Dose-dependent Increase In Exposure Research Articles

Abstract PR010: Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001

Abstract Background: RMC-6236 is an oral RASMULTI(ON) tri-complex inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream signaling. Preclinical studies with RMC-6236 demonstrated deep and sustained regressions across multiple RASMUT tumor types at well tolerated doses, particularly tumors harboring KRAS glycine-12 substitutions (KRASG12X). Methods: Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses of single agent RMC-6236 administered once daily (QD). Results: As of May 11, 2023, 54 patients received RMC-6236 at dose levels from 10 to 220 mg QD. The majority of patients had pancreatic cancer (26 [48%]), non-small cell lung cancer (13 [24%]), or colorectal cancer (10 [19%]). The most common (≥10% of patients) treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were all Grade 1 or 2 in severity. Most rashes were acneiform (35%) or maculopapular (13%), consistent with known on-target rash presentation from other RAS pathway inhibitors. Rash frequency, but not severity, was dose-dependent. One patient required a dose reduction due to Grade 2 acneiform rash. The most common GI-related toxicities were nausea (32%), diarrhea (19%), and vomiting (15%) that were manageable with standard supportive care. There were two Grade ≥3 TRAEs in patients with pancreatic cancer: Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment, and Grade 3 pancreatitis reported at the time of disease progression. Thirty-one patients (57%) remain on treatment, and 23 (43%) discontinued, including 17 (31%) due to progressive disease (PD) per RECIST v1.1, 2 (4%) due to clinical progression, and other reasons due to adverse event (Grade 4 large intestine perforation), death (due to PD), investigator’s decision, or patient withdrawal (1 patient each). RMC-6236 exhibited dose-dependent increases in exposure in patients with no apparent accumulation in the blood following repeated daily dosing. At 220 mg QD, exposure to RMC-6236 was within range of the preclinical exposures in mice that demonstrated significant tumor regressions. Preliminary evidence of anti-tumor activity, including partial responses per RECIST v1.1, was observed in patients across several tumor types and dose levels. Molecular responses were observed with reduction in circulating tumor DNA of the KRAS-mutated allele and other somatic mutations consistent with inhibition of mutant RAS by RMC-6236. Conclusions: RMC-6236 is safe and well tolerated at doses that induce anti-tumor activity in patients with tumors harboring KRASG12X mutations and has favorable pharmacokinetics with oral dosing. A recommended phase 2 dose has not yet been determined and dose escalation is ongoing. Citation Format: Alexander I Spira, Alexander N Starodub, Kathryn C Arbour, David Sommerhalder, Brian M Wolpin, Minal Barve, Ignacio Garrido-Laguna, Salman Punekar, Meredith Pelster, Sumit Kar, Jamie Wong, Tong Lin, Rakesh Raman, Lin Tao, Zeena Salman, Xiaolin Wang, W. Clay Gustafson, David S Hong. Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR010.

First-in-human first-in-class phase 1/2a study of the next generation CDK4-selective inhibitor PF-07220060 in patients (pts) with advanced solid tumors, enriched for HR+ HER2- mBC who progressed on prior CDK4/6 inhibitors and endocrine therapy.

3009 Background: PF-07220060 is a novel potent oral CDK4-selective inhibitor with significant sparing of CDK6. We report the first disclosure of the first-in-human, multicenter trial of PF-07220060 alone or with endocrine therapy (ET). Methods: This Phase 1/2a study in advanced solid tumors was enriched for pts with HR+ HER2- advanced/metastatic breast cancer (HR+/HER2- mBC) who had received ≥2 lines of treatment including ET and CDK4/6 inhibitors (CDK4/6i). Prior fulvestrant and chemotherapy were allowed. Primary objective was to assess safety and tolerability of PF-07220060 alone and in combination with ET. Secondary/exploratory objectives included anti-tumor activity, pharmacokinetics (PK) and pharmacodynamics (PD). Results: At data cut off (Nov 1, 2022), 34 pts with advanced solid tumors received PF-07220060 in monotherapy dose escalation (Part 1A: 100–500 mg BID), and 26 pts with HR+/HER2- mBC in combination (300mg/400mg BID) with letrozole or fulvestrant (Parts 1B + 1C). For pts with HR+/HER2- mBC, median age was 61.5y (range 41–82y), ECOG PS was 0 (38.5% pts) or 1, and median prior lines of systemic therapy (advanced setting) 4.5 (range 1–11); all had prior CDK4/6i, 19 (73.1%) prior fulvestrant and 20 (76.9%) prior chemotherapy. Most frequent all causality treatment-emergent adverse events (TEAEs) with PF-07220060 + ET were diarrhea (50.0%; 0% G3), neutropenia (50.0%; 15.4% G3) and nausea (38.5%; 3.8% G3) with no >G3 TEAEs. A similar safety profile was seen in monotherapy. Dose-limiting toxicities occurred at PF-07220060 500 mg monotherapy BID (n=2 G3 thrombocytopenia) and at 400 mg BID + fulvestrant (n=1 G3 leukopenia/neutropenia). Preliminary PK analyses showed PF-07220060 is rapidly absorbed with dose-dependent increases in exposure. PF-07220060 300 mg BID was selected as the recommended dose for expansion. PD biomarker modulation was seen in tumor (pRB, Ki67 inhibition) and blood (TK1 inhibition). In pts with HR+/HER2- mBC with measurable disease who progressed on prior CDK4/6i+ET (n=21) treated with PF-07220060 (300/400 mg BID) + ET, confirmed RECIST v1.1 responses were observed in 6 (28.6%) pts (1 complete [CR], 5 partial [PR]). Clinical benefit response (CR, PR, or ≥24 wks stable disease) was seen in 11 (52.4%) pts. Median progression-free survival was 24.7 wks (95% CI: 23.1, 47.4). At data cutoff, 8/26 (30.8%) pts with mBC continued PF-07220060 + ET without progression for up to 60+ wks. Updated efficacy, PK, PD, and biomarker data will be presented. Conclusions: PF-07220060 + ET showed efficacy in pts with HR+/HER2- mBC who progressed on prior CDK4/6i+ET. Tolerability of PF-07220060 alone and in combination with ET was encouraging. Dose expansions with PF-07220060 + ET in pts with HR+/HER2- mBC post CDK4/6i and in CDK4/6i naïve pts are ongoing. Clinical trial information: NCT04557449 .

