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This phase 3, randomized trial in China compared the efficacy and safety of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with placebo for anemia in patients with CKD who were not undergoing dialysis. Roxadustat was superior to placebo in increasing and maintaining hemoglobin levels.

This randomized, phase 3 trial compared the effectiveness of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with epoetin alfa in patients undergoing hemodialysis or peritoneal dialysis in China. Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia.

Background Tenapanor, a small molecule with minimal systemic availability, is a first-in-class sodium/hydrogen exchanger 3 (NHE3) inhibitor that acts in the gut. Here, we evaluate the pharmacodynamics and safety of tenapanor in healthy adults. Methods Two phase I, single-center, randomized, double-blind, placebo-controlled studies were performed. The first study assessed single-ascending oral tenapanor doses of 10, 50, 150, 450, and 900 mg ( n  = 8 per group; six tenapanor, two placebo) and multiple ascending doses over 7 days of 3, 10, 30, and 100 mg q.d. ( n  = 10 per group; eight tenapanor, two placebo). In the second study, different tenapanor regimens were evaluated over 7 days ( n  = 15 per group; 12 tenapanor, three placebo): 15 mg twice daily (b.i.d.), 30 mg once daily (q.d.), 30 mg b.i.d., 30 mg three times daily (t.i.d.), 60 mg b.i.d., escalating b.i.d. dose (daily total 30–90 mg), 30 mg b.i.d. with psyllium. Results Tenapanor produced generally dose-dependent increases in stool sodium excretion and decreases in urinary sodium excretion versus placebo; in addition, twice-daily dosing appeared to have a greater effect on sodium absorption than once-daily dosing with an equivalent daily dose. Tenapanor softened stool consistency and increased stool frequency and weight from baseline versus placebo. Tenapanor concentrations were below the quantification limit (0.5 ng/ml) in 98.5% of 895 plasma samples. Adverse events were mild or moderate in severity, and were typically gastrointestinal in nature. There were no clinically relevant changes in serum electrolytes. Conclusions Tenapanor was well tolerated and resulted in reduced intestinal sodium absorption and softer stool consistency versus placebo. Systemic exposure to tenapanor was minimal. These results support potential use of tenapanor in patients who could benefit from modification of gastrointestinal sodium balance. ClinicalTrials.gov identifiers NCT02819687, NCT02796131.

Tenapanor is a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. This study assessed the efficacy and safety of tenapanor in patients with constipation-predominant irritable bowel syndrome (IBS-C). In this phase 2, double-blind study, patients with IBS-C (Rome III criteria) were randomized (1:1:1:1) to receive tenapanor 5 mg, 20 mg, or 50 mg b.i.d., or placebo b.i.d. for 12 weeks. The primary end point was the complete spontaneous bowel movement (CSBM) responder rate, defined as the proportion of patients reporting an increase from baseline of ≥1 CSBM/week for ≥6/12 treatment weeks. Secondary end points included abdominal symptom responder rates (≥30% score improvement from baseline for ≥6/12 weeks) and a composite responder rate (CSBM and abdominal pain response in the same week for ≥6/12 weeks). Overall, 356 patients were randomized (mean age: 45.7 years; 86.8% women) and 304 completed the study. The CSBM responder rate was significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (60.7 vs. 33.7%; P<0.001), as was the composite responder rate (50.0 vs. 23.6%; P<0.001). Responder rates for abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) were significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (all P<0.05). Diarrhea was the most frequent adverse event (tenapanor b.i.d.: 20 mg, 12.4%; 50 mg, 11.2%). Tenapanor 50 mg b.i.d. significantly increased stool frequency and reduced abdominal symptoms in patients with IBS-C. Further research into tenapanor as a potential treatment for these patients is justified.

This review includes recent developments in the synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines with particular attention given to categorizing protocols based on the structural features of the ring architecture and crystallographically characterized reaction products.

