ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-2H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1–50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ⩾2 mg daily maintained peripheral HSD-1 inhibition ⩾88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ⩾81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ⩾2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

BackgroundNo approved OA therapies reduce pain and slow joint damage. Mouse data suggested that inhibiting IL-1α and -1β with ABT-981 would reduce pain and slow structural progression in EHOA.ObjectivesTo test the efficacy and safety of ABT-981 in EHOA.MethodsSubjects with HOA per ACR criteria, ≥3 inflamed IP joints (tender, swollen, or both), hand pain ≥6 (scale 0–10), and ≥1 erosive IP joint on X-ray (Verbruggen-Veys) were randomized to placebo (PBO) or ABT-981 200 mg SC every 2 wk for 26 wk. The primary outcome was AUSCAN hand pain at 16 wk. Subjects had radiographs of both hands and MRI of the index hand at baseline and 26 wk. Both radiographs (Verbruggen-Veys, GUSS™, OARSI, Kellgren-Lawrence [KL]) and MRIs (HOAMRIS) were read by 2 independent central readers. A modified intent-to-treat population (ie, randomized and treated) was analyzed. Continuous efficacy endpoints were assessed using ANCOVA models with treatment and country as main factors and baseline measurements as covariates with LOCF imputation for the primary endpoint.ResultsOf 131 treated subjects (85% women; mean age 66 y), 61/67 randomized to PBO and 49/64 to ABT-981 completed the study; subject characteristics were well matched. AUSCAN pain was not significantly different vs PBO at wk 16 (P=0.39; Table 1, Figure); X-ray data and other endpoints also were not statistically different vs PBO (Table 1). ABT-981 significantly decreased hsCRP, neutrophils, IL-1α, and IL-1β. Immunogenicity had no impact on ABT-981 pharmacokinetics. Besides injection site reactions and neutropenia, ABT-981 was well tolerated and safety was similar vs PBO, with no serious infections (Table 2).Table 1PBOABT-981PBOABT-981 P 1° Endpoint Baseline, mean±SDLS, mean change±SE at Wk 16AUSCAN pain (0–50)39±738±6−10.7±2.4−9.2±2.30.39 2° Endpoints Baseline, mean±SDLS, mean change±SE at Wk 26AUSCAN function (0–90)69±1571±13−14.3±4.2−16.4±4.00.49Tender joints (0–30)12±612±7−4.7±1.2−5.8±1.20.32Swollen joints (0–30)6±66±5−1.8±0.8−2.2±0.90.64X-ray erosive joints (0–16)2±2*3±2*0.26±0.08†0.18±0.08†0.33KL score (0–80)41±1346±130.13±0.190.10±0.190.87OARSI JSN (0–58)28±1032±90.14±0.190.03±0.190.51OARSI osteophytes (0–58)23±1126±100.25±0.150.14±0.160.45HOAMRIS synovitis (sum score; 0–52.5)11±410±40.92±0.480.85±0.510.89HOAMRIS erosive damage (sum score; 0–105)18±917±100.26±0.640.10±0.670.80HOAMRIS BML (sum score, 0–105)7±55±40.11±0.640.44±0.660.60*Verbruggen-Veys, erosive phase (E) + erosive with remodeling (E/R) or†new E or E/R or R.Table 2PBO (n=67)ABT-981 (n=64) Any AE/serious AE, %88/391/3Death, %00Infection/serious infection, %51/041/0Injection site reaction, %1636Neutropenia by NCI CTCAE grade, n G2 (1000 to <1500/mm3)09 G3 (500 to <1000/mm3)03 G4 (<500/mm3)00ConclusionsDespite adequate pharmacodynamics results, targeting IL-1 may be ineffective in EHOA, as ABT-981 did not improve outcomes.AcknowledgementsAbbVie funded the study (NCT02384538); participated in study design, data collection, analysis, and interpretation and in abstract writing, review, and approval; and funded writing ...