Abstract CT017: Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PIK3CA-mutant solid tumor patients, ReDiscover trial

Abstract BACKGROUND: Oncogenic activation of PI3Kα via mutation of PIK3CA is the most common kinase driver event across solid tumors, particularly breast cancer (BC). Alpelisib, an orthosteric inhibitor, validated mutant-PI3Kα as a therapeutic target; however, toxicity from non-selective inhibition of WT PI3Kα (hyperglycemia) and other PI3K isoforms limits its clinical activity. RLY-2608, a novel oral allosteric PI3Kα inhibitor, is designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition. We initiated a first-in-human study (NCT05216432) to define the MTD, safety, pharmacokinetics (PK), and anti-tumor activity of RLY-2608 in PIK3CA-mutant solid tumor patients (pts) and of RLY-2608 plus fulvestrant (combo) in pts with PIK3CA-mutant, HR+HER2-BC, who had received prior CDK4/6 inhibitor and endocrine therapy. METHODS: Adult pts with no prior PI3Ki/mTORi therapy received RLY-2608 QD or BID on a 4-week (wk) cycle following a Bayesian Optimal Interval dose escalation. Eligible BC pts received fulvestrant. PK, pharmacodynamics (ex vivo pAKT inhibition; tumor markers; ctDNAs), treatment emergent adverse events (TEAEs), and anti-tumor activity per RECIST 1.1 were assessed. RESULTS: As of 31Jan23, 40 pts (21 BC combo pts) with PIK3CA mutations (12 kinase, 18 helical, 10 other) received RLY-2608 at doses of 100-1600 mg/day. Median number of prior treatments was 4 (1-11). An MTD has not been reached and dose escalation continues. RLY-2608 PK were favorable with BID dosing providing low steady-state peak-to-trough variability for mutant-selective inhibition. This enabled dose-dependent increase in exposure and target inhibition with doses ≥600 mg BID and pAKT suppression (≥80%) in the expected therapeutic range with minimal/no impact on glucose homeostasis. Across arms, safety was consistent: most frequent TEAEs (>15%) were low grade (≤Gr 2) nausea (30%), fatigue (22.5%), headache (22.5%), hypokalemia (22.5%), and diarrhea (17.5%). No DLTs were observed, and no pts discontinued due to related AEs. Initial anti-tumor activity was observed in BC combo pts including declines in tumor markers, PIK3CA/ESR1 ctDNAs and radiographic tumor reduction in 7 of 10 RECIST measurable pts. At 600 mg BID, 6/6 BC combo pts had disease stabilization and remain on treatment, including all RECIST-measurable pts with tumor reduction. Overall, 17 (81%) BC combo pts remain on treatment with median duration of 12 (1-40) wks. CONCLUSION: Across PIK3CA genotypes, RLY-2608 demonstrated target inhibition and anti-tumor activity with minimal impact on glucose homeostasis. These proof-of-mechanism data indicate that RLY-2608 is the first allosteric, pan-mutant selective PI3Kα inhibitor and that RLY-2608 has broad therapeutic potential in PIK3CA-driven cancers. Citation Format: Andreas Varkaris, Komal Jhaveri, Cesar A. Perez, Janice S. Kim, Jason T. Henry, Vivek Subbiah, Alexander I. Spira, Lucía Sanz Gómez, Angel I. Guerrero-Zotano, Kari B. Wisinski, Xiaoyan Li, Gege Tan, Ramin Samadani, Tamieka Lauz Hunter, Wei Guo, Alison Timm, Djuro Karanovic, Beni B. Wolf, Erika P. Hamilton, Alison M. Schram. Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PIK3CA-mutant solid tumor patients, ReDiscover trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT017.

