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Introduction YLB113 is a biosimilar of the reference product (RP), etanercept, under development for treatment of patients with moderate-to-severe rheumatoid arthritis (RA) and other approved indications. A phase 3 study was conducted in Europe, Japan, and India to compare the efficacy, safety, and immunogenicity of YLB113 with the RP over a treatment period of 52 weeks. Methods Overall, 528 patients with moderate-to-severe RA receiving concomitant methotrexate were randomized to receive a once-weekly, subcutaneous dose of 50 mg YLB113 or the RP. The primary endpoint was ACR20 response rate at week 24, with similarity confirmed if the 95% confidence interval (CI) for YLB113 and the RP was within the range of − 15 to 15%. Safety and immunogenicity endpoints were assessed to week 52. Results Based on the European analysis, in the full analysis set, ACR20 response at week 24 was 83.3% and 88.5% for YLB113 and the RP, respectively. Responses were within the predefined clinical equivalence margin. The sensitivity analysis in the per protocol set revealed a similar proportion of subjects exhibiting ACR20 response at week 24 between groups, with a difference of − 5.1% (95% CI − 11.07 to 0.81). The incidence of treatment-emergent adverse events was comparable between groups, and the incidence of antidrug antibody development to week 24 favored YLB113 (0.8 vs. 8.3%). Conclusions This study demonstrated biosimilarity of YLB113 to the RP regarding efficacy, safety, and immunogenicity in patients with moderate-to-severe RA. Based on the same mechanism of action, biosimilarity could be extrapolated to other therapeutic indications approved for etanercept. Trial registration EudraCT Number: 2015-002,809-12. Electronic Supplementary Material The online version of this article (10.1007/s40744-019-00186-3) contains supplementary material, which is available to authorized users.

Background YLB113 is an investigational biosimilar of the reference product etanercept (ETN), being developed for the treatment of patients with moderate-to-severe rheumatoid arthritis (RA) and other approved indications of the reference product ETN. Objectives The phase 3 study of YLB113 was conducted in Europe, Japan, and India across more than 100 rheumatology clinics to compare efficacy, safety, and immunogenicity of YLB113 with ETN in patients with RA. Methods A total of 528 patients with moderate-to-severe RA receiving concomitant treatment with methotrexate were randomized to receive a once-weekly dose of 50 mg of subcutaneously administered YLB113 or ETN. The primary end point was the ACR20 response rate at Week 24, with equivalence confirmed if the 95% confidence interval (CI) was within the range of –15% to 15%. Other efficacy end points, such as DAS28 with safety and immunogenicity end points, were assessed periodically up to Week 52. Results The ACR20 response rate at Week 24 was 81.2% for YLB113 and 86.8% for ETN in the full analysis set, with a treatment difference of –5.6% (95% CI: –11.6, 0.5), which was completely within the predefined equivalence margin of −15% to 15%. The result for sensitivity analysis using the per protocol set population revealed that the proportion of subjects who showed ACR20 response at Week 24 was similar between both treatment groups, at –4.6% (95% CI: –10.1, 0.8). The incidence of treatment-emergent adverse events was comparable between YLB113 and ETN (55.5% vs 65.7%), and the incidence of antidrug antibody development up to Week 24 was in favor of YLB113 (0.8% vs 8.3%). Conclusion The present comparative study demonstrated the biosimilarity of YLB113 to ETN on the triad of efficacy, safety, and immunogenicity in patients with moderate-to-severe RA, and thus can be extrapolated to other therapeutic indications approved for ETN. The therapeutic equivalence of YLB113 and ETN in terms of the primary efficacy end point at Week 24 and long-term safety comparability until Week 52 was established with lower immunogenicity. Disclosure of Interests Hisashi Yamanaka Grant/research support from: AbbVie, Eisai, Bristol-Meyers, Novartis, Behringer, Astellas, Kaken, Nippon-Shinyaku, Pfizer, UCB, Ayumi, Ono, Daiichi-Sankyo, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, Torii, YLbio, Speakers bureau: Bristol-Meyers, Astellas, Pfizer, Daiichi-Sankyo, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, YLbio, Naoyuki Kamatani Speakers bureau: I was a speaker in meetings and paid for the speech by YLB Pharma, Teijin Pharma, Chugai, Pfizer, Fuji Yakuhin, Sanwa Kagaku, Asahi Kasei Pharma and Asteras-Amzen BioPharma., Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics, Toshihiko Hibino Consultant for: I had worked in Japanese Pharmaceutical Company (Showa Yakkako Company Co. Ltd.) as unaffiliated director until 2015 but have no conflict on business including newly built company (Ayumi Pharmaceutical Company Co. Ltd.) since then., Edit Drescher: None declared, Juan Sanchez-Burson: None declared, Manfred Rettenbacher Employee of: I’m an employee of Lupin Pharmaceuticals Ltd., Girish Bhatia: None declared, Snehal Gadve Consultant for: Was working as a consultant for YLB company, Chirag Shah Employee of: I’m an employee of Lupin Pharmaceuticals Ltd., Dhananjay Bakhle Employee of: I’m an employee of Lupin Pharmaceuticals Ltd.

