The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

Pharmacokinetics and tolerability of prefilled syringe and auto-injector presentations of MSB11456: results of a randomized, single-dose study in healthy adults.

BACKGROUND: Tocilizumab is a monoclonal immunoglobulin G interleukin-6 receptor antagonist. MSB11456 is a proposed tocilizumab biosimilar. OBJECTIVE: To determine the pharmacokinetic equivalence of a single subcutaneous injection of MSB11456, when delivered via autoinjector (AI) and prefilled syringe (PFS), in healthy adult subjects. RESEARCH DESIGN AND METHODS: In this randomized, open-label, single fixed-dose, crossover study, 91 subjects received subcutaneous administration of tocilizumab 162 mg via AI and PFS presentations. The primary endpoint pharmacokinetic parameters were analyzed using analysis of variance. Safety data were summarized descriptively. RESULTS: There were no differences in pharmacokinetic parameters between presentations, and safety parameters were comparable. The 90% confidence intervals for the geometric least squares mean ratios of all primary pharmacokinetic parameters were contained within the predefined 80.00% to 125.00% bioequivalence limits, indicating pharmacokinetic equivalence between the AI and PFS. CONCLUSIONS: MSB11456 administration via AI was bioequivalent to administration via PFS. MSB11456 can be administered by AI or PFS, increasing the available range of self-injection devices. TRIAL REGISTRATION: The trial is registered at EudraCT, number 2020-003419-86.

Tocilizumab is a biologic drug that is used to treat autoimmune diseases, including rheumatoid arthritis. MSB11456 has been shown to be equivalent to the US-licensed and EU-approved tocilizumab when administered by subcutaneous injection. There are different devices available to administer subcutaneous injections, and depending on the device, the patient's experience can be enhanced, convenience and compliance increased, and cost-effectiveness ensured for patients taking this medicine. This randomized, single fixed-dose, crossover study tested the pharmacokinetic similarity of MSB11456 when given subcutaneously via an auto-injector device versus a pre-filled syringe device in 100 healthy subjects. A total of 91 healthy volunteers received MSB11456 via both auto-injector and pre-filled syringe using a crossover design. Blood was collected before the first dose and at regular intervals during the study to determine the pharmacokinetics of tocilizumab and ensure safety. This study found that the pharmacokinetics of tocilizumab following administration using the autoinjector and the prefilled syringe were equivalent, and the safety profiles were similar. These findings indicate that the auto-injector can be considered another option that can be used to subcutaneously inject MSB11456.

Pharmacokinetics of a proposed tocilizumab biosimilar (MSB11456) versus US-licensed tocilizumab: results of a randomized, double-blind, single-intravenous dose study in healthy adults.

BACKGROUND: Tocilizumab, a recombinant monoclonal immunoglobulin G, targets the interleukin-6 receptor. MSB11456 is a proposed tocilizumab biosimilar. OBJECTIVES: To assess pharmacokinetic equivalence of intravenous MSB11456 to US-licensed tocilizumab. RESEARCH DESIGN AND METHODS: In this double-blind, parallel-group, single-dose study, 128 healthy adults were randomized to a single one-hour 8 mg/kg IV infusion of either MSB11456 or US-licensed tocilizumab. Blood samples were collected pre-dose and at regular intervals up to day 48 post-dose. The primary endpoint pharmacokinetic parameter was analyzed using analysis of variance (ANOVA) model on the natural logarithm of the endpoint (AUC0-last), with treatment as a fixed effect. Immunogenicity and safety data were summarized descriptively. RESULTS: Subjects received either MSB11456 (N = 62) or US-licensed tocilizumab (N = 66). Pharmacokinetic bioequivalence, defined as 90% confidence intervals for the geometric least squares mean ratio entirely contained within the 80.00% to 125.00% equivalence limits, was demonstrated between MSB11456 and US-licensed tocilizumab for the primary and secondary pharmacokinetic endpoints. Anti-drug antibody responses, frequency of neutralizing antibodies against tocilizumab, and safety profiles showed no notable between-treatment differences. Safety was comparable between treatments. CONCLUSIONS: Pharmacokinetic similarity of MSB11456 and US-licensed tocilizumab was demonstrated, with comparable immunogenicity and safety profiles, supporting MSB11455 as a biosimilar to US-licensed tocilizumab. The trial is registered at EudraCT, number 2019-003484-22.