First-in-Human (FIH) Study of the Fully-Human Kappa-Lambda CD19/CD47 Bispecific Antibody TG-1801 in Patients (pts) with B-Cell Lymphoma

Introduction: Cancer cells elude anti-tumor immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Blockade of signal regulatory protein (SIRP)-α on macrophages, or of its ligand CD47 expressed on tumor cells, improves tumor cell elimination however CD47 is a challenging target given its ubiquitous distribution in healthy tissues. Combination of CD47 blockade with the anti-CD20 antibody rituximab has resulted in encouraging clinical activity (Advani 2018), and CD19 is also an established target of multiple B-NHL therapies. TG-1801 is a bispecific agent designed with a CD19 high-affinity arm and a blocking CD47 arm for concurrent target engagement on the tumor cells surface. Herein we report results of the FIH study for the first time. Methods: The primary objectives were to characterize the safety profile and to determine the recommended phase 2 dose (RP2D) of TG-1801. Other objectives included assessment of pharmacokinetics (PK), preliminary antitumor activity (Lugano 2014), and pharmacodynamics (PD: B-cell depletion). Eligible patients must have had relapsed/refractory (R/R) B-cell lymphoma after at least one prior standard therapy. A 3+3 design was utilized to evaluate sequentially higher doses of TG-1801 at the following dose levels: 20 mg, 60 mg, 180 mg, 360 mg, and 500 mg. In the monotherapy arm, treatment consisted of weekly fixed dosing 1h-infusions of TG-1801 in a 4-week cycle: day (D)1, D8, D15, and D22 of cycle (C) 1 and C2. Patients who had at least stable disease after 2 cycles were given the option of receiving TG-1801 once every 4 weeks for an additional 4 infusions. Intra-patient dose escalations were permitted. An additional arm was enrolled with the combination therapy of ublituximab (anti-CD20 mAb) plus TG-1801. Patients received TG-1801 and ublituximab infusions in a 4 week-cycle: D1, D8, and D15 of C1; D1 of C2 thru C6; and D1 of C9 and every 3 cycles thereafter, up to 24 cycles. A 3+3 design was also utilized to evaluate two dose levels of TG-1801 (300 mg and 400 mg) with a standard dose of ublituximab (900 mg). Results: As of May 2022, 14 pts (MZL = 5, DLBCL including Richter's transformation = 5, FL = 4) received monotherapy and 16 pts received combination therapy (DLBCL = 9, FL = 4, MZL = 2, MCL = 1). Patients were heavily pretreated: median 3 prior systemic therapies (range, 1 - 8), all had received ≥1 prior anti-CD20; 14 pts (46%) were refractory to their last prior therapy. Twenty-one (70%) had extranodal disease, and 9 (30%) had bulky disease. One DLT of grade (G) 4 thrombocytopenia occurred at the 500 mg dose level. The most common (>20%) treatment emergent adverse events (TEAEs) at monotherapy doses of 20 mg to 360 mg (n=10) included fatigue, thrombocytopenia, and infusion-related reaction (3 pts each), with no G3/4 TEAE occurring in >20% of pts. Combination therapy was also well tolerated (TG-1801 at 300 mg N=3, 400 mg N=13) without DLT. The most common TEAE (≥20%) for combination therapy were: anemia (31%), headache, abdominal pain, fatigue, and thrombocytopenia (25% each), with no G3/4 TEAE occurring in >20% of pts. There were 2 permanent treatment discontinuations due to TEAE (1 infusion reaction [500 mg monotherapy], 1 rash [360 mg monotherapy]). Three partial responses (PR) were observed on monotherapy (n=14), all at 360 mg TG-1801, including 1 MZL pt with 7 prior lines that included PI3Ki, BTKi, auto transplant, and multiple prior anti-CD20s. All 3 pts completed 6 cycles of treatment and continued to further cycles of re-treatment. In the combination arm (n=16), a 44% response rate was observed with 1 complete response (CR) in a pt with FL and 6 PR (5 pts with DLBCL and 1 pt with FL) for a 56% ORR for DLBCL patients and 50% ORR for FL patients. The median duration of combination therapy exposure was 8.7 mo (range of 1-20 mo). Responses appear durable, with ten pts remaining on study, with 1 pt receiving 360 mg monotherapy and 9 pts receiving combination therapy. Dose dependent increases in exposure were observed and pharmacodynamic analysis demonstrated a >50% depletion of circulating lymphocytes within 7 days of the first infusion in all evaluable pts. Conclusions: TG-1801 monotherapy and combination therapy demonstrates clinical activity, particularly in relapsed and refractory DLBCL, with an acceptable preliminary safety profile. This study (NCT03804996) has completed enrollment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

OR12-2 Inhibition of Basal and ACTH-stimulated Cortisol Secretion in Humans Using an Oral Nonpeptide ACTH Antagonist (CRN04894)

