Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2081-2081 ◽  
Author(s):  
J. Lancet ◽  
I. Gojo ◽  
M. Baer ◽  
M. Burton ◽  
M. Klein ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Phase 1 ◽  
Dose Range ◽  
Hematologic Malignancies ◽  
Hsp90 Inhibitor ◽  
In Vitro Cytotoxicity ◽  
Water Soluble ◽  
Primary Study ◽  
Co Morbidity

2081 Background: Disruption of Hsp90-client protein heterocomplexes leads to degradation of a variety of oncoproteins. KOS-1022, an Hsp90 inhibitor and water-soluble geldanamycin derivative, is in trials in patients with solid tumors. Compared to a prior geldanamycin derivative (17-AAG), KOS-1022 is ∼3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies on the same schedule). Primary study objectives: establish safety and MTD of KOS-1022 in patients with advanced hematologic malignancies; characterize PK and PD. Methods: Escalating doses of KOS-1022 are given IV over 1 h twice weekly for 2 out of 3 weeks. Plasma KOS-1022 concentrations (1st and 4th infusion, Cycle 1) are quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts undergo flow cytometry to quantify Hsp70/90, pAKT/total AKT, markers of apoptosis and proliferation. Response in AML pts used IWG criteria. Results: 13 pts have been enrolled at doses of 8 (n=4), 16 (n=6), 24 (n=1) and 32 mg/m2 (n=2). All were AML (except 1 CML). Most (n=11) patients had 2–3 prior induction regimens. DLT was seen in 2 pts at 32 mg/m2 (acute myocardial infarction and elevation of troponin). Both patients had significant co-morbidity, including (1) prior myocardial infarction and (2) progressive AML with a similar troponin elevation during induction chemotherapy prior to study. Common drug-related toxicities (all Grade 1–2): fatigue, nausea, diarrhea and arthralgias. From 8 to 32 mg/m2, approximately linear PK was observed. Mean terminal half-lives varied from 13.0–31.2 hours. Day 1 clearance for 8, 16 and 32 mg/m2 was 5.6, 9.7 and 10.8 L/hr/m2; mean Vz (L/m2) for these groups were 238, 433 and 489. Although pre-infusion drug was quantifiable on Day 11 in most patients, Day 11/Day 1 AUC0–25h ratio was 0.96. Activity in AML: 2 CRi and 1 SD x 9 cycles were observed. Comparing BMAs taken at Day 8 and Day 15 to baseline: decreased Hsp90 (41% to 13%), increased Hsp70 (8% to 84%) with decreased pAKT (Ser), pAKT (Thr) and total AKT in CD34+ cells. Conclusions: KOS-1022 appears to be well tolerated, with preliminary signs of clinical and biologic activity in refractory leukemia. MTD has not been defined. Plasma PK is linear over this dose range. [Table: see text]

Phase 1, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Intravenous Alvespimycin (KOS-1022) in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1961-1961 ◽  
Author(s):  
Jeffrey Lancet ◽  
Maria R. Baer ◽  
Ivana Gojo ◽  
M. Burton ◽  
M. Quinn ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Phase 1 ◽  
Dose Range ◽  
Hsp90 Inhibitor ◽  
Water Soluble ◽  
Hematological Toxicity ◽  
Weekly Schedule ◽  
Co Morbidity

