A Randomized, Double-Blind, Phase III Study in India for Comparing Efficacy, Safety, and PK of ZRC-3277 (Pertuzumab Biosimilar) With Perjeta® in Patients With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: To evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after 6 cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the noninferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the 2 groups. RESULTS: In the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% noninferiority margin, obtained 2-sided 95% CIs (-12.19%, 3.11%) for the difference in ORR (-4.55%) between the 2 groups demonstrated the noninferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the 2 groups. CONCLUSION: Efficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®.

Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND).

BACKGROUND: Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency. METHODS: In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0-10.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat 100 mg oral tablets thrice a week for 24 weeks or biosimilar darbepoetin subcutaneous injection 0.75 µg/kg once in 2 weeks for 24 weeks. The primary outcome was the change from baseline in hemoglobin to evaluation period of Weeks 16-24. Key secondary outcomes included the number of patients with hemoglobin response, changes in the hepcidin levels, changes in the vascular endothelial growth factor (VEGF) levels, and changes in the lipid and lipoprotein profiles. RESULTS: Hemoglobin change from baseline to Weeks 16-24 was 1.95 g/dL in the desidustat group and 1.83 g/dL in the darbepoetin group (difference: 0.11 g/dL; 95% CI: -0.12, 0.34), which met prespecified non-inferiority margin (-0.75 g/dL). The hemoglobin responders were significantly higher (p = 0.0181) in the desidustat group (196 [77.78%]) compared to the darbepoetin group (176 [68.48%]). The difference of change in hepcidin from baseline to Week 12 and Week 24 (p = 0.0032 at Week 12, p = 0.0016 at Week 24) and the difference of change in low-density lipoprotein from baseline to Week 24 (p value = 0.0269) between the two groups was statistically significant. The difference of change from baseline in VEGF to Weeks 12 and 24 between the two groups was not statistically significant. CONCLUSION: Desidustat is non-inferior to darbepoetin in the treatment of anemia due to non-dialysis dependent CKD and it is well-tolerated.

Comparison of the Efficacy, Safety, Pharmacokinetic and Immunogenicity of UJVIRA (ZRC-3256, Trastuzumab Emtansine) With the Kadcyla (Trastuzumab Emtansine) in the Treatment of HER2-Positive Metastatic Breast Cancer: A Randomized, Open-Label, Multicenter Study in India.

BACKGROUND: UJVIRA is the first DCGI approved biosimilar of trastuzumab emtansine (Kadcyla) which may offer an alternative cost-effective treatment option for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients in India. This article summarizes the available clinical evidence supporting the biosimilarity of UJVIRA and Kadcyla with respect to efficacy, pharmacokinetic, safety, and immunogenicity. MATERIALS AND METHODS: A phase 3, randomized, open-label, active-controlled study was conducted at 31 sites across India. A total of 168 patients were enrolled and randomized to receive either UJVIRA or Kadcyla. Of which, only first 50 patients were included in pharmacokinetic assessment. UJVIRA or Kadcyla were administered at a dose of 3.6 mg/kg by intravenous infusion every 3 weeks (21 days) for 8 cycles or until disease progression or unmanageable toxicity, whichever was earlier. The study assessed efficacy (ORR), safety, pharmacokinetics, and immunogenicity. RESULTS: The ORR at the end of Week 24 was 37.76% in the UJVIRA and 33.33% in the Kadcyla group. The risk difference was 4.42% [-12.01, 20.85]. It met noninferiority margin of -15%. The pharmacokinetic parameters were comparable between groups. No antidrug antibody was detected in any of the treatment groups. The overall safety profile in terms of TEAEs and laboratory abnormalities was also comparable between the treatment groups. CONCLUSION: Results demonstrated biosimilarity between UJVIRA and Kadcyla in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Therefore, UJVIRA could prove to be a cost-effective treatment alternative for HER2-positive metastatic breast cancer patients in India.

Estimation of ZYKR1 in human urine and plasma utilizing LC-MS/MS positive electrospray ionization; a kappa opioid receptor (KOR) agonist.

ZYKR1, a short chain novel peptide with selective kappa opioid receptor agonist activity used as analgesics for the treatment of pain management. A sensitive and selective LC-MS/MS assay was developed and validated for estimation of ZYKR1 in human urine and plasma. ZY17258, an analogue compound was used as an internal standard. ZYKR1 was quantified using a selective reaction monitoring in electrospray ionization positive mode. The chromatographic separation was performed using mobile phase consisted of 0.05% v/v formic acid in water and methanol in gradient elution by analytical column Kinetex C8, 100 A°, 5 µm, 100 × 4.6 mm with 8.0 min analytical run time. Solid Phase extraction technique was used for purification of ZYKR1 and IS from human urine and plasma. The calibration curves were linear over range of 0.300 ng/mL to 300 ng/mL and 0.500 ng/mL to 500 ng/mL for human urine and plasma, respectively. No matrix effect and no significant carryover were observed. The extraction recovery was consistent and ranged from about 85% to 93% in human urine and in plasma respectively. Inter-day and intra-day accuracy (bias, %) and precision (CV, %) was -11.11 to 5.91 % and -2.25 to 6.65 % in human urine and -2.74 to 7.17 % and 2.24 to 15.18 % in plasma respectively were well within the acceptance criteria. Both the assays were devoid of endogenous matrix interference and commonly used concomitant drug interference. The validated assays were used for estimation of ZYKR1 from clinical pharmacokinetic study sample bioanalysis in healthy human subjects.

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.

BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 µg/mL [0.3] vs. 1.3 µg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).