William V. Williams

The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy

OBJECTIVE 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7–11%). RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (−0.6%), fasting plasma glucose (−24 mg/dl), and homeostasis model assessment–insulin resistance (HOMA-IR) (−24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.

Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis.

BACKGROUND Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17). OBJECTIVE We sought to demonstrate proof of concept in patients with stable plaque psoriasis. METHODS Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). RESULTS Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC(50)) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. LIMITATIONS This study was limited by the relatively short study duration and small sample size. CONCLUSION Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis.

The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double‐blind, randomized, and placebo‐controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once‐ and twice‐daily dosing for 10 days. As a Biopharmaceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose‐proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3‐hour plasma half‐life and insignificant accumulation following repeat dosing. A high‐fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.

Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [14C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t1/2 of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.

The Effect of CYP3A4 Inhibition or Induction on the Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC0‐∞) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)–6‐stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC0‐∞ by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.

The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers.

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double‐blind, randomized, and placebo‐controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi‐exponential fashion. Baricitinib demonstrates dose‐linear and time‐invariant pharmacokinetics, with low oral‐dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high‐fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment‐related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose‐related decline in absolute neutrophil count was seen with baricitinib.

Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor.

INCB018424 is a novel, potent Janus kinase (JAK)1/JAK2 inhibitor that blocks signal transduction of multiple proinflammatory cytokines.

Predicting Drug–Drug Interactions Involving Multiple Mechanisms Using Physiologically Based Pharmacokinetic Modeling: A Case Study With Ruxolitinib

Physiologically based pharmacokinetic modeling was applied to characterize the potential drug–drug interactions for ruxolitinib. A ruxolitinib physiologically based pharmacokinetic model was constructed using all baseline PK data in healthy subjects, and verified by retrospective predictions of observed drug–drug interactions with rifampin (a potent CYP3A4 inducer), ketoconazole (a potent CYP3A4 reversible inhibitor) and erythromycin (a moderate time‐dependent inhibitor of CYP3A4). The model prospectively predicts that 100–200 mg daily dose of fluconazole, a dual inhibitor of CYP3A4 and 2C9, would increase ruxolitinib plasma concentration area under the curve by ∼two‐fold, and that as a perpetrator, ruxolitinib is highly unlikely to have any discernible effect on digoxin, a sensitive P‐glycoprotein substrate. The analysis described here illustrates the capability of physiologically based pharmacokinetic modeling to predict drug–drug interactions involving several commonly encountered interaction mechanisms and makes the case for routine use of model‐based prediction for clinical drug–drug interactions. A model verification checklist was explored to harmonize the methodology and use of physiologically based pharmacokinetic modeling.

Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF).

Ruxolitinib is a selective inhibitor of Janus kinase 1 and 2, which is approved to treat intermediate or high‐risk myelofibrosis. The population pharmacokinetics for ruxolitinib were characterized by a modeling dataset of 272 subjects from a Phase 2 and a Phase 3 study and validated by an external validation dataset of 142 subjects from a second Phase 3 study. The PK of ruxolitinib was adequately described by a two‐compartment disposition model with first‐order absorption and linear elimination. All model parameters were estimated with good precision. Gender and body weight were identified as covariates for oral clearance (CL/F) and volume of distribution for central compartment (Vc/F), respectively. Apparent oral clearance was 22.1 and 17.7 L/h for a typical male and female subject, respectively, with 39.1% unexplained inter‐individual variability (IIV). The typical Vc/F for a subject with a median weight of 72.9 kg was estimated to be 58.6 L, with 28% unexplained IIV. The model predictive performance was validated by visual predictive check (VPC) and the external validation dataset. This analysis suggests that effects of gender and body weight on ruxolitinib PK are not clinically significant and hence no dose adjustment is needed based on gender and weight.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single‐dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 109/L and 150 × 109/L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.