A prospective, multicenter, clinical Study to evaluate the Safety, Pharmacokinetics, and Efficacy of Bleed Outcomes, with HemoRel-A® in severe Hemophilia A Patients.

PURPOSE: To evaluate efficacy for an on-demand treatment of acute bleeding events, pharmacokinetics, safety, and tolerability of HemoRel-A® in severe hemophilia A. METHODS: A total of 44 male subjects with severe hemophilia A with an annualized bleed rate of 12 while on-demand treatment with factor VIII (FVIII) were enrolled in the study and received HemoRel-A® for bleed treatment. The efficacy of HemoRel-A® was evaluated based on a four-point scale (excellent, good, moderate, or none). Six-point pharmacokinetic (PK) assessment was performed following a single dose of 50 IU/kg in 12 subjects after a 7-day wash-out period. Safety evaluations were performed at each visit and inhibitor testing was performed in all patients at screening and end of study. RESULTS: Forty-four male subjects received at least a single dose of the study medication and were included in the intent-to-treat (ITT) analysis and safety outcome. In 23 (7.52%) out of the 306 bleeding events, HemoRel-A® efficacy was rated as excellent, in 272 (88.89 %) bleeds it was rated as good, and in 11 (3.68%) bleeding events it was rated as moderate. No failure of efficacy was noted in any of the bleeding events. Thus overall out of 306 bleeding events, 295 (96.41%) showed excellent or good efficacy. Pharmacokinetic assessment based on plasma FVIII activity measured by the chromogenic assay in 12 patients showed comparative results similar to FVIII preparations. A total of 12 adverse events (AEs) were reported in this study. There was no inhibitor development in this previously treated patients (PTP) cohort. CONCLUSION: HemoRel-A® was established to be efficacious and safe in the treatment of acute bleeding events in subjects with severe hemophilia A. TRIAL REGISTRATION NUMBER: CTRI/2018/05/013790. Registration date: 9th May 2018.

Randomised, Double-blind, Comparative Clinical Study of New Ranibizumab Biosimilar in Neovascular (Wet) Age-Related Macular Degeneration.

PURPOSE: The study was undertaken for regulatory purposes to establish clinical biosimilarity and interchangeability of a ranibizumab biosimilar with reference product. PATIENTS AND METHODS: A total of 159 subjects with neovascular (wet) age-related macular degeneration (AMD) were dosed with ranibizumab. Initial double blind period of 16 weeks was followed by open-label phase till week 24. Efficacy assessment was performed at weeks 1, 4, 8, 12, 16, 20 and 24 based on best corrected visual acuity. Change in central macular thickness was assessed by optical coherence tomography from baseline to week 24. Immunogenicity assessment was done in both arms at baseline, week 16 and week 24. Safety evaluation included clinical and ophthalmic examination, adverse events, vital signs, laboratory parameters and immunogenicity in both treatment arms. RESULTS: In the biosimilar test arm, 104 (98.11%) and 105 (99.06%) patients lost fewer than 15 letters in visual acuity at week 16 and week 24, respectively, compared with 53 (100%) at both follow-ups in reference arm. In the test arm, 27 (25.47%) and 34 (32.08%) patients gained at least 15 letters in visual acuity till week 16 and week 24 respectively, compared with 17 (32.08%) and 23 (43.30%) in the reference arm. In the test arm, mean change in central macular thickness at 24 weeks was -89.93 µm against -64.42 µm in the reference arm. Difference was statistically not significant for any endpoint at 16 and 24 weeks for the primary and secondary endpoints. CONCLUSION: The evaluation of efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference for biosimilar ranibizumab with the reference product.

Randomized Comparative Clinical Study of First Global Omalizumab Biosimilar with Innovator Product in Moderate to Severe Persistent Asthma.