Background Upadacitinib (UPA), an oral selective and reversible JAK1 inhibitor, showed favorable efficacy and safety profile in Phase, 2b and, 3 studies in subjects with moderate to severe ulcerative colitis (UC). Population pharmacokinetics and exposure-response analyses were performed to characterize the relationships between UPA plasma exposures and key efficacy and safety endpoints using data from these studies. Methods The pharmacokinetics (PK), efficacy, and safety of UPA for induction and maintenance treatment in UC were evaluated in a Phase, 2b induction, two replicate Phase, 3 induction, and a Phase, 3 maintenance clinical trials. UPA PK was characterized using data from, 978 UC patients. UPA exposure-response relationships for key efficacy and safety endpoints at the end of induction and maintenance periods were characterized using data from, 1,234 and, 449 UC patients, respectively. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across UPA doses of, 7.5 mg to, 45 mg once daily (QD) for induction and, 15 mg to, 30 mg QD for maintenance. Results UPA PK in UC patients was consistent with other patient populations and between the induction and maintenance periods. The percentage of subjects achieving clinical and endoscopic efficacy endpoints at the end of the induction increased with increasing UPA average plasma concentration (Cavg), and became mostly flat at Cavg values approximately equivalent to the, 45 mg QD (Figure, 1). For maintenance treatment, there was a trend for increasing the percentage of subjects achieving clinical remission, steroid-free remission, endoscopic improvement, and histo-endoscopic mucosal improvement within the range of UPA plasma exposures evaluated. Exposures associated with UPA, 30 mg QD were estimated to provide a, 8% to, 10% increase in the percentage of subjects achieving these endpoints compared to, 15 mg QD (Figure, 2). There was no trend for exposure-response relationships within the range of evaluated UPA exposures for any of the evaluated safety endpoints (&gt;2 g/dL decrease in hemoglobin and &gt;2 g/dL decrease in hemoglobin and &lt; lower limit for normal, hemoglobin &lt;, 8 g/dL, lymphopenia ≥ Grade, 3, neutropenia ≥ Grade, 3, Herpes Zoster infection, serious infections, and pneumonia) at the end of induction or maintenance periods. Conclusion UPA plasma exposures associated with the, 45 mg QD induction dose maximized efficacy for clinical and endoscopic endpoints at Week, 8. Plasma exposures associated with UPA, 30 mg maintenance dose provide additional incremental benefit compared to, 15 mg QD. No trends were observed for increase in the evaluated safety events with increasing UPA plasma exposures at the end of induction or maintenance periods.

Background In order to support risankizumab dose recommendation for the treatment of Crohn’s disease (CD), population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted for risankizumab using data from Phases 2 & 3 studies in moderate to severely active CD patients to characterise PK and its relationship with clinical efficacy and safety. Methods PPK analyses used non-linear mixed-effects modelling, leveraging a previously developed PPK model for plaque psoriasis & CD, with additional evaluation of covariates relevant to CD. ER relationships were evaluated for efficacy endpoints (clinical remission/response based on CDAI or stool frequency/abdominal pain, endoscopic endpoints, etc.) at Week 12 (induction), Week 24 (re-induction; exploratory only), and Week 52 (maintenance), using graphical analyses at Week 12, 24 and 52 and logistic regression analyses at Week 12 and 52. ER analyses for safety evaluated key safety variables through Week 12, 24 and 52 using graphical analyses. Results Observed risankizumab concentrations in CD patients were adequately described by the risankizumab PK model. PK in subjects with CD was linear and time-independent, similar to healthy subjects and plaque psoriasis. The majority of the evaluated intrinsic and extrinsic factors showed no statistically significant effect on risankizumab PK, including age, race, country/region, liver function markers, creatinine, baseline CDAI, baseline SES-CD, duration of disease, prior biological therapies, immunosuppressant use, and immunogenicity. Sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance but their impact on exposure was not clinically relevant for efficacy or safety. ER analyses for induction demonstrated that exposures associated with 600 mg IV at Week 0, 4 and 8 achieved a near maximal response for all evaluated efficacy endpoints at Week 12, with negligible added benefit from 1200 mg IV. ER analyses for maintenance showed higher efficacy response at higher exposures for most of the Week 52 endpoints, particularly the more stringent endoscopic endpoints. ER analyses for safety indicated no apparent relationship between exposure and incidence of any AE, SAE, infection or serious infection over the 12 or 24 weeks of induction or 52 weeks of maintenance treatment. Conclusion PPK and ER analyses of risankizumab in subjects with CD supported the final dose recommendation of 600 mg IV at Week 0, 4, 8 followed by 360 mg SC at Week 12 and Q8W thereafter for the treatment of moderate to severely active CD.

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