Abstract Background: Alvespimycin (KOS-1022), an Hsp90 inhibitor and a derivative of geldanamycin, is in phase 1 trials investigating a variety of intravenous and oral schedules. Compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), KOS-1022 is ~3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies); its formulation is water-soluble. The objectives of this trial were to establish the MTD and recommended phase 2 dose in patients with refractory hematologic malignancies; to assess the safety, to document responses and to characterize the PK and PD of KOS-1022. Methods: Escalating doses of KOS-1022 were given IV over 1 hour twice weekly for 2 out of 3 weeks; premedications were not given. Plasma KOS-1022 concentrations (1st and 4th infusion in Cycle 1) were quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts were analyzed by flow cytometry to quantify HSP70/90, pAKT/total AKT and markers of apoptosis and proliferation. Toxicity was assessed by CTCAE v 3.0; responses in AML pts were assessed using Cheson JCO 2003 criteria. Results: 24 pts were enrolled at doses of 8 (n=4), 16 (n=7), 24 (n=11) and 32mg/m2 (n=2). All were AML, except 1 CML pt; 3 pts had FLT3 mutations. Median age 72; median ECOG PS 1; most (n=21) patients had had 2 or 3 prior induction regimens. Cardiac DLT was noted in 2 patients treated at 32 mg/m2 (acute myocardial infarction and elevation of troponin; significant co-morbidity existed for both pts: prior myocardial infarction on post-mortem/CHF/ventricular hypertrophy and rapidly progressive AML with troponin elevation during induction chemotherapy 6 weeks prior to study). Cardiotoxicity was not notable at the three lower doses. Common drug-related toxicities (all Grade 1–2): fatigue 29%, nausea 19%, diarrhea 14%, arthralgias and dizziness 14%. Grade 3–4 non-hematological toxicity (except for the DLT noted above) was not observed. KOS-1022 PK: Cmax was roughly dose-proportional and clearance (CL) showed no clear dose- or time-dependency. The median Cmax, CL, and elimination half-life for the 24 mg/m2 cohort (n=8) were 291 ng/mL, 16.0 L/hr/m2, and 18.1 h, respectively, after dosing on Day 1. Comparing exposure on Day 1 and Day 11 at 24 mg/m2 (n=6), AUC values were 1951 and 2168 ng*hr/mL, respectively; pre-infusion drug levels at this dose on Day 11 were 8 ng/mL. In the six pts with matched pairs of bone marrow aspirates, increased apoptosis by mitochondrial potential was observed on Day 15, after four infusions; (p=0.027). Activity in AML: 3 pts with CRi; one patient remained stable on study x 9 cycles (three of these pts had wild-type FLT3 and one had unknown FLT3 status). Conclusions: Encouraging signs of antileukemia activity were observed in a refractory population. Using a twice weekly schedule, 24 mg/m2 was well tolerated in this population. KOS-1022 plasma PK are generally linear over this dose range. Apoptosis of bone marrow cells by flow cytometry was observed after 4 infusions.

Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of oral alvespimycin (A; KOS-1022; 17-DMAG): Two different schedules in patients with advanced malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14059-14059 ◽  
Author(s):  
K. T. Flaherty ◽  
L. Gore ◽  
A. Avadhani ◽  
S. Leong ◽  
K. Harlacker ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Phase 1 ◽  
Fold Increase ◽  
Hsp90 Inhibitor ◽  
In Vitro Cytotoxicity ◽  
Water Soluble ◽  
Absolute Bioavailability ◽  
Post Dose ◽  
Peripheral Edema

14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUCinf for the 5 to 30 mg/m2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUCinf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]

Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2041-2041 ◽  
Author(s):  
A. Stopeck ◽  
E. Thomas ◽  
S. Jones ◽  
J. Cohen ◽  
G. Cropp ◽  
...  
Keyword(s):  
Phase 1 ◽  
Dose Range ◽  
Optimal Dose ◽  
Pharmacokinetic Profile ◽  
In Vitro Cytotoxicity ◽  
Epothilone D ◽  
Ecog Ps ◽  
Dose Levels

