (Table 1) [53, 55, 56, 60, 61, 69, 70, 73–75, 81, 82, 84–86, 91–99, 101–104], 22 reported data on main efficacy parameters in switched versus non-switched or pre-switch versus post-switch groups. The originator biologics/biosimilars assessed were infliximab (six studies [53, 55, 56, 61, 69, 70, 73]), erythropoietin-stimulating agents (ESAs) (four studies [74, 75, 81, 82]), filgrastim [93–95] (three studies), insulin [84–86], adalimumab [96–98], rituximab [60, 99] and etanercept [101–103] (two studies each), and genotropin [83, 92] and follicle stimulating hormone [104] (one study each).…”

“…The originator biologics/biosimilars assessed were infliximab (six studies [53, 55, 56, 61, 69, 70, 73]), erythropoietin-stimulating agents (ESAs) (four studies [74, 75, 81, 82]), filgrastim [93–95] (three studies), insulin [84–86], adalimumab [96–98], rituximab [60, 99] and etanercept [101–103] (two studies each), and genotropin [83, 92] and follicle stimulating hormone [104] (one study each).…”

“…The NOR-SWITCH infliximab trial was conducted across six indications and used a non-inferiority margin of 15% (adapted from rheumatoid arthritis studies), with results suggesting no loss of efficacy and no unexpected treatment-emergent adverse events (TEAEs) [53]. Eight studies reported similar outcomes between groups, but failed to provide a formal statistical analysis of between-group comparisons [55, 56, 69, 70, 75, 98, 102–104]. …”

“…The relative frequency of ADAs in biologic originator and biosimilars was reported in 27 studies, of which 18 were clinical studies [53, 55, 56, 60, 61, 69, 70, 73, 81, 82, 84–86, 91, 92, 95–99, 101–104] and nine were observational [46–48, 52, 57, 63, 67, 68, 71, 105]. In 26 studies (17 clinical: follow-up 12–52 weeks [53, 55, 56, 60, 61, 69, 70, 73, 81, 82, 84, 85, 91, 92, 95–99, 101–103]; nine observational: follow-up 6–13 months [46–48, 52, 57, 63, 67, 68, 71, 105]), there were either no cases of ADAs, or the incidence of ADAs was similar in both groups.…”

“…Response rates increased over time in all treatment groups until week 30 and then remained stable to week 52≥1 TEAE up to week 52, continued GP2015 vs continued ETN switched GP2015 vs switched ETN: 60 vs 57 vs 61 vs 59%. AEs of special interest, continued GP2015 vs continued ETN switched GP2015 vs switched ETN: 11 vs 5 vs 11 vs 5%Non-nADAs: 1% in the switched ETN group at week 36 (receiving GP2015 for 12 weeks at time of finding); 2% in continued ETN groupStrowitzki et al 2016 [104]Undergoing ovarian stimulation ( N  = 147)67FSH RP (Gonal–f), 1 cycle in RCT (study also included patients on Ovaleap throughout, with no switch)Ovaleap, 1 cycle in RCT plus ≤ 2 cycles in extension studyGonal-f/Ovaleap vs Ovaleap/Ovaleap, mean number of oocytes retrieved, cycle 2: 12.1 vs 12.0; cycle 3, mean: 15.0 vs 12.3 ( P NR)Frequency of TEAEs similar in 2 groups; there were 2 drug-related TEAEs, both in Ovaleap group: 1 injection-site erythema, pruritis and haematoma, 1 lower abdominal painDetected in 6 patients (none with nADAs); NR separately for 2 groups ABP501 adalimumab biosimilar, ACR American College of Rheumatology, ADAs anti-drug antibodies, AE adverse event, AS ankylosing spondylitis, BCD-020 rituximab biosimilar, BOW015 infliximab biosimilar, CD Crohn’s disease, CI confidence interval, CRP C-reactive protein, CT-P10 biosimilar rituximab, CT-P13 biosimilar infliximab, DAS28 Disease Activity Score in 28 joints, EP2006 filgrastim biosimilar, ESA erythropoietin-stimulating agent, ESR erythrocyte sedimentation rate, ETN etanercept, EULAR European League Against Rheumatism, FSH follicle-stimulating hormone, GP2015 etanercept biosimilar, HX575 epoetin alfa biosimilar, INX infliximab, LY IGlar LY2963016 insulin glargine, nADAs neutralising anti-drug antibodies, NR not reported, NS not significant, PASI Psoriasis Area and Severity Index, PsA psoriatic arthritis, RCT randomised controlled trial, RR relative risk , RP reference product, RTX rituximab, SAE serious adverse event, SB2 infliximab biosimilar, SB4 etanercept biosimilar, SB5 adalimumab biosimilar, SpA spondyloarthritis, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, TEAE treatment-emergent adverse event, UC ulcerative colitis, XM02 filgrastim biosimilar a Of 175 patients on adalimumab, those with PASI of ≥ 50 at 16 weeks were re-randomized 1:1 to remain on adalimumab or switch to ABP501 …”