Interleukin-1 blockade with RPH-104 (goflikicept) in patients with ST-segment elevation myocardial infarction (STEMI): secondary endpoints from an international, double blind, randomized, placebo-controlled, phase IIa study.

In a randomized double-blinded clinical trial of patients with ST segment elevation myocardial infarction (STEMI), goflikicept, an Interleukin-1 (IL-1) blocker, significantly reduced systemic inflammation, measured as the area-under-the-curve (AUC) for high-sensitivity C reactive protein (hsCRP) at 14 days. We report secondary analyses of biomarkers at 28 days, and cardiac function and clinical endpoints at 1 year. Patients received a single administration of goflikicept 80 mg (n=34), goflikicept 160 mg (n=34), or placebo (n=34). Both doses of goflikicept significantly reduced the AUC for hsCRP at 28 days compared with placebo, without statistically significant differences between the doses. There we no statistically significant differences between groups in the AUC for natriuretic peptides at 28 days. There were no significant differences between placebo, goflikicept 80 mg and 160 mg groups in deaths (2.9%, 2.9% and 0%), hospitalization for cardiovascular reasons (9.1%, 5.9%, and 0%), new-onset or progression of heart failure (9.1%, 5.9%, and 5.9%), and new or increased use of loop diuretics (24.2%, 14.7%, and 17.6%), nor in the number of patients with treatment emergent adverse events, with no treatment-related serious adverse events in any group. In conclusion, in patients with STEMI, IL-1 blockade with goflikicept 80 mg or 160 mg was well tolerated and associated with significant reduction of systemic inflammation. Further adequately powered studies are warranted to determine whether the reduction in systemic inflammation with goflikicept translates into a clinical benefit in patients with STEMI.

5-HT6 Receptor Antagonist as an Adjunct Treatment Targeting Residual Symptoms in Patients With Schizophrenia: Unexpected Sex-Related Effects (Double-Blind Placebo-Controlled Trial).

BACKGROUND: Treating patients who experience residual psychotic symptoms during remission of schizophrenia remains one of the most challenging problems. The mechanisms underlying these symptoms differ from those of acute hallucinations and delusions. 5-HT6 receptor antagonists have been considered promising agents in treatment of residual psychotic symptoms and cognitive dysfunction. The aim of the study was to assess the efficacy of a selective 5-HT6 inhibitor Avisetron in the reduction of residual psychotic symptoms in patients with schizophrenia on stable antipsychotic therapy. METHODS: Eighty clinically stable outpatient subjects with schizophrenia with residual psychotic symptoms were randomized in a double-blind manner to 6 weeks of Avisetron or placebo at 1:1 ratio. Subjects received 8 mg of Avisetron or placebo on top their stable antipsychotic treatment. Standard clinical scales and cognitive tests were used for endpoint assessment. The primary efficacy endpoint was the mean reduction of total Positive and Negative Syndrome Scale score after 6 weeks of treatment. RESULTS: No significant differences in the primary and secondary endpoints were found between the groups. However, based on the subgroup analysis, the significant improvement of total Positive and Negative Syndrome Scale score and residual psychotic symptoms was observed in female patients. CONCLUSIONS: It was a negative study with unexpected benefits of the drug only in females. We hypothesized that the role of patients' sex can impact the treatment response to serotonergic drugs in general. We suggest a possible synergistic interaction between estrogen and Avisetron by means of modulating the effect of estrogens on the serotonergic system. Future studies targeting the sex-related effects of serotonergic drugs are warranted.

AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease.

Within the past decade several novel targets have been indicated as key players in Alzheimer-type dementia and associated conditions, including a "frightening" memory loss as well as severe cognitive impairments. These proteins are deeply implicated in crucial cell processes, e.g., autophagy, growth and progression, apoptosis, and metabolic equilibrium. Since recently, 5-HT6R has been considered as one of the most prominent biological targets in AD drug therapy. Therefore, we investigated the potential procognitive and neuroprotective effects of our novel selective 5-HT6R antagonist, AVN-211. During an extensive preclinical evaluation the lead compound demonstrated a relatively high therapeutic potential and improved selectivity toward 5-HT6R as compared to reference drug candidates. It was thoroughly examined in different in vivo behavioral models directly related to AD and showed evident improvements in cognition and learning. In many cases, the observed effect was considerably greater than that determined for the reported drugs and drug candidates, including memantine, SB-742457, and Lu AE58054, evaluated under the same conditions. In addition, AVN-211 showed a similar or better anxiolytic efficacy than fenobam, rufinamide, lorazepam, and buspirone in an elevated plus-maze model, elevated platform, and open field tests. The compound demonstrated low toxicity and no side effects in vivo, an appropriate pharmacokinetic profile, and stability. In conclusion, AVN-211 significantly delayed or partially halted the progressive decline in memory function associated with AD, which makes it an interesting drug candidate for the treatment of neurodegenerative and psychiatric disorders. Advanced clinical trials are currently under active discussion and in high priority.

Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study.

UNLABELLED: The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. OBJECTIVE: To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. METHODS: A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests. RESULTS: With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test. CONCLUSION: Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.

Treatment of Idiopathic Recurrent Pericarditis With Goflikicept: Phase II/III Study Results.

BACKGROUND: Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease. Interleukin (IL)-1α and IL-1ß are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence. We created a phase II/III study with a new IL-1 inhibitor-goflikicept in IRP. OBJECTIVES: This study sought to evaluate the efficacy and safety of goflikicept treatment in patients with IRP. METHODS: We conducted a 2-center open-label study of goflikicept in patients with IRP with and without recurrence at time of enrollment. The study consisted of 4 periods: screening, run-in (open-label treatment period), randomized withdrawal, and follow-up. Patients with clinical response to goflikicept in the run-in period were randomized (1:1) to a placebo-controlled withdrawal period, where the time to first pericarditis recurrence (primary endpoint) was evaluated. RESULTS: We enrolled 22 patients, and 20 of these patients were randomized. Reduction of C-reactive protein level accompanied by reduction of chest pain and pericardial effusion compared to baseline was demonstrated during the run-in period. Recurrence of pericarditis occurred in 9 of 10 patients in the placebo group, and there were no recurrence events in goflikicept group within 24 weeks after randomization (P < 0.001). A total of 122 adverse events were reported in 21 patients (95.5%), with no deaths and no new safety signals identified for goflikicept. CONCLUSIONS: Treatment with goflikicept prevented recurrences and maintained IRP remission with a favorable risk-benefit ratio. Goflikicept reduced the risk of recurrence compared with placebo. (Study to Evaluate the Efficacy and Safety of RPH-104 Treatment in Patients With Idiopathic Recurrent Pericarditis; NCT04692766).

Preclinical Characterization of a Novel Anti-Cancer PD-L1 Inhibitor RPH-120.

RPH-120 is a novel fully human anti-PD-L1 IgG1 monoclonal antibody with specifically designed Asn300Ala mutation in Fc fragment. Surface plasmon resonance assay showed that affinity of the RPH-120 to the dimeric form of human PD-L1-Fc fusion protein was much higher than affinity to the monomeric His-tagged PD-L1. Further binding studies demonstrated that RPH-120 is able to bind to human and monkey but not mouse PD-L1. Tissue cross-reactivity study showed good comparability of human and Cynomolgus monkeys tissue staining. Bioactivity was assessed using mixed lymphocyte reaction assay. This study revealed that RPH-120 was able to activate T cells preventing PD1/PD-L1 interaction. Antitumor efficacy was analyzed in HCC-827 lung cancer xenografts in humanized CD34+ mice at three dosage levels: 20, 80, and 200 mg/kg. RPH-120 demonstrated significant tumor growth inhibition, and this inhibition was comparable to that of atezolizumab. In a single dose toxicity, toxicokinetic and dose range finding study performed in Cynomolgus monkeys, RPH-120 was administered via intravenous (IV) bolus or 60-min IV infusion, followed by 8-weeks recovery period. An acceptable toxicokinetic profile was demonstrated and administration at doses of up to 200 mg/kg was well tolerated by all animals. In conclusion, RPH-120 revealed promising in vitro and in vivo activity and safety. RPH-120 is a potent anti-PD-L1 drug candidate for cancer immunotherapy.

Discovery and potency optimization of 2-amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer.

A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.

CXCR4 receptor as a promising target for oncolytic drugs.

There has been considerable in vivo evidence that chemokine receptor CXCR4 and its endogenous ligand CXCL12 modulate some important physiological and pathophysiological processes, including cancer metastasis, angiogenesis, invasion, growth and progression. In this review we elucidate key aspects of CXCL12-CXCR4 signaling system with emphasis on peptide-based and small-molecule CXCR4 inhibitors.

Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors.

Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3beta kinase are described. The inhibitory activity of the synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy substituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle. These compounds selectively inhibit GSK-3beta kinase with IC(50) value of 0.35 and 0.41 microM, respectively.

AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.

Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer.

A new chemical series of antiproliferative compounds was identified via high-throughput screening on DU-145 human prostate carcinoma cell line (hit compound potency - 5.7 microM). Exploration of the two peripheral diversity vectors of the hit molecule in a hit-targeted library and testing of the resulting compounds led to SAR generalizations and identification of the 'best' pharmacophoric moieties. The latter were merged in a single compound that exhibited a 200-fold better potency than the original hit compound. Specific cancer cell cytotoxicity was confirmed for the most potent compounds.