2041 Background: Several epothilones are progressing through phase 1–3 clinical trials treating solid tumor malignancies. KOS-1584 is a 3rd generation epothilone with 3–12 fold increased potency compared to Epothilone D (as measured by in vitro cytotoxicity, in vivo xenografts or induction of G2/M arrest by flow cytometry) and improved pharmacologic/pharmacokinetic profile (enhanced tumor tissue penetration and reduced exposure to the CNS). This dose-escalation trial explores a weekly administration schedule of KOS-1584. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered to patients with advanced solid malignancies via 1-hour infusion on Days 1, 8 and 15 every 4 weeks. Plasma PK and pharmacodynamics (serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot) were assessed. Results: 12 pts (7 F; median age 60; median ECOG PS 1; median prior regimens 4, range 2–13) enrolled in 5 dose levels (0.8, 1.5, 2.5, 5.0 and 7.5 mg/m2). To date, no Cycle 1 DLT has been seen; one Grade 3 episode of arthritis occurred in Cycle 2. Drug-related toxicities, all Grade 1 or 2 in severity: fatigue (n=3), anorexia (n=2) and individual patients with constipation, nausea, mucositis, dehydration, headache and pruritus. Neurotoxicity has not been observed. PK/parent (n=8): t½ 18.5 ± 6.8h, Vz 504 ± 234 L and CL 19.7 ± 6.1 L/h (none of these parameters showed evidence of dose dependency). 5.0 mg/m2 Cmax 122.4 ± 60.6 ng/mL; AUCtot 688.2 ± 212 ng/mL*h. Dose proportional increase in exposure and Cmax was observed over the dose range tested to date. At 5.0 mg/m2 the1-hr infusion Cmax is 3-fold higher and AUCtot 50% higher than for the same dose delivered over 3 hours. As predicted by allometric scaling from animals, Vz is ∼4-fold and t½ 2-fold higher than that of Epothilone D. Activity consisted of extended stable disease (a patient with colon cancer for 3 cycles). Dose-dependent increases in polymerized microtubules were observed: prior to infusion ∼10% of tubulin was in its polymerized form; this increased to 20%, 30%, 35% and 48% for the 1st 4 dose levels at infusion end. Conclusions: Accrual is continuing in order to define the optimal dose on this regimen. Exposure and Cmax remain linear within this dose range; slower clearance is observed for the same dose administered over 1 hour compared to 3 hours. [Table: see text]

scholarly journals Comparative Study of Cigarette Smoke Cytotoxicity Using Two In Vitro Assay Systems

2014 ◽  
Vol 26 (3) ◽  
pp. 98-108
Author(s):  
Toshiro Fukushima ◽  
Hitomi Tanaka ◽  
Takeshi Yamamoto
Keyword(s):  
Cigarette Smoke ◽  
Rank Order ◽  
In Vitro Cytotoxicity ◽  
Water Soluble ◽  
Cytotoxic Agents ◽  
Main Stream ◽  
Total Particulate Matter ◽  
Vitro Assay ◽  
Modes Of Action

SUMMARYThe aim of this study was to compare the results obtained from two in vitro cytotoxicity assays that depend upon different mechanisms/modes of action. The Neutral Red Uptake (NRU) assay is based on endocytotic activity whereas the Water Soluble Tetrazolium Salts (WST-1) assay is based on mitochondrial dehydrogenase activity. Both were investigated in light of their wide use and documented validation. The total particulate matter (TPM) and gas vapor phase (GVP) of main stream smoke derived from Kentucky reference cigarettes 3R4F and 10 test cigarettes made of 100% flue-cured or 100% Burley tobacco were individually applied to the two assays using CHO-K1 cells. In addition, cigarette smoke constituents and known cytotoxic agents, documented to affect specific endpoints, were evaluated within both assays. Although the NRU assay was primarily more sensitive than the WST-1 assay, both assays provided comparable results in terms of the rank order for the cytotoxicity of cigarette smoke samples. In addressing the cytotoxicity of constituents in cigarette smoke, acrolein, hydroquinone and catechol gave clear dose-related decreases in cell viability (an end point common in both assays). Moreover, enzyme inhibitors of the mitochondrial respiratory chain and chemicals causing membrane disruption also showed similar responses regardless of the specific endpoint addressed within the cytotoxicity assay. In conclusion, results from the NRU and WST-1 assay are comparable therefore indicating results were independent of the different assay detection mechanisms/modes of action. [Beitr. Tabakforsch. Int. 26 (2014) 98-108]

scholarly journals The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2446-2455 ◽  
Author(s):  
Ian W. Flinn ◽  
Peter Hillmen ◽  
Marco Montillo ◽  
Zsolt Nagy ◽  
Árpád Illés ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Primary Study ◽  
Effective Treatment Option ◽  
Phase 3 ◽  
Dual Inhibitor