Recombinant human follicle stimulating hormone (r-hFSH) is effective and safe for controlled ovarian stimulation. Bemfola(®) (Finox AG, Burgdorf, Switzerland), a new biosimilar r-hFSH, has proven comparable non-clinical pharmacological profiles to those of the widely used Gonal-f(®) (Serono Pharma S.p.A., Bari, Italy). The objective of this study was to show that Bemfola(®) yields comparable clinical pharmacokinetic (PK) and safety profiles to Gonal-f(®) in healthy female subjects. In this randomized, Phase I trial conducted in healthy female volunteers (N = 32), a 2-period, balanced 2-treatment crossover design was used. A single subcutaneous dose of 225 IU Bemfola(®) or Gonal-f(®) was administered in each treatment period per sequence. Blood was collected for pharmacokinetic analysis until 10 days after each r-hFSH treatment. For down-regulation of endogenous FSH subjects were given a depot injection with leuprolide acetate prior to the study drug in either sequence. Pharmacokinetic data was available for 23 subjects. No appreciable differences in key PK parameters were detected between the r-hFSH products as per non-compartmental PK analysis [i.e. for Bemfola(®) and Gonal-f(®) respectively AUC0-192 424.90 and 432.75 IU h/L, C max 0.98 and 0.95 IU/L, T max 24.0 h (range 6.0-24.0) and 24.0 h (range 9.0-24.0), t 1/2 43.58 h [standard deviation (SD 14.17)] and 42.58 h (SD 16.47), and K e 0.0075 1/h (SD 0.003) and 0.0077 1/h (SD 0.002)]. Subgroup analysis for estradiol (E2) response was similar for Bemfola(®) and Gonal f(®) (AUC(0--120) p = 0.21 and C max p = 0.82). No major safety issues were identified and no immunogenic reaction to r-hFSH was observed. The results of this study indicate that a single dose of Bemfola(®) exhibits pharmacokinetic and safety profiles comparable to Gonal-f(®) in healthy young women.

BACKGROUND: Despite the availability of efficacious drugs, the success of treating hypertension is limited by patients' inconsistent drug intake. Immunization against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension, because vaccines induce relatively long-lasting effects and do not require daily dosing. Here we describe the preclinical development and the phase I clinical trial testing of a virus-like particle (VLP)-based antihypertensive vaccine. METHODS AND RESULTS: An angiotensin II-derived peptide was conjugated to the VLP Qbeta (AngQb). AngQb was highly immunogenic in mice and rats. To test for efficacy, spontaneously hypertensive rats (SHR) were immunized with 400 microg AngQb or VLP alone. Group mean systolic blood pressure (SBP) was reduced by up to 21 mmHg (159 +/- 2 versus 180 +/- 5 mmHg, P < 0.001), and total angiotensin II levels (antibody-bound and free) were increased ninefold (85 +/- 20 versus 9 +/- 1 pmol/l, P = 0.002) compared with VLP controls. SHR treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg per day by mouth) reached an SBP of 155 +/- 2 mmHg. Twelve healthy volunteers of a placebo-controlled randomized phase I trial were injected once with 100 microg AngQb. Angiotensin II-specific antibodies were raised in all subjects (100% responder rate) and AngQb was well tolerated. CONCLUSIONS: AngQb reduces blood pressure in SHR to levels obtained with an ACE inhibitor, and is immunogenic and well tolerated in humans. Therefore, vaccination against angiotensin II has the potential to become a useful antihypertensive treatment providing long-lasting effects and improving patient compliance.

The objective of this study was to assess and compare the features of the Bemfola, Gonal-f and Puregon injection pens.Females who intended to undergo hormonal treatment received the three different pens in a randomized, consecutive sequence. For each of the pens, the potential patients completed an Injection Pen Assessment Questionnaire, as well as a questionnaire comparing the handling, convenience and preference among the three pens.The mean score on the visual analogue scale (VAS) for the Bemfola pen (BP) was 77.8 ± 14.0; for the Puregon pen (PP), 72.1 ± 12.4; and for the Gonal-f pen (GP), 68.6 ± 16.4. The BP was superior to both competitor devices in pen size, inconspicuousness, ease of use and dose changing; no significant differences to both competitor pens were observed in the way the pen looks, the way the pen feels and the ease of injection of the volume. The 'overall' assessment was significantly better for the BP when compared to the GP (p = 0.0019), while no significant difference was observed between the BP and the PP.This study demonstrated significantly higher ratings for pen size, inconspicuousness, ease of use and dose adjustment for the BP compared to other marketed pens.

Information about the expression of neuropeptide receptors is limited in human peripheral tissues, such as the gastrointestinal tract, as compared to the brain. A detailed evaluation of binding sites for gastrin-releasing peptide (GRP), neuropeptide Y, vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP), gastrin/cholecystokinin, neurotensin, substance P and somatostatin was therefore undertaken in human colon using in vitro receptor autoradiography and subtype characterization with receptor-selective ligands. GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensin1 and sst2 receptors were abundantly expressed in the myenteric plexus. Y2, neurotensin1 and sst2 receptors were also strongly expressed in the submucosal plexus. Furthermore, expression of GRP receptors, neurokinin (NK)1 receptors, VIP type2-receptors and sst2 receptors was found in the mucosa-directed margin of the circular smooth muscle where the interstitial cells of Cajal are located. A variable and complementary expression of GRP receptors, VIP/PACAP receptors, Y2, neurotensin1, NK1 and somatostatin receptors was found in the circular and longitudinal smooth muscle. NK1 and Y1 receptors were often detected in arteries and veins, while VIP/PACAP and sst2 receptors were found in lymphoid follicles. Y2, VIP type1 and sst2 receptors were present in the colonic mucosa. Y2 was strongly expressed in the muscularis mucosae. This study shows that neuropeptide receptors are expressed in high amounts and in highly specific patterns in distinct targets in the human colon, suggesting a major physiological role for these peptides. The data represent the molecular basis to investigate the regulation by neuropeptides of colonic functions and to develop neuropeptide drugs aimed at interacting with these receptors in colonic diseases, such as Hirschsprung's and Crohn's diseases.