PURPOSE OF STUDY: Omalizumab the first anti-IgE antibody is proven with several real-world studies and meta-analyses as important adjuvant in severe allergic asthma. This study was undertaken for the first omalizumab biosimilar to establish clinical biosimilarity and interchangeability with originator product. MATERIALS AND METHODS: In this randomized, double-blind comparative study 105 subjects (70 subjects in the study group and 35 subjects in the reference group) were dosed up to week 16 as double blind phase and responders entered open label phase till week 24. All responders at week 16 received study product in open-label phase of the study as per their dosing schedule till week 24. The additional efficacy assessment visit was performed till week 24. Safety follow up visit was performed in responders at week 26. The pharmacokinetic (PK) and pharmacodynamic (PD) assessment was planned in 48 subjects after first dose of omalizumab. RESULTS: In double blind phase, 4 (5.80%) asthma exacerbations were reported in study arm compared to 1 (2.86%) asthma exacerbation in reference arm with no statistically significant difference (p>0.05). The time to first asthma exacerbation was 53 days in study arm compared to 62 days in reference arm. In study and reference arm, the mean change from baseline in forced expiratory volume in one second (FEV1%) was 7.51 and 5.98 at week 4; and 12.30 and 8.94 at week 16 respectively while mean change from baseline in forced expiratory volume in one second/forced vital capacity (FEV1/FVC%) was 4.20 and 4.06 at week 4 and 6.77 and 7.10 at week 16 respectively (no statistically significant difference, p>0.05). At week 16, 4 (5.80%) subjects in study arm had 50-75% inhaled corticosteroids (ICS) dose reduction compared to 2 (5.71%) subjects in reference arm. The proportion of subjects with meaningful improvement in Asthma Quality of Life Questionnaire (AQLQ) (improvement in overall AQLQ score ≥0.5), mean change in overall Asthma Control Questionnaire (ACQ) score and proportion of responders based on Global evaluation of treatment effectiveness (GETE) assessment also was similar at 16 weeks. A total of 101 adverse events were reported out of which 63 were reported in the study or biosimilar arm and 38 were reported in the reference or innovator arm. Two serious adverse events (SAEs) were reported, one in each arm. No deaths occurred during this study and the safety observations are consistent with the known safety profile of omalizumab. All the samples analysed in this study were negative for anti-omalizumab antibodies. There was no significant difference in the PK and PD evaluation. CONCLUSION: The evaluation of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference of the biosimilar omalizumab with the reference product.

Comparative pharmacokinetics, efficacy, and safety of bevacizumab biosimilar to reference bevacizumab in patients with metastatic colorectal cancer.

OBJECTIVE: To establish clinical biosimilarity of BevaciRel™ bevacizumab biosimilar (study bevacizumab) with the reference innovator bevacizumab in terms of pharmacokinetics, efficacy, and safety in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A total of 119 patients with mCRC were enrolled across 20 centers and randomized to receive study and reference bevacizumab in this Phase III clinical study. Of these, 116 patients were administered bevacizumab 5 mg/kg intravenously every 2 weeks with folinic acid, fluorouracil, and irinotecan regimen. The primary endpoint of the study was objective response rate (ORR) at week 25, and the secondary endpoints assessed were progression-free survival (PFS), overall survival (OS), and assessment of pharmacokinetics and safety along with immunogenicity in both treatment arms. RESULTS: The ORR was 60.53% in study bevacizumab and 66.67% in reference arm. The proportions of subjects showing CR and PR were comparable in both the arms. The median PFS at 1 year was 3.83 months in test arm and 4.6 months in reference arm. The mean OS was 10.91 months in test arm and 14.68 months in reference arm. The difference in ORR, median PFS, and OS was not statistically significant (P > 0.05). The median Tmaxwas 6.00 h in both the arms. The median t½ was 330.63 h and 226.14 h, respectively, for test and reference bevacizumab. The adverse event profile of both products was in line with the known profile of bevacizumab. CONCLUSION: The study biosimilar bevacizumab was found to be noninferior and clinically biosimilar to the reference bevacizumab, thereby meeting an unmet medical alternative need in mCRC.

A comparative phase III clinical study to evaluate efficacy and safety of TrastuRel™ (biosimilar trastuzumab) and innovator trastuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.

INTRODUCTION: The present study for biosimilar trastuzumab was a multicentric, randomized, two-arm parallel-group, comparative phase III study in patients with metastatic breast cancer. MATERIALS AND METHODS: Stage I of the study was conducted among 42 participants with equal distribution in the study and reference arm. After a loading dose of 8 mg/kg trastuzumab was administered intravenously on day 1 of the first cycle; serum samples were obtained at 0, 1.5 (end of IP infusion), 3, 6, 8, 24, 96, 168, and 336 h after the first infusion for the first cycle only. Cmax and AUC0-336 were calculated for a single dose. Stage II enrolled a total of 106 patients across 20 centers who were randomized to receive biosimilar trastuzumab (study trastuzumab) or the reference trastuzumab with paclitaxel. The primary endpoint of the objective response rate (ORR) was analyzed after last the dosed participant had completed 25-week evaluation. The secondary outcome measures included time to tumor progression, progression-free survival and overall survival at week 48, and safety evaluation. RESULTS: For reference and study trastuzumab products, mean Cmax of 229.02 and 210.68 µg/mL and AUC0-336 of 24298.29 and 25809.33 (µg × h/mL), respectively, were obtained. The efficacy results demonstrated that study trastuzumab and reference trastuzumab had comparable ORR (48.44% vs. 44.44%). The proportions of participants showing complete response and partial response in each arm were found to be comparable. There were 56 (68.29%) participants in the study arm and 13 (59.09%) participants in the reference arm who had at least one adverse event during the study. Immunogenicity assessment also revealed no participants with positive antibody titer in any of the study arms. CONCLUSION: The pharmacokinetics, overall response rate at 25 weeks, and safety of the biosimilar trastuzumab was comparable to the reference trastuzumab.