Tocilizumab is a biologic drug that is prescribed for autoimmune conditions such as rheumatoid arthritis in adults and arthritis in children where the cause is unknown. Because of the high cost of biologic drugs, alternate similar drugs are being designed and tested to ensure that they are as effective and as safe as drugs that are currently available. These new drugs are called biosimilars. MSB11456 is a proposed tocilizumab biosimilar. Our study tested how the pharmacokinetics, immunogenicity, and safety of intravenously administered MSB11456 compared to that of the already approved tocilizumab drug marketed in the US (US-licensed tocilizumab). One hundred and twenty-eight healthy adult volunteers received a one-hour 8 mg/kg intravenous infusion of either MSB11456 or US-licensed tocilizumab in this randomized, double-blind, parallel-group, single-dose study. Blood samples were taken before and at scheduled times during the study, up to 48 days after the first dose for analysis. In this study, we showed that the pharmacokinetics of MSB11456 were equivalent to the US-licensed tocilizumab. The safety and immune response to the drugs were also similar. These findings indicate that MSB11456 can be considered a biosimilar to tocilizumab. Biosimilars can reduce the cost of drugs by increasing competition and improve access to these, generally expensive, treatment options.

Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment.

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child-Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (Cmax) reached at 4.0 h. There was no difference in Cmax, indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86-1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7-99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required.Clinical Trial Registration ClinicalTrials.gov NCT04252495.

Preclinical assessment and randomized Phase I study of CT-P63, a broadly neutralizing antibody targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. Despite a successful vaccination programme, the emergence of mutated variants that can escape current levels of immunity mean infections continue. Herein, we report the development of CT-P63, a broad-spectrum neutralizing monoclonal antibody. In vitro studies demonstrated potent neutralizing activity against the most prevalent variants, including Delta and the BA.1 and BA.2 sub-lineages of Omicron. In a transgenic mouse model, prophylactic CT-P63 significantly reduced wild-type viral titres in the respiratory tract and CT-P63 treatment proved efficacious against infection with Beta, Delta, and Omicron variants of SARS-CoV-2 with no detectable infectious virus in the lungs of treated animals. A randomized, double-blind, parallel-group, placebo-controlled, Phase I, single ascending dose study in healthy volunteers (NCT05017168) confirmed the safety, tolerability, and pharmacokinetics of CT-P63. Twenty-four participants were randomized and received the planned dose of CT-P63 or placebo. The safety and tolerability of CT-P63 were evaluated as primary objectives. Eight participants (33.3%) experienced a treatment-emergent adverse event (TEAE), including one grade ≥3 (blood creatine phosphokinase increased). There were no deaths, treatment-emergent serious adverse events, TEAEs of special interest, or TEAEs leading to study drug discontinuation in the CT-P63 groups. Serum CT-P63 concentrations rapidly peaked before declining in a biphasic manner and systemic exposure was dose proportional. Overall, CT-P63 was clinically safe and showed broad-spectrum neutralizing activity against SARS-CoV-2 variants in vitro and in vivo.

A phase 1, open-label, drug-drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors.

PURPOSE: This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. METHODS: Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. RESULTS: Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug-drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration-time curve from time zero to last quantifiable measurement (AUC0-last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. CONCLUSION: Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment.

PURPOSE: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. METHODS: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. RESULTS: Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration-time curve from time 0 to infinity (AUC0-inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668-3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. CONCLUSION: Patients with moderate hepatic impairment showed mildly increased AUC0-inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

Evaluation of the Safety, Acceptability, and Pharmacokinetic Profile of a Gel Formulation of OB-002 in Healthy Volunteers.

OB-002 is an extremely potent CCR5 antagonist that has previously been shown to completely block transmission in a nonhuman primate model of HIV infection. The purpose of this study was to characterize the safety, acceptability, and pharmacokinetic profile of a gel formulation of OB-002 (OB-002H). The trial had two phases, an open label single dose exposure (vaginal and rectal) and a randomized placebo controlled multiple dose phase during which study participants received five vaginal daily doses of OB-002H gel or matched placebo in a 2:1 ratio. Serum OB-002 levels were quantified at multiple time points up to 24 h after the first dose. A total of thirty female and male participants were enrolled in the study (12 in the single dose phase and 18 in the multiple dose phase). All adverse events were Grade 1 or 2, and the majority was unrelated to study product. Only two product-related transient Grade 2 events (both vulval dryness) occurred in the study, both in the OB-002H gel randomized multiple dose arm. All colposcopic and anoscopic assessments following product exposure were normal. There was no evidence of systemic absorption of OB-002. Overall, the product had a positive acceptability profile, and most study participants would consider using the product for protection against HIV or pregnancy. Future studies are needed to assess the extended safety and acceptability of OB-002H gel in sexually active participants. Clinical Trial Registration Number: NCT04791007.

