Publications

Oral small molecule inhibitors of tumor necrosis factor alpha (TNFα) are emerging as attractive therapeutic agents for the treatment of various autoimmune diseases. Balinatunfib (SAR441566), a novel oral inhibitor of tumor necrosis factor receptor 1 (TNFR1) signaling, changes the configuration of the soluble TNFα (sTNFα) trimer and prevents its heterotrimerization with TNFR1 but not TNFR2, thereby blocking TNFR1 signaling. Herein, we report the results from a first-in-human (FIH) study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) following single ascending doses (SAD) and multiple ascending doses (MAD) of balinatunfib in healthy male participants. Single (5–600 mg) and multiple (100–600 mg total daily dose for up to 14 days) oral doses of balinatunfib were well-tolerated in all participants. Consistent PK data were obtained across the studies, with a median tmax of 2.5–5 hours, a mean terminal half-life of 22–30 hours, and a time to steady state of 5–6 days. A supra-proportional exposure increase was observed in both SAD and MAD studies, which was less pronounced at doses ≥ 180 mg. Food had no relevant effects on the PK characteristics of balinatunfib. As the main PD read-out, complete TNFα occupancy was shown at all tested time points after the treatment started. Balinatunfib, as the first clinically tested oral TNFR1 signal inhibitor, demonstrated a good safety profile along with favorable PK/PD characteristics that allowed both once and twice daily dosing, confirming a successful preclinical-to-clinical translation and guiding dose selection for further clinical efficacy studies.

Aim

Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705).

Methods

The study consisted of three parts: Part A was a double-blind placebo-controlled single ascending dose trial in three dose groups (200, 600, and 1600 mg) with four participants receiving either the investigational niclosamide formulation or placebo (3:1) under fasted and/or fed conditions. Part B was a crossover study comparing 1600 mg investigational niclosamide solution with the marketed 2000 mg chewing tablet in four healthy volunteers. Part C was a double-blind placebo-controlled multiple-dose trial comparing 1200 mg and 1600 mg (verum: placebo 4:2) in two dose groups with six subjects each, who received daily doses for seven days.

Results

No serious or severe adverse events occurred. The most frequent adverse events were mild to moderate gastrointestinal reactions. There was also no apparent dependence between drug exposure levels (AUC, Cmax) and the severity and incidence of adverse events detectable. A relevant food effect was observed with a mean AUClast about 2-fold higher in fed condition compared to fasted condition. In Part B, dose-normalized Cmax and AUClast were similar for niclosamide solution and tablet. Absorption of niclosamide solution was highly variable. Some individuals showed high absorption (Cmax > 2µg/ml) whereas others did absorb only marginally. Importantly, there was no dose linearity in the range of 200 mg – 1600 mg. No signs of relevant systemic drug accumulation after multiple administrations were observed.

Conclusion

Overall safety and tolerability observed in healthy subjects were benign. This is also true for individuals with high absorption (Cmax > 2µg/ml), encouraging further research into niclosamide as a potential therapeutic agent. Galenic optimization, however, will remain challenging as evident from the observed exposure variability and non-linear PK. Non-linearity, if confirmed by additional data, might make niclosamide more suitable for multi-dose rather than high single dose regimens. The observed food effect should also be considered when further investigating systemic niclosamide exposures.

Background and Objective

MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.

Methods

This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.

Results

MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3–1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25–400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).

Conclusion

The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.

Introduction 

MK-5172 is a novel, HCV NS3/4A protease inhibitor with potent activity against multiple genotypes (GT) in development for the treatment of chronic HCV infection. In a combined single and multiple ascending-dose study in healthy subjects, MK-5172 was shown to be well-tolerated and exhibited a pharmacokinetic (PK) profile supportive of once-daily (QD) dosing. The pharmacokinetics and pharmacodynamics (i.e., anti-viral efficacy) following QD administration of MK-5172 monotherapy to patients with chronic GT1 or GT3 HCV infection were assessed in a placebo-controlled study.

Methods

HCV-infected patients were enrolled in an 11-panel study (6 GT1 panels, 5 GT3 panels). In each panel, male patients were administered oral QD doses of MK-5172 or matching placebo for 7 days. Blood samples for MK-5172 concentration determination were collected on Days 1-12. Pharmacodynamic (PD) samples were collected on Days 1-15 and at select times up to 2 months. An Emax model was used to characterize the PK/PD relationship in HCV GT3 patients.

Results 

QD administration of MK-5172 to GT1 and GT3 patients resulted in a median Tmax of 2-4 hours and biphasic elimination with a mean terminal half-life of ~22-33 hours. Steady-state was achieved within 7 days of dosing. Mean steady-state AUC0-24hr and Cmax in GT1 and GT3 patients increased in a greater than dose proportional manner, which is consistent with single- and multiple-dose pharmacokinetics in healthy subjects. PK exposure is comparable between GT1 and GT3 patients for 100-600 mg QD doses, with a GT1/GT3 geometric mean ratio (GMR) of ~0.4-1.8 for AUC0-24hr and Cmax. HCV patients have moderately increased exposures compared to healthy subjects, with a steady-state GT1/healthy GMR of ~1.2-2.1 for AUC(0-24hr) and Cmax. The Emax model used to characterize the PK/PD relationship for patients suggests that steady-state AUC(0-24hr) of ~5 uM*hr and C24hr of ~30 nM would result in a 3-log reduction in viral load in GT3 patients. The PK/PD relationship for GT1 patients is not yet established since there is a limited dose-response in GT1 patients (a mean viral load reduction of ~4-5 log for all doses studied).

Conclusions

MK-5172 plasma PK is comparable between GT1 and GT3 patients and exhibits a PK profile supportive of once daily dosing in HCV patients. The extent and rate of absorption are moderately increased in patients compared to healthy subjects, which may be attributed to hepatic dysfunction in patients or differences in transporter-mediated disposition. The PK/PD relationship is well-characterized by an Emax model, which estimates the plasma PK required to achieve the target efficacy in HCV patients.

Rationale

This phase I study assessed the absolute bioavailability and tolerability of subcutaneous (SC) versus intravenous (IV) administration of Icatibant in healthy volunteers.

Methods

A total of 24 healthy males aged 18-50 years entered this single-centre study. Subjects received 0.4 mg/kg Icatibant IV (as a 1 mg/ml solution, for 30 min) or SC (as a 10 or 20 mg/ml solution) in an open-label crossover design.

Results

At a dose of 0.4 mg/kg, the mean absolute bioavailability (AUC0-N) for SC Icatibant was 96.1% (95% confidence interval [CI]: 86.7, 106.4) for the 10 mg/ml formulation, and 83.4% (95% CI: 70.9, 98.2) for 20 mg/ml. AUC0-inf values were comparable for SC (3114 and 2615 h*ng/ml, for 10 and 20 mg/ml, respectively) and IV (3208 h*ng/ ml) Icatibant. Mean Cmax values were 1429 ng/mL for the 10 mg/mL SC injection, 1149 ng/mL for the 20 mg/mL SC injection, and 2971 ng/mL for the IV infusion. Regardless of administration route or Icatibant concentration, Cmax was reached by approximately 0.5 h. Elimination half life (1.2-1.5 h) was similar for SC and IV administration. All adverse events were mild, and local site reactions usually resolved spontaneously within 1 h. There were no serious adverse events. Laboratory parameters, vital signs and ECG did not show relevant changes during the study.

Conclusions

Bioavailability of Icatibant is similar for SC and IV administration routes. Icatibant was safe and well tolerated at the dose of 0.4 mg/kg.