Abstract CRN04894 is a potent orally bioavailable MC2R (adrenal cortex specific ACTH receptor) antagonist (Kb=0.34 nM) that is >1000-fold selective for MC2R over other melanocortin receptor subtypes. In rats receiving continuous administration of ACTH via subcutaneously implanted osmotic pumps, oral administration of CRN04894 over 7 days has previously been shown to result in dose-dependent suppression of basal and ACTH stimulated corticosterone levels. This compound is in clinical development for the treatment of diseases of ACTH excess including congenital adrenal hyperplasia (CAH) and Cushing's Disease. We report initial results from a randomized double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04894 in 39 healthy volunteers. After an overnight fast, single doses of CRN04894 were administered at approximately 8 am, 2 hours prior to an IV bolus of ACTH 1-24 (cosyntropin). Serial cortisol over 600 minutes and pharmacokinetics over 168 hours post CRN04894 dose were measured. Two different challenge doses of ACTH 1-24 were studied: 250 μg (supra-pharmacological) and 1 μg (comparable to ACTH concentrations encountered in CAH and Cushing's Disease). CRN04894 was rapidly orally absorbed (median tmax 0.5-1.5 hour), and demonstrated a dose dependent increase in systemic exposure, with an apparent terminal elimination t1/2 of approximately 20 hours. Unstimulated (basal) cortisol measured 2 hours after CRN04894 administration fell in a dose-dependent manner, resulting in reduction near the theoretical maximum with the 80 mg dose cohort (-56.1% [SEM 4.0%, n=12] vs +17.4% in placebo [SEM=18.1%, n=9]). Dose-dependent cortisol suppression following a supra-pharmacological ACTH-stimulated (250 μg) was also observed, with a 41% reduction in the area under the curve (AUC60-600min) post-stimulation at the 80 mg dose. Furthermore, a single dose of 80 mg of CRN04894 reduced the cortisol response (AUC15-120 min) to a disease relevant 1 μg ACTH challenge by 48%, maintaining cortisol concentrations within the normal range seen prior to dosing in a basal unstimulated state. Single doses of CRN04894 were well tolerated with no need for glucocorticoid supplementation. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that MC2R antagonist CRN04894 was well tolerated after oral delivery in healthy volunteers and demonstrated dose-dependent increases in exposure with lowering of basal and ACTH-stimulated cortisol secretion, including in the presence of disease relevant excess ACTH exposure. Multiple ascending dose evaluations are underway in anticipation of studies in patients with diseases of ACTH excess. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Nonclinical Pharmacokinetic Evaluation of Desidustat: a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

Desidustat is a novel prolyl hydroxylase domain(PHD) inhibitor for the treatment of anemia. The objective of this study was to investigate the pharmacokinetics and drug-drug interaction properties of desidustat using invitro and invivo nonclinical models. Invitro, Caco2 cell permeability, plasma protein binding, metabolism, cytochrome P450 (CYP) inhibition, and CYP induction were examined. In vivo, pharmacokinetic studies of oral bioavailability in mice, rats, dogs and monkeys, dose linearity, tissue distribution, and excretion in rats were conducted. In Caco-2 cells, the apparent permeability of desidustat was high at low pH and low at neutral pH. The oral bioavailability (%F) of desidustat was 43-100% with a mediantime to reach peak concentration (Tmax)of about 0.25-1.3h across species. Desidustat displayed a low mean plasma clearance (CL) of 1.3-4.1mL/min/kg (approximately 1.8-7.4% of hepatic blood flow), and the mean steady-state volume of distribution (Vss) was 0.2-0.4L/kg (approximately 30-61% of the total body water). Desidustat showed a dose-dependent increase in exposures over the 15-100mg/kg dose range. It was rapidly distributed in various tissues, with the highest tissue-to-blood ratio in the liver (1.8) and kidney (1.7). Desidustat showed high plasma protein binding and was metabolically stable in human liver microsomes, hepatocytes, and recombinant CYPs. It did not show significant inhibition of major drug-metabolizing CYP enzymes (IC50>300µM) or the potential to induce CYP1A2 and CYP3A4/5 (up to 100µM) in HepG2 cells. It may have minimal potential of clinical drug-drug interaction when used in combination with iron supplements or phosphate binders. Desidustat was primarily excreted unchanged in urine (25% of the oral dose) and bile (25% of the oral dose) in rats. The mean elimination half-life of desidustat ranged from 1.0 to 5.3h and 1.3 to 5.7h across species after intravenous and oral administration, respectively. Taken together, desidustat is well absorbed orally. It showed a dose-dependent increase in exposure, did not accumulate in tissue, and was eliminated via dual routes. It is metabolically stable, has minimal potential to cause clinical drug-drug interactions (DDIs), and demonstrates discriminable pharmacokinetic properties for the treatment of anemia.

CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory and High Risk Chronic Lymphocytic Leukaemia (CLL)

