Gedeon Richter (company)

Denosumab is a monoclonal antibody targeting the receptor activator of nuclear factor kappa-b ligand widely used for the prevention of skeletal-related events in patients with bone metastases. This Phase 1 randomized, double-blind, two-arm, parallel-group study assessed the equivalence in pharmacokinetics (PK) and compared the pharmacodynamics (PD), safety, and immunogenicity of the proposed biosimilar RGB-14-X and reference denosumab in healthy males. Participants were randomized 1:1 to a single subcutaneous 60 mg dose of RGB-14-X or reference denosumab, with 252 days of follow-up. Primary PK endpoints were maximum observed serum concentration (Cmax) and area under the concentration-time curve from time 0 to last quantifiable concentration (AUC0-last) and extrapolated to infinity (AUC0-inf). Secondary objectives were to compare additional PK parameters, safety and tolerability, PD and immunogenicity between groups. Of 165 participants randomized, 162 (98.2%) completed the study. The geometric mean ratios and corresponding 90% confidence intervals of RGB-14-X versus reference denosumab for Cmax, AUC0-last, and AUC0-inf were within the pre-specified range of 0.80-1.25, demonstrating equivalence. No notable differences were observed in secondary PK or PD parameters between groups; maximum reduction in concentration of the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and the extent and duration of reduction in CTX levels over time were similar. RGB-14-X was well tolerated with a similar safety profile to reference denosumab. No anti-drug or neutralizing antibodies were detected in either group. RGB-14-X demonstrated biosimilarity to reference denosumab, with equivalent PK and similar PD, safety, and immunogenicity outcomes in healthy males.

Introduction Symptoms of depression are prevalent across major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia, yet treatment strategies are traditionally indication specific. Cariprazine, a dopamine D3/D2 partial agonist approved for all three disorders in the U.S., provides an opportunity to evaluate the efficacy of a single compound on depressive symptoms across diagnostic categories. Objectives This meta-analysis aimed to pool clinical trial data to determine the efficacy of cariprazine versus placebo in alleviating depressive symptoms, regardless of primary diagnosis. Methods Only randomized controlled trials comparing cariprazine with placebo were included. Data were drawn from post-hoc and pooled analyses across different psychiatric indications and dose ranges. The primary outcome was change from baseline in depressive symptom scores, standardized across trials by converting effect sizes to Cohen’s d. Meta-analyses were performed in RStudio (version 2024.04.2+764) using the metafor package. A multilevel random-effects model accounted for overlapping placebo groups in trials with multiple dose arms, with comparisons grouped by study (random = ~1 | STUDY). Effect sizes are reported as pooled standardized mean differences (Cohen’s d) with 95% confidence intervals. Between-study heterogeneity was assessed using Q, I², and τ². Forest plots display individual and pooled estimates of cariprazine’s antidepressant effects. Results Four trials in bipolar depression (MD-52, MD-53, MD-54, MD-56; doses 1.5–3 mg/day) were included, alongside five adjunctive MDD trials (MD-71, MD-72, MD-75, 301, 302; doses 1–4.5 mg/day) and three schizophrenia studies (MD-04, MD-05, MD-16; pooled dose range 1.5–9 mg/day). Across all indications, the pooled least square mean difference in depressive symptoms for cariprazine versus placebo was –1.45 (95% CI: –2.18 to –0.71), indicating a significant overall benefit. The largest effects were observed in bipolar depression and MDD, with smaller but positive effects in schizophrenia, where depressive symptoms were assessed via the PANSS Depression/Anxiety Marder factor score rather than dedicated depression scales. Image 1: Image 1: Long description. Conclusions Cariprazine significantly improved depressive symptoms across bipolar disorder, MDD, and schizophrenia. These findings support its potential as a transdiagnostic treatment for depression across psychiatric disorders. Disclosure of Interest Z. Dombi Employee of: Gedeon Richter Plc, R. Csehi Employee of: Gedeon Richter Plc, Á. Barabássy Employee of: Gedeon Richter Plc.