Evaluation of Drug-Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp Substrates in Patients With an Advanced Solid Tumor.

This phase I study (CO-338-044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P-glycoprotein (P-gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i.d. Geometric mean (GM) ratios (90% confidence interval (CI)) of area under the concentration-time curve (AUC) from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93-2.65); S-warfarin, 1.49 (1.40-1.58); omeprazole, 1.55 (1.32-1.83); midazolam, 1.39 (1.14-1.68); and digoxin, 1.20 (1.12-1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99-1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure.

Association of the CHADS2 and CHA 2DS 2-VASc scores with left atrial enlargement: a prospective cohort study of unselected atrial fibrillation patients.

Assessment of thromboembolic risk is crucial for proper management of atrial fibrillation (AF) patients. Currently used risk score base only on scarce clinical data and do not take into consideration parameters including echocardiographic findings. The aim of this study was to evaluate if left atrium (LA) enlargement is associated with higher thromboembolic risk assessed by CHADS2 and CHA2DS2-VASc scores in a cohort of unselected non-valvular AF patients. Data from 582 AF hospitalizations occurring between November 2012 and January 2014 were analyzed. All patients underwent a standard transthoracic echocardiography and had their thromboembolic risk assessed in both CHADS2 and CHA2DS2-VASc scores. In 494 enrolled patients (48.5 % male; mean age 73.4 ± 11.5 years) AF was classified as paroxysmal in 233 (47.3 %), as persistent in 109 (22.1 %), and as permanent in 151 (30.6 %) patients. LA was enlarged in 426 (86.2 %) patients. Enlargement was classified as mild in 99 (20.0 %) patients, as moderate in 130 (26.3 %) patients, and as severe in 196 (39.7 %) patients. Patients with enlarged LA had higher mean CHADS2 score (2.0 ± 1.5 vs. 2.6 ± 1.3; p = 0.0005) and CHA2DS2-VASc (3.8 ± 2.0 vs. 4.4 ± 1.8; p = 0.02) score than patients with normal LA. The both mean scores rose along with rising LA diameter. LA enlargement is highly prevalent in AF patients. Higher thromboembolic risk assessed by both CHADS2 and CHA2DS2-VASc scores is associated with presence of LA enlargement. Echocardiographically assessed LA size may be an additional parameter useful in thromboembolic risk stratification of AF patients.

[The use of AF SUPRESSION pacing algorithm in supression of paroxysmal atrial fibrillation in patients with bradycardia--one center experience]. / Zastosowanie stymulacji z algorytmem AF SUPRESSION w zwalczaniu napadów migotania przedsionków u chorych z bradykardia--doswiadczenia wstepne.

Heart pacing with algorithms preventing episodes of paroxysmal atrial fibrillation (PAF) is one of the modern methods of PAF treatment. The usefulness of AF suppression TM pacing algorithm in Integrity AFx DR pacing was evaluated. The study group consisted of 7 patients with paroxysmal AF (for average 2,5 year; requiring on average 6 cardioversions in ICCU per year) and standard pacemaker indications. The small number of enrolled patients resulted from high cost of the pacemaker. In our study we turned on AF suppression TM pacing algorithm 3 months after pacemaker implantation and evaluated the number of PAF episodes at 3 and 6 months. Pharmacotherapy was not changed. Antiarrhythmic stimulation resulted in reduction of the number of PAF (on average by 11) at 3 months and was well-tolerated by the patients. AF Suppression(tm) pacing algorithm is effective only if PAF is preceded by supraventricular extrasystole.

[Treatment of metabolic syndrome: drugs often but diet always - a case report]. / Leki czesto - dieta zawsze. Mlody mezczyzna z zespolem metabolicznym.

A case of a 32-year-old male with obesity and hypertension who was admitted to hospital with suspected acute myocardial infarction (MI) is presented. An initial diagnosis of MI was ruled-out, however, diabetes and marked hypertriglyceridemia were detected. Introduction of diet and proper diabetes control with insulin caused a marked decrease in triglyceride and cholesterol levels. After discharge the patient did not comply to dietary recommendations and stopped fibrates due to gastro-intestinal side effects which resulted in a marked elevation in lipid levels. Finally, statin therapy and better compliance to dietary recommendations resulted in the normalisation of cholesterol level, a marked decrease in triglyceride concentration and a loss of 5 kg of body weight. The need for combined treatment consisting of pharmacologic agents and life-style changes is stressed.