IntroductionThe B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton's tyrosine kinase (Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-clinical models (Yasuhiro T et al, AACR 2013). MethodsThis Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/refractory, high risk CLL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating 3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data on 16 evaluable patients, median age 67 yrs (range 40-77), with high risk cytogenetics (17p [38% (6/16)] or 11q [19% (3/16)], 12/16 displaying unmutated IgVH status, 8/16 displaying TP53 mutation), median baseline tumour burden 4,534mm2 [461-14,492 mm2]. Patients had received a median of 3 prior therapies [2-7], including fludarabine (16/16) and rituximab-containing therapy (13/16). Baseline median haematology parameters included hemoglobin 11.3 g/dL [8.5 -15.2], WBC 56.02 x 109/L [2.06-394.74], platelets 95.5 x 109/L [23-173], lymphocytes 50.6 x 109/L [0.5-390], neutrophils 2.46 x 109/L [0.5-11.1]. Patients were treated with ONO-4059 at doses ranging from 20mg-320mg (cohorts 1-5) and the study is currently ongoing with additional dose escalation cohorts to be completed. ResultsONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 15 ONO-4059-related Grade 1 (n=10) and 2 (n=5) adverse events were reported in 8 out of 16 patients, including one event of diarrhea (G2) and two events of rash (G1, G2). ONO-4059-related G3 or G4 haematological toxicities were infrequent and independent of dose; neutropenia (n=3 [G4 x1, G3 x 2]), febrile neutropenia (n=1 [G3]) occurring in 2 patients at the 20mg dose level only. Only one Grade 3 ONO-4059-related non-haematological event (pyrexia) was reported. Infection rate was low with only one event of bronchitis reported (G2, related). Three ONO-4059-related SAEs were reported in two patients (febrile neutropenia [G3] and pyrexia [G3] in one patient [20 mg]; rash [G2] in another [80 mg]). The pharmacokinetics of ONO-4059 reflects rapid absorption and elimination, a half-life of ∼6 hours, a dose dependent increase in exposure with no accumulation of ONO-4059 exposure and low inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated Btk) being maintained for at least 24 hours across all dose levels.Responses have occurred across all dose levels. All patients experienced rapid reductions in lymphadenopathy observed early in treatment, between D1-D28 of the first cycle, accompanied by an increase in absolute lymphocyte count in some, but not all patients. Best overall response rate according to IWCLL criteria (including modified PR with lymphocytosis) was 70% [based on CT-scan and P/E for 7/10 evaluable patients]; with 2 PR, 5 PR with lymphocytosis (For 7 responding patients, median reduction of lymph nodes was 67% [Range 61%-79%]), 2 SD, 1 patient PD (possible Richter's). All patients showed an improvement in haematological parameters after ≥3 months on treatment. Patients (ONO-4059 20mg [1pt] and 40mg [1pt] respectively) who had grade 3 thrombocytopenia at study baseline had a significant improvement in platelet count (>100 x 109/L) with ONO-4059 treatment. To date, 15 of 16 patients remain on treatment with a median progression-free survival of 99 days [Range 8-268].In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor with a favourable safety profile along with promising efficacy in this heavily pre-treated population, with responses observed in relapsed, refractory and 17p deleted patients. Disclosures:Salles:Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin:Janssen: Honoraria; Celgene: Honoraria. Morschhauser:ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:ONO Pharma: Honoraria, Research Funding. Hutchinson:ONO Pharma: Research Funding. Fegan:ONO Pharma: Honoraria. Cartron:ONO Pharma: Honoraria. Knurowski:ONO Pharma: Consultancy. Saunders:ONO Pharma: Consultancy; Pharmacyclics: Consultancy. Wright:ONO Pharma: Consultancy. Honda:ONO Pharma: Employment. Mazur:ONO Pharma: Consultancy. Yoshizawa:Ono Pharma: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment.

Preclinical and clinical characterization of the ROR\u03b3t inhibitor JNJ-61803534

The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.

Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study.

3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465.

Investigational CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

Investigational CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Abstract 3014: Pharmacokinetics of the CDC7 inhibitor LY3143921 hydrate, a CRUK first-in-human phase I trial in patients with advanced solid tumors

Abstract Background: LY3143921 hydrate is an orally administered ATP-competitive inhibitor of CDC7, a serine/threonine kinase regulatory protein overexpressed in many cancer types. Following successful preclinical studies, a first-in-human phase I trial of LY3143921 hydrate was initiated in patients with advanced solid tumors. We report the pharmacokinetics of LY3143921 hydrate in this ongoing Cancer Research UK study. Methods: Eligible patients were those with histologically proven advanced/metastatic solid tumors for which no further standard therapy options were available. Patients were administered LY3143921 hydrate as a single oral dose on Day -7, followed by daily administration (dose levels 30-270mg) or twice daily administration (dose levels 150 and 180mg) on study days 1-21. Drug administration was carried out with patients in either a fasted or fed state as shown in Table 1. Samples for pharmacokinetic analysis were obtained following a single drug dose on Day -7 at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours. Additional samples were taken on Day 1 of treatment at doses of 150 and 180mg to investigate potential differences in pharmacokinetics in fed versus fasted states (Day -7 fed versus Day 1 fasted). Samples were analysed using a validated LC-MS/MS assay with a LLOQ of 0.1 ng/mL. Pharmacokinetic analysis was carried out using Certara WinNonlin software (version 6.3) to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent volume of distribution (Vz/F) and apparent clearance (CL/F) of LY3143921 hydrate. Assessment of dose proportionality was made by assessment of graphical plots of AUC versus dose level. Table 1:Summary of LY3143921 hydrate pharmacokinetic data on Day -7 (single dose data)Dose level (mg)Number of patientsFed / fastedCmax (ng/mL)AUC0-24h (ng/mL.h)Half-life (h)CL/F (L/h)Vz/F (L)301Fasted184.44253.3570.1339601Fasted175.05022.42119.44181201Fasted113031382.1738.212018010Fasted144 - 8142505 ± 9904.2 ± 4.079.5 ± 23.9475 ± 4732704Fasted474 - 15126374 ± 14753.4 ± 1.843.8 ± 8.9226 ± 1581503Fed334 - 6321997 ± 4964.4 ± 1.977.2 ± 16.4514 ± 2881803Fed492 - 16002994 ± 9793.2 ± 0.864.2 ± 19.4290 ± 112 Results: Table 1 provides a summary of the pharmacokinetic parameters obtained on Day -7 following a single dose of LY3143921 hydrate (data expressed as range or mean ± SD as appropriate). Overall dose-dependent increases in exposure (based on Cmax and AUC) were observed. There was a general trend towards higher Cmax and AUC values following administration in a fasted versus fed state following a dose of 180 mg, but this was inconsistent across the limited number of patients for who these data were available on both Day -7 (fed) and Day 1 (fasted). Conclusion: The pharmacokinetic data generated to date are consistent with dose dependent increases in drug exposure observed with a flat dosing regimen for LY3143921 hydrate. Citation Format: Shelby Barnett, Melanie Griffin, Richard H. Wilson, Elizabeth R. Plummer, Jeffry T. Evans, Victoria Coyle, Sally Clive, Lisa Godfrey, Nicola Dobbs, Lesley McGuigan, Sue Brook, Gavin Halbert, Gareth J. Veal. Pharmacokinetics of the CDC7 inhibitor LY3143921 hydrate, a CRUK first-in-human phase I trial in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3014.