A novel continuous‐flow synthesis for the antipsychotic aripiprazole has been developed via a two‐step, halogen‐free route. The first step features the underutilized N‐hydroxybutylation reaction employing in situ‐generated THF hydroperoxide under reductive conditions. The continuous‐flow setup ensures rapid and safe transformation through a telescoped sequence, incorporating on‐demand generation and immediate quenching of the remaining hazardous reagent without isolation. This strategy was also applicable to the synthesis of other pharmaceutically relevant intermediates. The first step was integrated with a continuous‐flow Mitsunobu reaction employing the Tsunoda reagent to give aripiprazole with high productivity. Overall, the developed process offers an environmentally benign alternative to conventional methods, achieving superior atom economy and reaction mass efficiency while eliminating the need for halogenated alkylating agents typically used in high excess.

Synthesized more than 60 years ago, vinpocetine-the active ingredient of Cavinton®, with over five decades of clinical use-has remained the subject of extensive investigation, particularly during the past 15 years. During this time, a large body of experimental preclinical evidence has accumulated demonstrating its neuroprotective potential and complex mechanisms of action in cerebral ischemia-hypoxia. Comprehensive in vitro studies and animal experiments have significantly elucidated the molecular basis of vinpocetine and the signaling pathways through which it prevents or mitigates ischemic injury. In this review, we summarize earlier and more recent experimental results that highlight the multifaceted nature of vinpocetine's neuroprotective actions, which include inhibition of phosphodiesterase type 1, blockade of voltage-dependent NaV1.8 channels, reduction of oxidative stress, and suppression of neuroinflammatory processes triggered by cerebral ischemia-hypoxia. Taken together, it can be hypothesized that, under in vivo conditions, vinpocetine's individual actions are additive or synergistic, thereby contributing in a combined manner to recovery from cerebral ischemic insult.

Aim. Тo evaluate the bioequivalence of Valsartan + Indapamide 160 mg + 1.5 mg modified release tablets developed by Gedeon Richter Polska Sp. z o. o. (Poland) compared to the reference products Diovan® (Siegfried Barbera S.L. (formerly Novartis Farmaceutica S.A.), Spain) coadministered with Arifon® Retard (Servier RUS LLC, Russia).Material and methods. Three randomised, single-centre, open-label, crossover studies with two sequences were conducted in a population of healthy adult volunteers of both sexes aged 18–45 years who met the inclusion criteria and had no exclusion criteria. Study A included four periods assessing single-dose administration under fasting conditions (n=56), Study B included two periods assessing single-dose administration under fed conditions (n=52), and Study C included two periods assessing multiple-dose administration under fasting conditions (n=52). The washout period was at least 14 days between all periods. Plasma concentrations were determined using validated analytical methods of high-performance liquid chromatography and tandem mass spectrometry. However, as valsartan was not modified release its exposure was not measured in all studies. Pharmacokinetic parameters including AUC0-inf, Cmax and AUC0-t in study A and B, and AUC0-τ, Cmax,ss and Cτ,ss in study C were determined using non-compartmental analysis. Bioequivalence was concluded if the 90% confidence intervals for the test/reference ratios of given parameters fell within the 80.00-125.00% range, except for Study A valsartan Cmax parameter, where the range was widened to 78.05-128.13%.Results. In Study A, the GMRs for AUC0-t and Cmax were 105.97% and 108.15% for indapamide and 104.07% and 104.15% for valsartan, respectively.In Study B, GMRs for the specified parameters for indapamide were 101.03% and 96.47%. In Study C, the GMR values for AUC0-τ and Cmax,ss were 109.69% and 111.75% for indapamide. All 90% confidence intervals were within the predefined bioequivalence limits. The drug was well tolerated. Only mild and well-known treatment-emergent adverse events were reported, without any treatment discontinuation. Conclusions. The fixed dose combination of valsartan and indapamide 160 mg + 1.5 mg, modified released tablets manufactured by Gedeon Richter Polska Sp. z o. o. is bioequivalent to Diovan® co-administered with Arifon® Retard, and is safe and well tolerated. The results support the use of this fixed dose combination as an effective alternative to the concurrent administration of the reference products for the treatment of hypertension