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1.
Front Pharmacol ; 8: 740, 2017.
Article in English | MEDLINE | ID: mdl-29089894

ABSTRACT

Background: Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis. Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement. Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose) or placebo (n = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF). Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1-600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.

2.
Anesth Analg ; 124(3): 821-830, 2017 03.
Article in English | MEDLINE | ID: mdl-27622720

ABSTRACT

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.


Subject(s)
Biomedical Research/standards , Clinical Trials as Topic/standards , Endpoint Determination/standards , Hypnotics and Sedatives/standards , Patient Safety/standards , Patient-Centered Care/standards , Anesthesia/adverse effects , Anesthesia/standards , Biomedical Research/methods , Clinical Trials as Topic/methods , Congresses as Topic/standards , Conscious Sedation/methods , Conscious Sedation/standards , District of Columbia , Endpoint Determination/methods , Humans , Hypnotics and Sedatives/adverse effects , Hypnotics and Sedatives/therapeutic use , Patient Satisfaction , Patient-Centered Care/methods , Treatment Outcome
3.
J Pharmacol Exp Ther ; 354(3): 350-7, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26116630

ABSTRACT

LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.


Subject(s)
Antibodies, Monoclonal/pharmacology , Calcitonin Gene-Related Peptide/metabolism , Capsaicin/pharmacology , Regional Blood Flow/drug effects , Administration, Cutaneous , Adolescent , Adult , Animals , Biomarkers/metabolism , Double-Blind Method , Humans , Laser-Doppler Flowmetry/methods , Macaca fascicularis , Male , Middle Aged , Pain/drug therapy , Young Adult
5.
Lancet Neurol ; 13(9): 885-92, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25127173

ABSTRACT

BACKGROUND: Migraine remains poorly treated, with few effective preventive drugs available. We assessed the safety and efficacy of LY2951742, a fully humanised monoclonal antibody to calcitonin gene-related peptide, for migraine prevention. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 proof-of-concept study at 35 centres in the USA. Patients aged 18-65 years with four to 14 migraine headache days per month were randomly assigned (1:1) to LY2951742 or placebo by a computerised randomisation scheme. LY2951742 (150 mg) or placebo were given as a subcutaneous injection once every 2 weeks for 12 weeks. The primary endpoint was the mean change in number of migraine headache days per 28-day period assessed at 9-12 weeks. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Patients and treating investigators were masked to treatment allocation. Analyses were by intention to treat. A mixed-effects model of repeated measures was used, including patient baseline value, treatment, visit, and treatment-by-visit interaction as fixed effects, and patients as random effects. Safety measures were analysed according to the treatment received. This study has been completed and is registered with ClinicalTrials.gov, NCT01625988. FINDINGS: Between July 31, 2012, and Sept 18, 2013, 218 patients were randomly assigned to LY2951742 (n=108, but one patient withdrew before treatment) or placebo (n=110). The mean change from baseline to week 12 in the number of migraine headache days was -4·2 (SD 3·1; 62·5% decrease) in the LY2951742 group compared with -3·0 (SD 3·0; 42·3% decrease) in the placebo group (least-squares mean difference -1·2, 90% CI -1·9 to -0·6; p=0·0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs seven [6%] of 110), upper respiratory tract infections (18 [17%] vs ten [9%]), and abdominal pain (six [6%] vs three [3%]). There were two serious adverse events reported in the treatment arm and four in the placebo arm, none of which were deemed to be related to the study drug. INTERPRETATION: These results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of calcitonin gene-related peptide in the pathogenesis of migraine. Further controlled studies are needed to assess the safety and efficacy of monoclonal calcitonin gene-related peptide antibodies for the preventive treatment of migraine. FUNDING: Arteaus Therapeutics.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Migraine Disorders/prevention & control , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Calcitonin Gene-Related Peptide/immunology , Double-Blind Method , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Placebos , Time Factors , Treatment Outcome , Young Adult
6.
Anesthesiology ; 121(6): 1203-16, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25170571

ABSTRACT

BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. METHODS: CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. RESULTS: Compared with etomidate, CPMM was half as potent as a hypnotic (ED50 approximately 0.8 mg/kg), was more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 vs. 1,623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. CONCLUSION: The studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation.


Subject(s)
Anesthetics, Intravenous/pharmacology , Anesthetics, Intravenous/pharmacokinetics , Etomidate/analogs & derivatives , Etomidate/pharmacology , Etomidate/pharmacokinetics , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/pharmacokinetics , Adrenal Cortex/drug effects , Anesthesia , Animals , Area Under Curve , Behavior, Animal/drug effects , Chemistry, Pharmaceutical , Dogs , Male , Models, Statistical , Propofol/pharmacokinetics , Propofol/pharmacology
7.
Clin Cancer Res ; 19(21): 6020-9, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24045182

ABSTRACT

PURPOSE: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). EXPERIMENTAL DESIGN: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. RESULTS: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. CONCLUSIONS: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzoquinones/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Lactams, Macrocyclic/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sarcoma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Benzoquinones/pharmacology , Female , Gastrointestinal Neoplasms/mortality , Gastrointestinal Stromal Tumors/mortality , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Humans , Lactams, Macrocyclic/pharmacology , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology , Sarcoma/mortality , Treatment Outcome , Young Adult
8.
Leuk Lymphoma ; 52(12): 2308-15, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21851215

ABSTRACT

Abstract A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m(2) followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m(2). The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2-4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzoquinones/therapeutic use , Lactams, Macrocyclic/therapeutic use , Multiple Myeloma/drug therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzoquinones/adverse effects , Benzoquinones/pharmacokinetics , Female , Humans , Lactams, Macrocyclic/adverse effects , Lactams, Macrocyclic/pharmacokinetics , Male , Middle Aged , Recurrence , Treatment Outcome
9.
J Clin Oncol ; 28(33): 4953-60, 2010 Nov 20.
Article in English | MEDLINE | ID: mdl-20940188

ABSTRACT

PURPOSE: IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. RESULTS: Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). CONCLUSION: IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.


Subject(s)
Benzoquinones/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/therapeutic use , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Benzoquinones/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Female , Gene Rearrangement , Humans , Lactams, Macrocyclic/adverse effects , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Prospective Studies , Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases
10.
Blood ; 110(2): 678-85, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17395781

ABSTRACT

Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL-induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.


Subject(s)
Enzyme Inhibitors/pharmacology , Fusion Proteins, bcr-abl/genetics , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Hematopoietic Stem Cells/pathology , Leukemia, Experimental/pathology , Protein-Tyrosine Kinases/antagonists & inhibitors , Amino Acid Substitution , Animals , Cell Line, Tumor , Hematopoietic Stem Cells/drug effects , Leukemia, Experimental/drug therapy , Leukemia, Experimental/genetics , Mice , Survival Analysis
11.
Proc Natl Acad Sci U S A ; 103(46): 17408-13, 2006 Nov 14.
Article in English | MEDLINE | ID: mdl-17090671

ABSTRACT

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , HSP90 Heat-Shock Proteins/metabolism , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacokinetics , Benzoquinones/pharmacokinetics , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Lactams, Macrocyclic/pharmacokinetics , Mice , Mice, Inbred BALB C , Microsomes, Liver/drug effects , Neoplasms/pathology , Xenograft Model Antitumor Assays
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