Abstract Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

scholarly journals Preparation, Cytotoxicity, and In Vitro Bioimaging of Water Soluble and Highly Fluorescent Palladium Nanoclusters

2020 ◽  
Vol 7 (1) ◽  
pp. 20 ◽  
Author(s):  
Suresh Thangudu ◽  
Poliraju Kalluru ◽  
Raviraj Vankayala
Keyword(s):  
In Vitro Cytotoxicity ◽  
Molecular Probes ◽  
Water Soluble ◽  
Quantum Yields ◽  
Cell Labelling ◽  
Metal Nanoclusters ◽  
Extinction Coefficients ◽  
Cytotoxicity Studies

Fluorescent probes offer great potential to identify and treat surgical tumors by clinicians. To this end, several molecular probes were examined as in vitro and in vivo bioimaging probes. However, due to their ultra-low extinction coefficients as well as photobleaching problems, conventional molecular probes limit its practical utility. To address the above mentioned challenges, metal nanoclusters (MNCs) can serve as an excellent alternative with many unique features such as higher molar extinction coefficients/light absorbing capabilities, good photostability and appreciable fluorescence quantum yields. Herein, we reported a green synthesis of water soluble palladium nanoclusters (Pd NCs) and characterized them by using various spectroscopic and microscopic characterization techniques. These nanoclusters showed excellent photophysical properties with the characteristic emission peak centered at 500 nm under 420 nm photoexcitation wavelength. In vitro cytotoxicity studies in human cervical cancer cells (HeLa) cells reveal that Pd NCs exhibited good biocompatibility with an IC50 value of >100 µg/mL and also showed excellent co-localization and distribution throughout the cytoplasm region with a significant fraction translocating into cell nucleus. We foresee that Pd NCs will carry huge potential to serve as a new generation bioimaging nanoprobe owing to its smaller size, minimal cytotoxicity, nucleus translocation capability and good cell labelling properties.

Palladium(II) and Platinum(II) Complexes of Novel Water-Soluble Phosphane CAP: Structure, Interligand Hydrogen-Hydrogen Bonding and in Vitro Cytotoxicity

2017 ◽  
Vol 2 (28) ◽  
pp. 8721-8725 ◽  
Author(s):  
Sergey N. Britvin ◽  
Andrey M. Rumyantsev ◽  
Anna A. Silyutina ◽  
Marina V. Padkina
Keyword(s):  
Hydrogen Bonding ◽  
In Vitro Cytotoxicity ◽  
Water Soluble

scholarly journals 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S322-S322
Author(s):  
Jennifer Woo ◽  
Ken Hearne ◽  
Andy Kelson ◽  
Luisa Yee ◽  
Cecilia Espadas ◽  
...  
Keyword(s):  
Clinical Study ◽  
Phase 1 ◽  
Dose Range ◽  
In Vivo Studies ◽  
Resistance Testing ◽  
Antibiotics Resistance ◽  
Gallium Nitrate ◽  
Bacterial Clearance

Abstract Background Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented. Methods MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates. Results In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route. Conclusion In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501. Disclosures All authors: No reported disclosures.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8022-8022
Author(s):  
Jeroen Elassaiss-Schaap ◽  
Peter van Zandvoort ◽  
Jeannette Lo ◽  
Nitya Nair ◽  
Jackie Walling ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Dose Range ◽  
Serum Levels ◽  
Open Label ◽  
Immune Resistance ◽  
Dosing Regimens ◽  
Low Incidence ◽  
Dose Levels

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.

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