A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers.

AIMS: The pharmacokinetic (PK) similarity between MB02, a proposed bevacizumab biosimilar, and reference bevacizumab approved from the USA (US-bevacizumab) and European Union (EU-bevacizumab) was evaluated. Safety and immunogenicity were also assessed. METHODS: In this phase 1, randomized, double blind, single dose, parallel group study, 114 healthy male volunteers were randomized 1:1:1 to receive a 3 mg/kg intravenous dose of MB02, US-bevacizumab or EU-bevacizumab, and evaluated for 100 days. PK similarity between MB02 and reference bevacizumab was determined using the standard bioequivalence criteria (0.80-1.25) for the area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC(0-∞) ) and the maximum observed serum concentration (Cmax ). RESULTS: Baseline demographics were similar across treatment groups. All study drugs exhibited similar PK profile. The 90% confidence interval for the geometric lead square means ratios for the primary parameters AUC(0-∞) and Cmax for MB02, US-bevacizumab and EU-bevacizumab were fully contained within the pre-defined bioequivalence limits for the 3 pairwise comparisons: AUC(0-∞) (MB02:US-bevacizumab 0.998 [0.944 to 1.05]; MB02:EU-bevacizumab 1.07 [1.00 to 1.14]; and US-bevacizumab:EU-bevacizumab 0.934 [0.884 to 0.988]) and Cmax (MB02:US-bevacizumab 0.983 [0.897 to 1.08]; MB02:EU-bevacizumab 1.06 [0.976 to 1.16]; and; US-bevacizumab: EU-bevacizumab 0.926 [0.851 to 1.01]). Treatment emergent adverse events were reported in 87 subjects (76.3%), most being mild and with comparable incidence among treatment groups. Thirty-three subjects (28.9%) reported 56 possibly related treatment emergent adverse events with comparable incidence across treatments, the most frequent being headache (10.5%) and fatigue (3.5%). Anti-drug antibody incidence was low and similar between treatment groups. CONCLUSIONS: This study demonstrates the PK similarity and bioequivalence of MB02 to the reference bevacizumab, whether approved from USA or EU. The safety and immunogenicity profile of MB02 was shown also to be similar to the bevacizumab reference product (NCT04238663).

Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial.

Safe and effective new oral therapies for autoimmune, allergic, and inflammatory conditions remain a significant therapeutic need. Here, we investigate the human pharmacokinetics, pharmacodynamics (PDs), and safety of the selective, covalent Bruton's tyrosine kinase (BTK) inhibitor, remibrutinib. Study objectives were explored in randomized single and multiple ascending dose (SAD and MAD, respectively) cohorts with daily doses up to 600 mg, and a crossover food effect (FE) cohort, in adult healthy subjects without (SAD [n =80]/FE [n =12]) or with asymptomatic atopic diathesis (MAD [n =64]). A single oral dose of remibrutinib (0.5-600 mg) was rapidly absorbed (time to maximum concentration = 0.5 h-1.25 h) with an apparent blood clearance of 280-560 L/h and apparent volume of distribution of 400-15,000 L. With multiple doses (q.d. and b.i.d.), no pronounced accumulation of remibrutinib was detected (mean residence time was <3 h). Food intake showed no clinically relevant effect on remibrutinib exposure suggesting no need for dose adaptation. With remibrutinib doses greater than or equal to 30 mg, blood BTK occupancy was greater than 95% for at least 24 h (SAD). With MAD, remibrutinib reached near complete blood BTK occupancy at day 12 predose with greater than or equal to 10 mg q.d. Near complete basophil or skin prick test (SPT) inhibition at day 12 predose was achieved at greater than or equal to 50 mg q.d. for CD63 and at greater than or equal to 100 mg q.d. for SPT. Remibrutinib was well-tolerated at all doses without any dose-limiting toxicity. Remibrutinib showed encouraging blood and skin PDs with a favorable safety profile, supporting further development for diseases driven by mast cells, basophils, and B-cells, such as chronic spontaneous urticaria, allergic asthma, or Sjögren's syndrome.

Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection.

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug-drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions. Graphical Abstract.

A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects.

BACKGROUND AND OBJECTIVE: BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the ß1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (fGPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes. METHODS: This study was subdivided into three parts. Part A was a single-centre, randomised, double-blind, placebo-controlled safety and tolerability study including healthy young male autoantibody-negative Whites (N = 23) and Asians (N = 1), testing doses of 15, 50 and 150 mg BC 007 (Cohorts 1-3) and elderly male and female Whites (N = 8), testing a dose of 150 mg BC 007 (Cohort 4), randomly assigned in a 3:1 ratio to BC 007 or placebo. Open-label Part B included fGPCR-AAb-positive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included fGPCR-AAb-positive subjects for testing doses of 300, 450, 750, 1350 mg and 1900 mg BC 007. Lower doses were either given as an infusion or divided into a bolus plus infusion up to a dose of 300 mg followed by a constant bolus of 150 mg up to a dose of 750 mg, while at doses of 1350 mg and 1900 mg it was a slow infusion with a constant infusion rate. Infusion times increased with increasing dose from 20 min (15, 50 or 150 mg) to 40 min (300, 450 or 750 mg), 75 min (1350 mg) and 105 min (1900 mg). RESULTS: The mean observed BC 007 area under the concentration-time curve (AUC0-24) increased with increasing dose in a dose proportional manner (slope estimate of 1.039). No serious adverse events were observed. Drug-related adverse events were predominantly the expected mild-to-moderate increase in bleeding time (aPTT), beginning with a dose of 50 mg, which paralleled the infusion and returned to normal shortly after infusion. fGPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. CONCLUSION: BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised fGPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but fGPCR-AAb-positive subjects. CLINICALTRIALS. GOV REGISTRATION NUMBER: NCT02955420.

In-Vivo Degradation of DNA-Based Therapeutic BC 007 in Humans.

BACKGROUND AND OBJECTIVES: Since there is no clear evidence in the literature to show how non-modified single-stranded DNA (ssDNA) drugs are metabolized in humans, we assessed the metabolism of BC 007, an ssDNA therapeutic, under development as a neutralizer of autoantibodies against G-protein-coupled receptors. In-vitro, investigating its stability in monkey plasma and serum, a successive 3'-exonuclease degradation resulting in several n-x degradation products has been previously reported. Here, we investigated the metabolism of BC 007 in humans after intravenous application to autoantibody-positive healthy subjects, in line with Phase I safety testing. METHODS: 1H-NMR was applied for n-x degradation product search and beta-aminoisobutyric acid (bAIBA) measurement in urine; ultra-performance liquid chromatography-mass spectrometry was also used for the latter. Colorimetric assays were used for quantification of uric acid in serum and urine. RESULTS: Fast degradation prohibited the detection of the intermediate n-x degradation products in urine using 1H-NMR. Instead, NMR revealed a further downstream degradation product, bAIBA, which was also detected in serum shortly after initial application. The purine degradation product, uric acid, confirmed this finding of fast metabolism. CONCLUSION: Fast and full degradation of BC 007, shown by nucleic bases degradation products, is one of the first reports about the fate of a ssDNA product in humans.