Abstract CT127: A phase I study of cMET inhibitor bozitinib in patients with advanced NSCLC harboring cMET alterations

Abstract Introduction: Cellular mesenchymal-epithelial transition (cMET) dysregulation has been described in non-small-cell lung cancer (NSCLC) and implicated as a negative prognostic factor. It can occur as amplification, overexpression or mutations leading to exon 14 skipping. Bozitinib (PLB-1001, CBT-101) is a potent highly selective cMET inhibitor, which has demonstrated superior activity in both in vitro and in vivo NSCLC models. Methods: This was a phase I, open-label multicenter study conducted in locally advanced or metastatic NSCLC patients that included a dose-escalation (19 patients) and a dose-expansion phase (18 patients) (NCT02896231). A traditional 3+3 design was adopted for dose escalation. The primary objective was to characterize the safety and tolerability of single agent Bozitinib. The secondary objectives included pharmacokinetics (PK) analysis and antitumor activity assessed by RECIST v1.1. cMET dysregulation was defined by: IHC 3+ expression in >50% of tumor cells or gain of copy numbers (GCN) ≥5 or cMET/centromere ≥2.2 by FISH or MET copy number ≥2.25 or with exon 14 skipping by next-generation sequencing (NGS). Only central laboratory testing was acceptable. Patients≥18 years with locally advanced or metastatic NSCLC with an ECOG performance status ≤2 were enrolled. Those previously treated with cMET inhibitor or HGF targeting therapy were excluded. Patients were orally administrated with Bozitinib capsules in a total of 6 dose cohorts: 5 BID dose cohorts (50 mg BID, 100 mg BID, 150 mg BID, 200 mg BID and 275 mg BID), and 1 QD dose cohort (300 mg QD). The enrollment had been completed by October 31 2019 with 37 enrolled patients. Results: Of the 37 enrolled patients, with a median age of 61: 8 had overexpression; 11 had exon 14 skipping; 8 had amplification and 10 patients had more than 1 type of MET alterations. Bozitinib was generally well-tolerated in all cohorts. Treatment-related AEs of any grade were observed in 35 patients and those of ≥ grade 3 were observed in 10 patients (in 200mg BID, 275mg BID and 300mg QD groups), including ALT increase, AST increase, bilirubin increase and peripheral edema. Common AEs occurring in more than 20% of patients included: ALT increase (40.5%), AST increase (40.5%), bilirubin increase (40.5%), peripheral edema (32.4%) and QTc interval prolongation (18.9%). Bozitinib showed good linear PK characteristics, with dose-dependent increases in exposure and a half-life around 13.8-44.6h. 36 were included in the BOR analysis. One patient was excluded due to the development of brain metastases after first dose. This cohort presented an ORR of 30.6% (11/36) and a DCR of 94.4% (34/36). Sub-analysis of ORR for patients with overexpression, amplification and exon 14 skipping were 35.7%, 41.2% and 66.7%, respectively. ORR for patients with overexpression and amplification (N=6) was 50%. ORR for patients harboring both exon 14 skipping and amplification (N=4) was 100%. Conclusions: Based on safety profiles, PK and efficacy analyses, 200mg BID was determined to be RP2D. Bozitinib was well-tolerated with manageable safety profiles when administered at RP2D. Preliminary antitumor activity was observed in patients with exon 14 skipping and/or amplification, particularly in those with NGS-identified exon 14 skipping. Citation Format: Jinji Yang, Qing Zhou, Huajun Chen, Lin Wu, Jun Zhao, Renhua Guo, Yun Fan, Hepeng Shi, Weizhe Xue, Peilong Zhang, Han-Zhang Han, Xuan Lin, Shuyin Chen, Lu Zhang, Hao Liu, Xinru Mao, Bin Gan, Yilong Wu. A phase I study of cMET inhibitor bozitinib in patients with advanced NSCLC harboring cMET alterations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT127.

A Phase 2 Study of AMO-02 (Tideglusib) in Congenital and Childhood-Onset Myotonic Dystrophy Type 1 (DM1)

BackgroundGSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy. MethodsSixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained. ResultsAMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments. ConclusionAMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.

