ObjectivesThere is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants.MethodsCRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL).ResultsSixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).ConclusionsThere was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary.Trial registration numberNCT02019602; Results.

AimsTo assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)‐17A and IL‐17F, in subjects with mild plaque psoriasis.MethodsRandomized, double‐blind, first‐in‐human study of bimekizumab in 39 subjects who received single‐dose intravenous bimekizumab (8–640 mg) or placebo (NCT02529956).ResultsBimekizumab demonstrated dose‐proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment‐emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically‐meaningful effects on skin of patients with mild psoriasis as early as Week 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8–12 in subjects receiving 160–640 mg bimekizumab. The duration of effect at doses ≥160 mg was evident up to Weeks 12–20 after a single intravenous dose, dependent on endpoint.ConclusionsThis is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL‐17A and IL‐17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically‐meaningful efficacy by Week 2, with a maximal or near‐maximal magnitude of response that was maintained up to study Weeks 12–20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL‐17A and IL‐17F, including psoriasis.

GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first‐in‐human randomized, double‐blind, placebo‐controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 (NCT02179502), and a randomized, open‐label, crossover relative bioavailability study to compare the PK of tablet and capsule formulations of GLPG1690 600 mg and to assess the effect of food on PK of the tablet formulation (NCT03143712). Forty and 13 subjects were randomized in the first‐in‐human and relative bioavailability studies, respectively. GLPG1690 was well tolerated, with no dose‐limiting toxicity at all single and multiple doses. GLPG1690 was rapidly absorbed and eliminated, with a median tmax and mean t1/2 of approximately 2 and 5 hours, respectively. GLPG1690 exposure increased with increasing dose (mean Cmax, 0.09‐19.01 µg/mL; mean AUC0‐inf, 0.501‐168 µg·h/mL, following single doses of GLPG1690 20‐1500 mg). PD response, evidenced by rapid reduction in plasma lysophosphatidic acid (LPA) C18:2 levels, increased with increasing GLPG1690 plasma levels, plateauing at approximately 80% reduction in LPA C18:2 at around 0.6 µg/mL GLPG1690. Tablet and capsule formulations had similar PK profiles, and no clinically significant food effect was observed when comparing tablets taken in fed and fasted states. The safety, tolerability, and PK/PD profiles of GLPG1690 support continued clinical development for IPF.

PurposePI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans.MethodsThese phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5–90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histological assessment of psoriatic skin biopsies.ResultsSeletalisib was well tolerated at doses ≤15 mg (Study-1) and ≤45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were associated with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects versus 1 in 1 placebo-treated subject). Mean seletalisib plasma concentration-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t 1/2 values were supportive of once-daily dosing (geometric mean t1/2: Study-1, 17.7–21.1 h; Study-2, 18.1–22.4 h). No clinically significant food effect was observed (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histological assessment of skin biopsies and other markers of psoriatic biology and preliminary evidence of target engagement in psoriatic skin tissue.ConclusionsSeletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-017-2205-7) contains supplementary material, which is available to authorized users.

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600‐mg ziritaxestat labeled with a carbon‐14 tracer (14C‐ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100‐μg microdose, labeled with a microtracer amount of 14C radiation, was administered in a separate part of the study, following an unlabeled 600‐mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug‐related product. There were 7 treatment‐emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

In vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence. A single dose of oral contraceptive (0.03 mg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP)) was administered on days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from days 8 to 23. Co-administration resulted in a 2.8-fold and 2.4-fold increase in EE maximum plasma concentration (C max ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC 0-inf ), respectively (day 18 vs. day 1). DRSP C max and AUC 0-inf increased by 1.1-fold and 1.2-fold, respectively. DRSP is a CYP3A4 substrate, meaning increased EE exposure with ziritaxestat was not due to CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by liquid chromatography with tandem mass spectrometry in day 1 and day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUC from time of administration up to the time of the last quantifiable concentration (AUC last ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 vs. day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 μM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.

ImportanceThere is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).ObjectiveTo assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and ParticipantsThe 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.InterventionsPatients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and MeasuresThe primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).ResultsAt the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.Conclusions and RelevanceZiritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.Trial RegistrationClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

Objectives This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren’s syndrome (PSS). Methods Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. Results Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: –2.59 (95% CI: –7.30, 2.11; P=0.266) and –1.55 (95% CI: –3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. Conclusion Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. Trial registration https://clinicaltrials.gov, NCT02610543.