Relacorilant, a first-in-class selective glucocorticoid receptor antagonist, increases a tumour's sensitivity to chemotherapy by reducing cortisol signalling. This study aimed to show whether the addition of relacorilant to nab-paclitaxel improves progression-free and overall survival in females with platinum-resistant ovarian cancer. This randomised, controlled, open-label phase 3 trial (ROSELLA [GOG-3073/ENGOT-ov72]) was done at 117 hospitals and community oncology treatment centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Patients had to be aged 18 years or older and had to have a confirmed diagnosis of platinum-resistant, epithelial (ie, high-grade serous, endometrioid, or carcinosarcoma with a ≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer; up to three previous lines of anticancer therapy and previous bevacizumab and disease progression or intolerance to the most recent therapy; measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1); an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate organ function. Patients were assigned (1:1) to relacorilant (150 mg orally the day before, of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). The dual primary endpoints were progression-free survival assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours (version 1.1) and overall survival, and were assessed in all randomly assigned patients by intention to treat. The safety population included all randomly assigned patients who received at least one dose of the assigned treatment. This trial was registered at ClinicalTrials.gov, NCT05257408, and is ongoing. Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the combination group (n=188) or to the nab-paclitaxel monotherapy group (n=193). Patients receiving relacorilant plus nab-paclitaxel had a statistically significant improvement in progression-free survival assessed by blinded independent central review compared with those receiving nab-paclitaxel monotherapy (hazard ratio 0·70 [95% CI 0·54–0·91]; median 6·54 months [95% CI 5·55–7·43] vs 5·52 months [3·94–5·88]; stratified log-rank p=0·0076). At the planned interim analysis, there was a clinically meaningful difference in overall survival with the addition of relacorilant to nab-paclitaxel (0·69 [95% CI 0·52–0·92]; 15·97 months [95% CI 13·47–not reached] vs 11·50 months [10·02–13·57]; log-rank p=0·0121). Adverse events were similar across study groups when adjusted for nab-paclitaxel exposure; no new safety signals were observed. The addition of relacorilant to nab-paclitaxel prolonged progression-free survival and interim results also showed an improvement in overall survival. Together, the results position the combination of relacorilant and nab-paclitaxel as a potential new standard treatment for patients with platinum-resistant ovarian cancer. Corcept Therapeutics.

An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85–94) patients in the treatment-naive cohort, 168 (82%, 77–87) in the non-responder cohort, and 192 (82%, 77–87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. Bristol-Myers Squibb.

Tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of single ascending doses (SADs) and multiple ascending doses (MADs) of PF-06260414, a novel selective androgen receptor modulator, were assessed after oral administration in healthy subjects. Range of SAD and MAD levels tested were 1 to 400 mg and 3 to 100 mg BID, respectively (n = 8 per cohort). In addition, a 60-mg once-daily (n = 8) cohort and a Japanese cohort receiving 30 mg BID (n = 7) also received PF-06260414. Plasma was collected to study PK properties and hypothalamic-pituitary-gonadal (HPG) axis hormones. Tolerability was evaluated from adverse events (AEs), physical examinations, vital signs, ECGs, and clinical laboratory results. PF-06260414 was well tolerated with no serious AEs. The most frequently reported AEs were increase in alanine aminotransferase and headache, which were reported by 7 and 3 subjects, respectively. PF-06260414 had fast absorption (median Tmax, approximately 1–2 hours), a mean t½ of approximately 6.9 to 12.8 hours, time-independent PK properties and dose proportionality. Cmax and AUCτ geometric means in Japanese subjects were 98.6% and 79.5% higher than in Western subjects, respectively, but had similar HPG axis modulation. Changes in HPG axis hormones monitored in SADs were similar to placebo. Maximum placebo-corrected modulations were observed for total testosterone and sex hormone–binding globulin in the MAD 100-mg BID regimen. This study was the first to compare a number of different factors of PF-06260414, including tolerability, PK and PD properties, and ethnic differences between Japanese and Western healthy subjects. PF-06260414 had favorable PK properties and found that sex hormone–binding globulin, total testosterone, and HDL were most sensitive to modulation. ClinicalTrials.gov identifier: NCT02070939.

Roxadustat (Ai Rui Zhuo ® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.

Purpose BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton’s tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. Methods In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5–900 mg) or multiple doses (25–350 mg, once daily for 14 days). In a drug–drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. Results BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. Conclusions BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.