A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of the Pharmacokinetics and Pharmacodynamics of REGN3918, a Human Antibody Against Complement Factor C5, in Healthy Volunteers

INTRODUCTION: Blockade of complement factor C5 has demonstrated benefit in Paroxysmal Nocturnal Hemoglobinuria (PNH), atypical Hemolytic Uremic Syndrome and Generalized Myasthenia Gravis. We developed a human IgG4P antibody, REGN3918, that binds with high affinity to wild-type and variant (R885H/C) human C5. REGN3918 was well-tolerated in monkey toxicology studies with up to 26 weeks of dosing at up to 100 mg/kg/week. This finding was supportive of conducting this first-in-human study of REGN3918 in healthy volunteers.OBJECTIVE: The primary objective of this ongoing study is to evaluate the safety and tolerability of single ascending intravenous (IV) and subcutaneous (SC) doses and a multiple dose regimen consisting of an IV loading dose plus multiple weekly SC doses of REGN3918 administered in healthy volunteers. The secondary objectives of the study are to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of REGN3918.METHODS: 56 subjects were randomized to 4 sequential ascending IV dose cohorts plus 2 sequential ascending SC cohorts followed by 1 multiple dose cohort (consisting of an IV loading dose and weekly SC doses). Each cohort consisted of 8 subjects randomized to receive REGN3918 or placebo (6 active: 2 placebo). An adaptive design was implemented to allow for dose level and dosing interval adjustment utilizing in-study PK and PD measures. The PD profile of REGN3918 was assessed utilizing a sheep red blood cell complement activity assay (CH50 assay) as well as serum concentrations of total C5. REGN3918 was administered as follows:•Cohort 1: 1 mg/kg IV, single dose•Cohort 2a: 3 mg/kg IV, single dose•Cohort 2b: 300 mg SC, single dose•Cohort 3a: 10 mg/kg IV, single dose•Cohort 3b: 600 mg SC, single dose•Cohort 4: 30 mg/kg IV, single dose•Cohort 5: Loading dose of 15 mg/kg IV followed by 4 repeat SC doses of 400 mg administered once weekly for four weeks.RESULTS: REGN3918 was found to be well tolerated in single doses of up to 30 mg/kg IV and 600 mg SC. The multiple dose Cohort 5 has completed dosing in all subjects and is currently in safety follow-up. Thus far, there has been one SAE, salpingitis in a subject with an intra-uterine contraceptive device. The SAE occurred in a Cohort 5 subject after completion of dosing and has since resolved. REGN3918 exhibited dose-dependent increases in exposure in serum, with a trend toward prolonged serum concentrations at IV doses ≥10 mg/kg. Following SC administration, concentrations of REGN3918 in serum peaked at 4 to 8 days post dose and bioavailability was estimated as approximately 70%. REGN3918 exposure led to dose-dependent inhibition of CH50. In all 4 IV dosing cohorts, suppression of hemolysis was observed at 15 min post-injection. Complete suppression of hemolysis was achieved with ≥ 3mg/kg dosing. At 30 mg/kg, complete suppression of hemolysis was maintained for >6 weeks, consistent with observed prolonged REGN3918 concentrations following this dose. In the 2 SC cohorts, peak suppression of hemolysis was observed 3-7 days post dosing, again consistent with observed peak concentrations of REGN3918 in serum. In the multiple dose cohort 5, complete suppression of CH50 was observed over the four-week dosing period.CONCLUSIONS: REGN3918 was well tolerated and resulted in dose-dependent inhibition of hemolytic activity in normal healthy volunteers. A single IV infusion of R3918, at 30 mg/kg, blocked hemolytic activity completely for >6 weeks. Complete inhibition of hemolytic activity was maintained over a 4-week dosing period by a weekly SC regimen following an IV loading dose. DisclosuresWeyne:Regeneron Pharmaceuticals: Employment, Equity Ownership. Ni:Regeneron Pharmaceuticals: Employment, Equity Ownership. DelGizzi:Regeneron Pharmaceuticals: Employment, Equity Ownership. Godin:Regeneron Pharmaceuticals: Employment. Morton:Regeneron Pharmaceuticals: Employment, Equity Ownership. Prasad:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rankin:Regeneron Pharmaceuticals: Employment, Equity Ownership. Simek-Lemos:Regeneron Pharmaceuticals: Employment, Equity Ownership. Wang:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rippley:Regeneron Pharmaceuticals: Employment, Equity Ownership. Harari:Regeneron Pharmaceuticals, Inc.: Employment.

