Saroglitazar, a Dual PPAR α/γ Agonist, Improves Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver Disease: A Pooled Analysis.

BACKGROUND & AIMS: Cardiovascular disease is the leading cause of mortality in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effects of saroglitazar, a dual peroxisome proliferator-activated receptor α/γ agonist, on serum lipids in patients with NAFLD. METHODS: A total of 221 patients (saroglitazar, 130; placebo, 91) with NAFLD from phase 2 and 3 double-blinded placebo-controlled randomized clinical trials were pooled to assess the impact of saroglitazar magnesium 4 mg on traditional lipids, very low density lipoprotein cholesterol (VLDL-C), and small dense LDL-C (sdLDL-C). Change from baseline in lipid parameters was performed by using analysis of covariance including treatment as fixed effect and baseline value, diabetes, hypertension, and statin use as covariates. RESULTS: Treatment with saroglitazar significantly improved total cholesterol (-17 mg/dL, 95% confidence interval [CI], -24 to 9; P < .001), triglyceride (-45 mg/dL, 95% CI, -60 to 31; P < .001), low-density lipoprotein cholesterol (-8 mg/dL, 95% CI, -15 to -1; P = .01), and VLDL-C (-8 mg/dL, -14 to -3; P < .001). Saroglitazar improved serum lipids as early as 4-6 weeks of initiation of therapy, and these effects persisted for duration of therapy. Saroglitazar also improved the highly atherogenic sdLDL-C (-10 mg/dL, -17 to -2; P = .01). In subgroup analysis of patients with either diabetes or hypertension, saroglitazar significantly improved serum lipids. CONCLUSIONS: Saroglitazar improved the serum atherogenic lipoprotein profile in patients with NAFLD, irrespective of comorbid conditions and statin use. Saroglitazar has the potential to not only positively affect liver disease but also reduce cardiovascular risk in patients with NAFLD. (Trials registrations: CTRI 2015/10/006236, CTRI 173300410A0106, NCT03863574, and NCT03061721).

Saroglitazar improves nonalcoholic fatty liver disease and metabolic health in liver transplant recipients.

NAFLD is common after liver transplantation (LT) and is associated with an increased metabolic burden. Currently, there is a paucity of investigations into the treatment of post-LT NAFLD. In the present study, we evaluated the safety and efficacy of saroglitazar, a novel dual peroxisome proliferator-associated receptor α/γ agonist, on the treatment of post-LT NAFLD and metabolic burden. This is a phase 2A, single-center, open-label, single-arm study in which patients with post-LT NAFLD received saroglitazar magnesium 4 mg daily for 24 weeks. NAFLD was defined by a controlled attenuation parameter ≥264 dB/m. The primary endpoint was the reduction in liver fat as measured by MRI proton density fat fraction (MRI-PDFF). Secondary MRI-based metabolic endpoints included visceral adipose tissue, abdominal subcutaneous adipose tissue volumes, muscle fat infiltration, and fat-free muscle volume. Saroglitazar treatment led to a reduction in MRI-PDFF from 10.3±10.5% at baseline to 8.1±7.6%. A relative 30% reduction from baseline MRI-PDFF value was noted in 47% of all patients and 63% of patients with baseline MRI-PDFF >5%. Reduction in serum alkaline phosphatase was an independent predictor of MRI-PDFF response. Saroglitazar did not decrease fat-free muscle volume nor increase muscle fat infiltration, but did lead to a mild increase in visceral adipose tissue and abdominal subcutaneous adipose tissue. The study drug was well tolerated and a mild nonsignificant increase in serum creatinine was noted. Saroglitazar did not affect the weight. The study provides preliminary data demonstrating the safety and metabolic benefits of saroglitazar in LT recipients and underscores the importance of future studies to establish its efficacy after LT.

Saroglitazar is noninferior to fenofibrate in reducing triglyceride levels in hypertriglyceridemic patients in a randomized clinical trial.

Saroglitazar, being a dual PPAR-α/γ agonist, has shown beneficial effect in diabetic dyslipidemia and hypertriglyceridemia. Fibrates are commonly used to treat severe hypertriglyceridemia. However, the effect of saroglitazar in patients with moderate to severe hypertriglyceridemia was not evaluated. We conducted a study to compare the efficacy and safety of saroglitazar (4 mg) with fenofibrate (160 mg) in patients with moderate to severe hypertriglyceridemia. This was a multicenter, randomized, double-blinded, double-dummy, active-control, and noninferiority trial in adult patients with fasting triglyceride (TG) levels of 500-1,500 mg/dl. The patients were randomized in a 1:1 ratio to receive daily dose of saroglitazar or fenofibrate for 12 weeks. The primary efficacy end point was the percent change in TG levels at week 12 relative to baseline. The study comprised of 41 patients in the saroglitazar group and 41 patients in the fenofibrate group. We found that the percent reduction from baseline in TG levels at week 12 was significantly higher in the saroglitazar group (least square mean = -55.3%; SE = 4.9) compared with the fenofibrate group (least square mean = -41.1%; SE = 4.9; P = 0.048). Overall, 37 treatment-emergent adverse events (AEs) were reported in 24 patients (saroglitazar: 13; fenofibrate: 11). No serious AEs were reported, and no patient discontinued the study because of AEs. We conclude that saroglitazar (4 mg) is noninferior to fenofibrate (160 mg) in reducing TG levels after 12 weeks of treatment, was safe, and well tolerated.

Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis.

BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

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.).

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.

A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG).

BACKGROUND: Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. METHODS: This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. RESULTS: A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. CONCLUSIONS: This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). CLINICAL TRIALS REGISTRATION: CTRI/2017/07/009038.

A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of nonalcoholic fatty liver disease, is characterized by hepatocellular injury and inflammation.1 Patients with NASH are at higher risk of progression to cirrhosis and it is therefore targeted for drug development efforts.2 Lifestyle modifications and weight loss are the only recommended modalities and no drug is yet approved for the treatment of patients with NASH. Saroglitazar is a dual PPAR α/γ agonist, which has shown promise for treatment of nonalcoholic fatty liver disease.3 Because of its combined PPAR-α/γ agonism, it has a clinically favorable impact of glucose and lipid metabolism. Saroglitazar has shown to improve liver-related histology in patients with NASH and was recently approved for treatment of NASH in India.4 The current study builds on the published literature in this proof of concept study to determine if there is a signal for histologic improvement of NASH with saroglitazar in a Western population.

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study).

BACKGROUND: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. METHODS: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. RESULTS: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg and - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study. CONCLUSIONS: Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015.

New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence.

BACKGROUND: Saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) agonist, in clinical trials, has shown an improvement in lipid and glycemic parameters through the PPAR-α and γ agonist actions, respectively. It was granted marketing authorization in India in 2013 for diabetic dyslipidemia. This review was conducted to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted after marketing authorization in India. METHODS: In this review, we selected real world clinical studies of Saroglitazar published as manuscripts and abstracts presented at scientific conferences. In all these studies, patients with diabetic dyslipidemia were treated with Saroglitazar 4 mg once daily for at least 12 weeks and different lipid and glycemic parameters were measured at the baseline and end of the study. RESULTS: In 18 selected studies (5 published manuscripts and 13 abstracts), a total of 5824 patients with diabetic dyslipidemia were prescribed Saroglitazar 4 mg for a duration ranging from 12 to 58 weeks. Across all the studies, mean age of patients ranged from 49.6 to 59.1 years and the proportion of female patients ranged from 22% to 42%. Across all the studies, there was a consistent mean reduction in triglyceride levels (~ 45% to 62%), total cholesterol levels (~ 17% to 26%), non-high-density lipoprotein cholesterol levels (~ 21% to 36%), low-density lipoprotein cholesterol levels (~ 11% to 27%), and glycosylated hemoglobin levels (~ 0.7% to 1.6%) with an increase in mean high-density lipoprotein cholesterol levels (up to 9%) from baseline to end of the study. Saroglitazar also improved alanine aminotransferase levels and fatty liver (evaluated by FibroScan™) in non-alcoholic fatty liver disease patients with diabetic dyslipidemia. Body weight remained unchanged and no significant adverse events (AEs) were reported in the studies. CONCLUSION: Saroglitazar effectively improved lipid and glycemic parameters without significant AEs in patients with diabetic dyslipidemia in real-world clinical studies of up to 58 weeks duration.

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study.

BACKGROUND: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. METHODS: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. RESULTS: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. CONCLUSION: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).

The athero-contour: A novel tool for global and rapid assessment of atherogenic parameters. A use case in saroglitazar treatment of MAFLD patients.

BACKGROUND AND AIMS: Comprehensive assessment of pharmacotherapy effects on atherogenic parameters (AP) that influence the risk of cardiovascular disease (CVD) is challenging due to interactions among a large number of parameters that modulate CVD risk. METHODS: We developed an illustrative tool, athero-contour (AC), which incorporates weighted key lipid, lipo- and glycoprotein parameters, to readily illustrate their overall changes following pharmacotherapy. We demonstrate the applicability of AC to assess changes in AP in response to saroglitazar treatment in patients with metabolic associated fatty liver disease (MAFLD) in the EVIDENCES IV study. RESULTS: The baseline AC of saroglitazar and placebo groups was worse than the mean of the general population. After 16-week treatment, AC improved significantly in the saroglitazar group due to alterations in very low-density lipoprotein, triglyceride, and glycoproteins. CONCLUSION: Using AC, we could readily and globally evaluate and visualize changes in AP. AC improved in patients with MAFLD following saroglitazar therapy.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel kappa opioid receptor agonist ZYKR1: a randomized double-blind placebo-control phase 1 study in healthy adult human participants.

To perform first-in-human single-dose escalation trial of ZYKR1, which is a potent, selective, and peripherally-restricted kappa opioid receptor agonist, is the purpose of this study. This randomized, double-blind, placebo-controlled single ascending dose study conducted at Zydus Research Centre, Ahmedabad, India included healthy male participants aged 18-55 years and weighing > 50 kg. The primary objective was to evaluate the safety and tolerability of ZYKR1. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PD) of ZYKR1. Participants received ZYKR1 (0.5 - 6 mcg/kg) or placebo infused intravenously in 15 ± 1 min. Of total five dose groups (0.5 - 6 mcg/kg), each group included eight participants with six and two randomized to ZYKR1 and placebo, respectively. Three participants experienced six treatment-emergent adverse events (TEAEs); two were gastrointestinal disorders (nausea and vomiting at 2 mcg/kg); and four were related to the nervous system (headache (at 2 mcg/kg) and facial tingling, facial numbness and paresthesia (at 6 mcg/kg)); all TEAEs were mild and resolved without sequelae. The Cmax of ZYKR1 was achieved after 15 - 20 min of start of infusion. The mean exposures (Cmax and AUC0 - t) increased in a dose-proportional manner. The mean t1/2 ranged from 2.20 to 2.98 h across the dose range. Increase in the mean prolactin level was significantly higher in treatment groups compared with that in the placebo group. Intravenous ZYKR1 at doses up to 6 mcg/kg showed acceptable safety and tolerability and demonstrated a short half-life with principal route of excretion as renal. ZYKR1 displayed a potent PD effect reflected by increased prolactin levels, supporting further study in patients. Trial registration Clinical Trial Registry of India: CTRI/2018/07/014927. Date of registration: 18/07/2018.

Pharmacokinetics and Safety Evaluation of Single-Dose Saroglitazar Magnesium in Subjects with Hepatic Impairment.

Saroglitazar magnesium, a dual peroxisome proliferator-activated receptor agonist, is under evaluation for treating various liver conditions. While the pharmacokinetics (PK) of saroglitazar have been extensively studied in diverse preclinical models and healthy subjects, a comprehensive assessment of its PK behavior under conditions of hepatic impairment is lacking. In this Phase 1, open-label, parallel-group study, the PK of a single dose of 4-mg saroglitazar magnesium was investigated in subjects having varying degrees of hepatic impairment with and without portal hypertension compared with appropriately matched individuals having normal hepatic function. Treatment-emergent adverse events for safety were also evaluated. Thirty-two subjects were enrolled in the hepatic-impaired groups and 23 subjects in the normal hepatic function group. Mild and moderate hepatic impairment did not significantly affect the PK of saroglitazar, compared with normal hepatic function. Although severe hepatic impairment did not alter maximum observed plasma concentration and half-life; saroglitazar exposure (area under the plasma concentration-time curve from time 0 to infinity) increased 3-fold, while the clearance was 61% lower compared to the subjects with normal hepatic function. This may require close monitoring or dose adjustments in individuals with severe hepatic impairment. A single oral dose of saroglitazar magnesium 4 mg was found to be safe and well tolerated in subjects with varying degrees of hepatic function.

A Food-Effect Study to Evaluate the Oral Bioavailability of Desidustat.

This randomized, single-treatment, 2-sequence study evaluated the food effect on oral bioavailability of desidustat. Healthy adult male and female subjects were enrolled and randomly assigned to receive desidustat 50 mg orally in a fasting state in one period and a fed state in the other period. A standardized high-fat, high-calorie breakfast was served to assess the food effect. The pharmacokinetic results showed that the time to maximum blood concentration of desidustat was delayed significantly (P < .0001) in the fed state compared to the fasting state. The ingestion of food decreased the maximum blood concentration (Cmax ) compared to the fasting state (mean Cmax , 3248 ng/mL in the fed state vs 5496 ng/mL in the fasting state). The geometric mean ratio of fed/fasting for log-normal (ln) Cmax was 57. The exposure decreased in the fed state compared to the fasting state (mean area under the concentration-time curve [AUC] over the dosing interval, 25 559 ng â€¢ h/mL in the fed state versus 33 705 ng â€¢ h/mL in the fasting state; mean AUC from time 0 to infinity [AUC0-∞ ], 25,910 ng â€¢ h/mL in the fed state vs 34 233 ng â€¢ h/mL in the fasting state). The geometric mean ratio of fed/fasting for lnAUC from time 0 to the last quantifiable concentration and ln AUC0- ∞  was 77 and 76, respectively. The 90%CI of fed/fasting ratio of the geometric mean of lnCmax , AUC over the dosing interval, and AUC0-∞ of desidustat 50 mg did not fall within 80%-125% margin. Therefore, the absence of food effect could not be established. It can be inferred that food has a significant effect on the oral absorption of desidustat. Therefore, food must not be consumed 1 hour before and 2 hours after the oral administration of desidustat.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

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.

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.

BACKGROUND: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. METHODS: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). FINDINGS: 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 109. INTERPRETATION: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. FUNDING: Cadila Healthcare and Medicines for Malaria Venture.

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.