RTA 1701 is an oral RORγt inhibitor that suppresses the IL-17A response in non-human primates

Abstract RTA 1701 is an orally-bioavailable, selective RORγt inhibitor. RORγt orchestrates the differentiation of Th17 cells and contributes to autoimmune disease pathogenesis. Inhibition of RORγt suppresses Th17 cells and the associated secretion of the effector pro-inflammatory cytokine IL-17A. As such, RTA 1701 is highly efficacious in rodent models of rheumatoid arthritis and multiple sclerosis. This study was conducted to evaluate the pharmacokinetics of RTA 1701 and its effects on ex vivo stimulation of IL-17A production in whole blood after oral administration to naïve healthy cynomolgus monkeys. Monkeys received a single administration of RTA 1701 (0.3, 3, 30, or 300 mg/kg). After a one-week washout, monkeys received the same doses of RTA 1701 once daily for 14 consecutive days. Blood was collected after a single dose and after 14 days of dosing for analysis of plasma RTA 1701 concentrations through 72 hours post-dose and for evaluation of RTA 1701 effects on ex vivo stimulation of IL-17A at 24, 30, and 72 hours post-dose. RTA 1701 exhibited oral bioavailability in monkeys with dose-dependent increases in exposure over the wide range of doses evaluated. Further, oral administration produced systemic exposure to RTA 1701 at sufficient levels to produce significant and dose-dependent suppression of ex vivo stimulation of IL-17A secretion in whole blood at 24 and 30 hours after single and repeat dosing, with IL-17A levels returning to baseline within 72 hours after a single dose. Collectively, these data demonstrate that RTA 1701 is orally bioavailable in non-human primates and significantly suppresses the IL-17A response. These data also support the future clinical development of RTA 1701 for the potential treatment of autoimmune diseases.

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680mg in eight subjects. Part2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part1. During Part2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of AG-519, an Allosteric Activator of Pyruvate Kinase-R, in Healthy Subjects

BACKGROUNDPyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R) due to mutations in the PKLR gene. PK catalyzes the last enzymatic step in the glycolytic pathway and is the main source of adenosine triphosphate (ATP) production in red blood cells. PKLR mutations lead to defective proteins that are hypothesized to reduce ATP levels in red cells, leading to hemolysis. Small molecule allosteric activation of PK-R resulting in increases in ATP and decreases in 2,3-diphosphoglycerate (2,3-DPG) in healthy volunteers has been observed with an earlier molecule, AG-348, the first small molecule PK-R activator to enter clinical trials (Yang et al. EHA 2015, S138). AG-519 is the second small molecule PK-R activator to enter clinical trials. AG-519 is a potent, highly selective and orally bioavailable PK-R activator devoid of the aromatase inhibitory effects that were observed with AG-348.AIMSAG-519 is currently being tested in a randomized, double-blind, phase 1 study in healthy volunteers (NCT02630927), with the objective of identifying a safe and pharmacodynamically active dose and schedule to support potential ongoing development in patients with PK deficiency. Here we report the first 4 cohorts of the multiple ascending dose (MAD) phase of this study. The single ascending dose (SAD) phase of the study and the first two cohorts of the MAD phase of the study have been reported previously (Barbier et al. EHA 2016, P752).METHODSHealthymen and women (non-childbearing potential) aged 18-60 years who provided informed consent were eligible. The MAD phase of the study consisted of 5 dose cohorts. The dose levels administered were determined during interim data reviews of each completed MAD cohort, as well as data from completed SAD cohorts. At each dose level, 8 subjects were enrolled and randomized to receive AG-519 (n=6) or placebo (n=2) twice daily (BID; approximately every 12 hours) for 14 days. Safety assessments included adverse events (AEs), vital signs, electrocardiogram and clinical laboratory parameters. Serial blood samples were drawn to measure plasma concentrations of AG-519 and whole blood concentrations of 2,3-DPG and ATP for pharmacokinetic and pharmacodynamic (PD) assessments.RESULTSData are available for 32 subjects enrolled across 4 dose cohorts in the MAD phase of the study: 8 subjects each in cohort 1 (125 mg BID), cohort 2 (375 mg BID), cohort 3 (25 mg BID), and cohort 4 (300 mg BID). Blinded safety reviews indicated that multiple doses up to 375 mg have been well tolerated with no serious AEs or dose-limiting toxicities reported to date. One case of probable drug-induced Grade 2 thrombocytopenia was previously reported in 1 subject in the 375 mg cohort; the event was rapidly reversible with no clinical sequelae. The protocol was amended to require daily monitoring of platelets in subsequent cohorts and no other subjects have developed thrombocytopenia during treatment. The preliminary analysis of free testosterone and estradiol confirmed the absence of aromatase inhibitory activity.AG-519 steady-state was reached the third day after the first dose based on trough concentration values. The clearance of AG-519 after multiple doses was similar to that observed after single doses in the SAD cohorts. Dose-dependent increases in ATP in blood (Figure 1) and decreases in 2,3-DPG in blood correlated with dose-dependent increases in exposure of AG-519, with a peak effect at or below 375 mg BID. ATP response at 25 mg appears to be greater than 50% of maximal response. Results from the fifth MAD cohort, which evaluated the PD results with 10 mg BID, will be presented.ATP = adenosine triphosphate; BID = twice dailyCONCLUSIONAG-519 is well tolerated in healthy subjects at doses ranging from 25 mg to 375 mg BID for 14 days. The robust dose-dependent changes in ATP and 2,3-DPG concentrations in blood from healthy volunteers are consistent with increased activity of PK-R, the expected PD effect of AG-519. These data support the hypothesis that AG-519 may be able to enhance glycolytic activity in red cells of patients with PK deficiency to address the underlying cause of the disease. [Display omitted] DisclosuresBarbier:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bodie:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Connor:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Le:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy.