33 results on '"Colby S. Shemesh"'
Search Results
2. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations
- Author
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Vincent Lemaire, Colby S. Shemesh, and Anand Rotte
- Subjects
Clinical trials ,Cancer immunotherapy ,Combination development ,Cancer ,Pharmacology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The success of antibodies targeting Programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in cancer treatment and the need for improving response rates has led to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone. As more and more drugs with translational potential are identified, the number of clinical trials evaluating combinations has increased considerably and the demand to prioritize combinations having potential for success over the ones that are unlikely to be successful is rising. This review aims to address the unmet need to prioritize cancer immunotherapy combinations through comprehensive search of potential drugs and ranking them based on their mechanism of action, clinical efficacy and safety. As lung cancer is one of the most frequently studied cancer types, combinations that showed potential for the treatment of lung cancer were prioritized. A literature search was performed to identify drugs with potential in combination with PD-1/PD-L1 blockers and the drugs were ranked based on their mechanism of action and known clinical efficacy. Nineteen drugs or drug classes were identified from an internal list of lead molecules and were scored for their clinical potential. Efficacy and safety data from pivotal studies was summarized for the selected drugs. Further, overlap of mechanisms of action and adverse events was visualized using a heat map illustration to help screen drugs for combinations. The quantitative scoring methodology provided in this review could serve as a template for preliminary ranking of novel combinations.
- Published
- 2021
- Full Text
- View/download PDF
3. Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors
- Author
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Weize Huang, Felix Stader, Phyllis Chan, Colby S. Shemesh, Yuan Chen, Katherine L. Gill, Hannah M. Jones, Linzhong Li, Gianluca Rossato, Benjamin Wu, Jin Y. Jin, and Pascal Chanu
- Subjects
alveolar soft part sarcoma ,atezolizumab ,physiologically-based pharmacokinetic (PBPK) modeling ,pediatric extrapolation ,pediatric oncology ,solid tumor ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients.Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations.Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old.Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults.Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.
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- 2022
- Full Text
- View/download PDF
4. Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region
- Author
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Colby S. Shemesh, Phyllis Chan, Hui Shao, Derek-Zhen Xu, Daniel Combs, Shweta Vadhavkar, René Bruno, and Benjamin Wu
- Subjects
atezolizumab ,bevacizumab ,hepatic impairment ,geographic region ,clinical pharmacology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.
- Published
- 2021
- Full Text
- View/download PDF
5. Integrated Two‐Analyte Population Pharmacokinetic Model of Polatuzumab Vedotin in Patients With Non‐Hodgkin Lymphoma
- Author
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Dan Lu, Tong Lu, Leonid Gibiansky, Xiaobin Li, Chunze Li, Priya Agarwal, Colby S. Shemesh, Rong Shi, Randall C. Dere, Jamie Hirata, Dale Miles, Pascal Chanu, Sandhya Girish, and Jin Yan Jin
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.
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- 2020
- Full Text
- View/download PDF
6. Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer
- Author
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Colby S. Shemesh, Pascal Chanu, Kris Jamsen, Russ Wada, Gianluca Rossato, Francis Donaldson, Amit Garg, Helen Winter, Jane Ruppel, Xin Wang, Rene Bruno, Jin Jin, and Sandhya Girish
- Subjects
Atezolizumab ,Cancer immunotherapy ,Clinical pharmacology ,Exposure-safety ,Immune checkpoint inhibitor ,Pediatric oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Methods Patients aged
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- 2019
- Full Text
- View/download PDF
7. Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden
- Author
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Colby S. Shemesh, Phyllis Chan, Fatema A. Legrand, David S. Shames, Meghna Das Thakur, Jane Shi, Lorna Bailey, Shweta Vadhavkar, Xian He, Wei Zhang, and René Bruno
- Subjects
atezolizumab ,biomarkers ,clinical pharmacology ,mutation ,pharmacokinetics ,tumor ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract We retrospectively investigated the pharmacokinetics and exposure‐efficacy/safety relationships of single‐agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs
- Published
- 2020
- Full Text
- View/download PDF
8. Assessment of the Drug Interaction Potential of Unconjugated and GalNAc3-Conjugated 2′-MOE-ASOs
- Author
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Colby S. Shemesh, Rosie Z. Yu, Mark S. Warren, Michael Liu, Mirza Jahic, Brandon Nichols, Noah Post, Song Lin, Daniel A. Norris, Eunju Hurh, Jane Huang, Tanya Watanabe, Scott P. Henry, and Yanfeng Wang
- Subjects
antisense oligonucleotides ,pharmacokinetics ,drug interaction ,metabolism ,transport ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2′-O-(2-methoxyethyl)-modified antisense oligonucleotides (2′-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2′-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored. The inhibition on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 and induction on CYP1A2, CYP2B6, and CYP3A4 were investigated in cryopreserved hepatocytes using up to 100 μM of each ASO. No significant inhibition (half maximal inhibitory concentration [IC50] > 100 μM) or induction was observed based on either enzymatic phenotype or mRNA levels. In addition, transporter interaction studies were conducted with nine major transporters per recommendations from regulatory guidances and included three hepatic uptake transporters, organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3; three renal uptake transporters, organic anion transporter 1 (OAT1), OAT3, and OCT2; and three efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP). None of the four ASOs (10 μM) were substrates of any of the nine transporters, with uptake
- Published
- 2017
- Full Text
- View/download PDF
9. Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform
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Andrew H Ko, Kyu-Pyo Kim, Jens T Siveke, Charles D Lopez, Jill Lacy, Eileen M O’Reilly, Teresa Macarulla, Gulam A Manji, Jeeyun Lee, Jaffer Ajani, Maria Alsina Maqueda, Sun-Young Rha, Janet Lau, Nedal Al-Sakaff, Simon Allen, Danny Lu, Colby S Shemesh, Xinxin Gan, Edward Cha, and Do-Youn Oh
- Subjects
Cancer Research ,Oncology - Abstract
BackgroundThe MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20).MethodsIn 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety.ResultsIn MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred.ConclusionAtezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent’s known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).
- Published
- 2023
10. Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities
- Author
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Iraj Hosseini, Patrick Twomey, Colby S. Shemesh, Sandhya Girish, Anand Rotte, Joy C. Hsu, Ben-Quan Shen, and Benjamin Wu
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T-Lymphocytes ,medicine.medical_treatment ,Review ,Bioinformatics ,Cancer Vaccines ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Drug Development ,Cancer immunotherapy ,Antigens, Neoplasm ,law ,Neoplasms ,Drug Discovery ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Dosing ,Precision Medicine ,Molecular Biology ,030304 developmental biology ,Pharmacology ,Clinical Trials as Topic ,0303 health sciences ,Clinical pharmacology ,business.industry ,Cancer ,Dendritic Cells ,medicine.disease ,Clinical trial ,Drug development ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunotherapy ,business ,Adjuvant - Abstract
Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8(+) and CD4(+) T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.
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- 2021
11. Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer
- Author
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Russ Wada, Kris M. Jamsen, Sandhya Girish, Colby S. Shemesh, Helen Winter, Xin Wang, Jane Ruppel, Gianluca Rossato, Rene Bruno, Pascal Chanu, Francis Donaldson, Amit Garg, and Jin Jin
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Cancer immunotherapy ,Pediatric oncology ,Immune checkpoint inhibitor ,law.invention ,0302 clinical medicine ,law ,Neoplasms ,Immunology and Allergy ,Population pharmacokinetics ,Young adult ,Atezolizumab ,Child ,Volume of distribution ,Clinical pharmacology ,Immunogenicity ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Progression-Free Survival ,Treatment Outcome ,Exposure-safety ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Molecular Medicine ,Female ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Models, Biological ,lcsh:RC254-282 ,03 medical and health sciences ,Young Adult ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Dosing ,Pharmacology ,business.industry ,Cancer ,Infant ,medicine.disease ,030104 developmental biology ,business - Abstract
Background The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Methods Patients aged
- Published
- 2019
12. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations
- Author
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Colby S. Shemesh, Vincent Lemaire, and Anand Rotte
- Subjects
Drug ,Cancer Research ,media_common.quotation_subject ,medicine.medical_treatment ,Antineoplastic Agents ,Cancer immunotherapy ,Review ,Treatment of lung cancer ,Bioinformatics ,Clinical trials ,Neoplasms ,medicine ,Animals ,Humans ,Combination development ,Lung cancer ,Adverse effect ,RC254-282 ,Cancer ,media_common ,Pharmacology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Clinical trial ,Pharmaceutical Preparations ,Oncology ,Mechanism of action ,Drug Therapy, Combination ,Immunotherapy ,medicine.symptom ,business - Abstract
The success of antibodies targeting Programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in cancer treatment and the need for improving response rates has led to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone. As more and more drugs with translational potential are identified, the number of clinical trials evaluating combinations has increased considerably and the demand to prioritize combinations having potential for success over the ones that are unlikely to be successful is rising. This review aims to address the unmet need to prioritize cancer immunotherapy combinations through comprehensive search of potential drugs and ranking them based on their mechanism of action, clinical efficacy and safety. As lung cancer is one of the most frequently studied cancer types, combinations that showed potential for the treatment of lung cancer were prioritized. A literature search was performed to identify drugs with potential in combination with PD-1/PD-L1 blockers and the drugs were ranked based on their mechanism of action and known clinical efficacy. Nineteen drugs or drug classes were identified from an internal list of lead molecules and were scored for their clinical potential. Efficacy and safety data from pivotal studies was summarized for the selected drugs. Further, overlap of mechanisms of action and adverse events was visualized using a heat map illustration to help screen drugs for combinations. The quantitative scoring methodology provided in this review could serve as a template for preliminary ranking of novel combinations. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02111-5.
- Published
- 2021
13. Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region
- Author
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Phyllis Chan, Benjamin Wu, Colby S. Shemesh, Shweta Vadhavkar, Derek-Zhen Xu, Daniel Combs, Rene Bruno, and Hui Shao
- Subjects
atezolizumab ,medicine.medical_specialty ,hepatic impairment ,Bevacizumab ,Bilirubin ,Population ,bevacizumab ,Gastroenterology ,chemistry.chemical_compound ,Pharmacokinetics ,Atezolizumab ,Internal medicine ,medicine ,Adverse effect ,education ,RC254-282 ,education.field_of_study ,geographic region ,Hepatology ,business.industry ,Organ dysfunction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Oncology ,chemistry ,Hepatocellular carcinoma ,clinical pharmacology ,medicine.symptom ,business ,medicine.drug ,Research Article - Abstract
Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.
- Published
- 2021
14. Application of a Two-Analyte Integrated Population Pharmacokinetic Model to Evaluate the Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Polatuzumab Vedotin in Patients with Non-Hodgkin Lymphoma
- Author
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Rong Shi, Leonid Gibiansky, Chunze Li, Jin Yan Jin, Colby S. Shemesh, Pascal Chanu, Tong Lu, Jamie Hirata, Dan Lu, Uzor Ogbu, Sandhya Girish, Dale Miles, Priya Agarwal, and Randall C. Dere
- Subjects
Male ,Oncology ,Immunoconjugates ,Pharmaceutical Science ,030226 pharmacology & pharmacy ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,population pharmacokinetics ,Obinutuzumab ,Medicine ,Drug Dosage Calculations ,Pharmacology (medical) ,Aged, 80 and over ,Clinical Trials as Topic ,education.field_of_study ,non-Hodgkin lymphoma ,Lymphoma, Non-Hodgkin ,Age Factors ,Antibodies, Monoclonal ,Middle Aged ,integrated two-analyte ,Polatuzumab vedotin ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Rituximab ,Research Paper ,Biotechnology ,medicine.drug ,Adult ,Bendamustine ,medicine.medical_specialty ,Population ,Models, Biological ,antibody-drug conjugate ,Young Adult ,03 medical and health sciences ,Sex Factors ,Pharmacokinetics ,Internal medicine ,Humans ,Computer Simulation ,Clinical significance ,Dosing ,education ,Aged ,Pharmacology ,business.industry ,Body Weight ,Organic Chemistry ,chemistry ,business - Abstract
Purpose The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. Methods Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. Results No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100–146 kg versus 38–versus versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. Conclusions In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100–146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.
- Published
- 2020
15. Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden
- Author
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Xian He, David S. Shames, Wei Zhang, Meghna Das Thakur, Jane Shi, Fatema A. Legrand, Phyllis Chan, Rene Bruno, Shweta Vadhavkar, Colby S. Shemesh, and Lorna Bailey
- Subjects
Oncology ,Male ,030226 pharmacology & pharmacy ,law.invention ,0302 clinical medicine ,law ,Neoplasms ,General Pharmacology, Toxicology and Pharmaceutics ,Aged, 80 and over ,education.field_of_study ,Clinical pharmacology ,Middle Aged ,Tumor Burden ,Treatment Outcome ,Neurology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Original Article ,Female ,pharmacokinetics ,atezolizumab ,Adult ,medicine.medical_specialty ,tumor ,Population ,Antineoplastic Agents ,RM1-950 ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,Young Adult ,Pharmacokinetics ,Atezolizumab ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Adverse effect ,education ,Aged ,Retrospective Studies ,Dose-Response Relationship, Drug ,business.industry ,biomarkers ,Original Articles ,Clinical trial ,Regimen ,Mutation ,Therapeutics. Pharmacology ,clinical pharmacology ,business - Abstract
We retrospectively investigated the pharmacokinetics and exposure‐efficacy/safety relationships of single‐agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs, In this work, we show that tissue tumor mutational burden (tTMB) is a biomarker of efficacy with the immune checkpoint inhibitor atezolizumab. The analyses herein support a role for atezolizumab monotherapy in a tumor‐agnostic high‐tTMB population.
- Published
- 2020
16. Assessment of the Drug Interaction Potential of Unconjugated and GalNAc3-Conjugated 2′-MOE-ASOs
- Author
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Song Lin, Michael Liu, Tanya Watanabe, Colby S. Shemesh, Eunju Hurh, Mirza Jahic, Jane Huang, Rosie Z. Yu, Mark S. Warren, Noah Post, Brandon S. Nichols, Scott P. Henry, Daniel A. Norris, and Yanfeng Wang
- Subjects
0301 basic medicine ,drug interaction ,Organic cation transport proteins ,CYP3A4 ,Organic anion transporter 1 ,biology ,Chemistry ,lcsh:RM1-950 ,Cytochrome P450 ,Transporter ,Drug interaction ,Pharmacology ,Organic anion-transporting polypeptide ,03 medical and health sciences ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,Biochemistry ,Drug Discovery ,transport ,biology.protein ,Molecular Medicine ,Asialoglycoprotein receptor ,antisense oligonucleotides ,pharmacokinetics ,metabolism - Abstract
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2′-O-(2-methoxyethyl)-modified antisense oligonucleotides (2′-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2′-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored. The inhibition on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 and induction on CYP1A2, CYP2B6, and CYP3A4 were investigated in cryopreserved hepatocytes using up to 100 μM of each ASO. No significant inhibition (half maximal inhibitory concentration [IC50] > 100 μM) or induction was observed based on either enzymatic phenotype or mRNA levels. In addition, transporter interaction studies were conducted with nine major transporters per recommendations from regulatory guidances and included three hepatic uptake transporters, organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3; three renal uptake transporters, organic anion transporter 1 (OAT1), OAT3, and OCT2; and three efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP). None of the four ASOs (10 μM) were substrates of any of the nine transporters, with uptake
- Published
- 2017
17. 267P Phase Ib/II open-label, randomized evaluation of second- or third-line (2L/3L) atezolizumab (atezo) + entinostat (entino) in MORPHEUS-HR+ breast cancer (M-HR+BC)
- Author
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J. Xu, Kyunghun Lee, Edward Cha, Hope S. Rugo, F. Bene Tchaleu, Colby S. Shemesh, Melinda L. Telli, Antoinette R. Tan, S-A. Im, Kelly DuPree, Jin Zhu, Shlomit S. Shachar, Xiaosong Zhang, Amir Sonnenblick, and M. Nikanjam
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Entinostat ,Hematology ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Third line ,chemistry ,Atezolizumab ,Internal medicine ,Medicine ,Open label ,business - Published
- 2021
18. Abstract CT185: Assessment of the impact of anti-drug antibodies on PK and clinical outcomes with atezolizumab + bevacizumab in HCC
- Author
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Michel Ducreux, Andrew X. Zhu, Colby S. Shemesh, Ann-Lii Cheng, Sven Stanzel, Richard S. Finn, Coen Bernaards, Wendy Verret, Peter R. Galle, Alexandr Vilimovskij, and Ning Ma
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Drug ,Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,biology ,business.industry ,media_common.quotation_subject ,Incidence (epidemiology) ,Cancer ,medicine.disease ,Cmin ,Atezolizumab ,Internal medicine ,medicine ,biology.protein ,Disease characteristics ,Antibody ,business ,medicine.drug ,media_common - Abstract
Background: Atezo + bev is the standard of care for pts with unresectable HCC and no prior systemic therapy. We report on post hoc exploratory analyses of the immune response to atezo and the impact assessment of ADAs on PK and clinical outcomes in the Ph 3 study IMbrave150. Methods: ADAs were assessed using an industry-standard validated test and sampling frequencies. We report tx-emergent ADA incidence and adjusted efficacy by ADA status at landmark Wk 6, adjusted for imbalances in BL health and disease characteristics using IPW. PK and safety by ADA status were also evaluated. Results: An assessment of BL characteristics in ADA+ (n=94) vs ADA− (n=224) pts showed a higher rate of negative HCC prognostic factors, including CPS A6, BCLC Stage C and MVI in ADA+ pts. ADA− pts had a higher rate of EHS. There was considerable overlap in exposure distributions across ADA+ and ADA− pts. Despite the trend for a 38.4% lower Cycle 1 Cmin in ADA+ vs ADA− pts, at any time during tx, 93% of ADA+ and 99% of ADA− pts had Cmin ≥6 μg/mL (target exposure). Per OS adjustment modeling analyses: HR=0.96 (95% CI 0.62-1.48) for ADA+ (n=61.7) and HR=0.55 (95% CI 0.41-0.74) for ADA− pts (n=242.3) with atezo + bev vs sor. Adjusted PFS and ORR results were similar between ADA subgroups (table). Among ADA+ (n=88) and ADA− pts (n=227), G3-4 AEs occurred in 64% and 53% of pts, G5 AEs in 8% and 3% of pts and SAEs in 52% and 32% of pts, respectively. Conclusions: Most pts achieved atezo target exposure regardless of ADAs. ADA+ pts had a similar OS while ADA− pts had improved OS with atezo + bev vs sor. PFS and ORR benefits vs sor were clinically meaningful and similar between ADA subgroups. While there were some numerical differences in AE rates between ADA+ and ADA− pts, ADAs did not have a clinically significant effect on the incidence or severity of AEs. In ITT pts, a statistically significant OS benefit and overall favorable benefit-risk balance with atezo + bev have been established in HCC, and the combination has been approved in over 60 countries. PFS- and ORR-adjusted analyses at landmark Wk 6ADA+ADA−IRF PFS per RECIST 1.1n51223HR (95% CI) for atezo + bev vs sor0.59 (0.39-0.91)0.60 (0.47-0.77)IRF ORR per RECIST 1.1n61.7232.3ORR difference for atezo + bev vs sor (95% CI), %19 (6-32)19 (10-28)318 pts were evaluable post BL and therefore were included in these analyses. Efficacy data cutoff: Aug 31, 2020. Safety data cutoff: Aug 29, 2019. Methods and results from IMbrave150 (Ph 3; NCT03434379) have been published (Finn et al NEJM 2020). ADA, anti-drug antibody; AE, adverse event; atezo, atezolizumab; BCLC, Barcelona Clinic Liver Cancer; bev, bevacizumab; BL, baseline; Cmin, minimum blood plasma concentration; CPS, Child-Pugh score; EHS, extrahepatic spread; G, grade; HCC, hepatocellular carcinoma; IPW, inverse probability weighting; IRF, independent review facility; ITT, intent to treat; MVI, macrovascular invasion; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Ph, Phase; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; sor, sorafenib; tx, treatment. Citation Format: Peter R. Galle, Richard S. Finn, Ann-Lii Cheng, Coen Bernaards, Colby S. Shemesh, Alexandr Vilimovskij, Wendy J. Verret, Sven F. Stanzel, Ning Ma, Michel Ducreux, Andrew X. Zhu. Assessment of the impact of anti-drug antibodies on PK and clinical outcomes with atezolizumab + bevacizumab in HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT185.
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- 2021
19. Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + Imprime PGG (Imprime) + bevacizumab (bev) vs regorafenib (rego) in MORPHEUS: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)
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Edward Cha, Rachael A Safyan, Colby S. Shemesh, Stefan Zimmermann, Lorna Bailey, Christelle Lenain, Jochen Schulze, Simon Allen, Danny Lu, Yong Sang Hong, James M. Cleary, Tae-You Kim, and Marwan Fakih
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Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Colorectal cancer ,business.industry ,Imprime PGG ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Atezolizumab ,Microsatellite Stable ,Internal medicine ,Regorafenib ,medicine ,Open label ,business ,medicine.drug - Abstract
3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers. Here, atezo (anti-PD-L1) was tested with Imprime and bev (anti-VEGF) for MSS mCRC, a poorly immunogenic cancer generally resistant to checkpoint inhibitors. Imprime acts as a pathogen-associated molecular pattern that, when bound to anti-β glucan antibodies (ABA), activates the innate immune system with the potential to 1) promote priming and expansion of tumor-specific T cells, 2) promote M2-M1 macrophage polarization and 3) enhance the immunomodulatory effects of atezo and bev. Therefore, we hypothesized that atezo + Imprime + bev would induce an antitumor response beyond that of rego, a standard-of-care multikinase inhibitor, in patients (pts) with MSS mCRC. Methods: Pts with MSS mCRC unselected for the Imprime-specific biomarker (ABA) and refractory to 1-2 prior lines of standard therapy received atezo (1200 mg IV every 3 weeks [q3w]) + Imprime (4 mg/kg IV on Days 1, 8, 15) + bev (7.5 mg/kg IV q3w) or control tx with rego (160 mg orally days 1-21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included disease control rate (DCR; response or stable disease ≥ 12 weeks), progression-free survival (PFS), overall survival (OS) and safety. Results: Pts were followed-up for ≥18 wk. 15 pts received atezo + Imprime + bev and 13 received rego. Grade (Gr) 3/4 tx-related adverse events (TRAEs) were seen in 13% of atezo + Imprime + bev and 62% of rego pts. No Gr 5 AEs occurred in atezo + Imprime + bev pts and 1 (8%) was reported in a rego pt. One pt in each arm (7% vs 8%, respectively) withdrew from tx due to a TRAE. No radiological responses were seen in either arm. Five pts (33%) receiving atezo + Imprime + bev and 8 (62%) receiving rego had stable disease as best response. DCR was 13% with atezo + Imprime + bev and 23% with rego. Median PFS was 1.5 mo (95% CI: 1.4, 2.8) and 2.8 mo (95% CI: 1.6, 3.1), and median OS was 5.7 mo (95% CI: 4.4, 10.5) and 10.2 mo (95% CI: 4.8, NE) with atezo + Imprime + bev and rego, respectively. There was no apparent correlation between baseline PD-L1 expression or CD8+ lymphocyte tumor infiltration and clinical benefit. Further, the systemic exposure of atezo, Imprime and bev and immunogenicity of atezo and bev are in line with previous clinical experience. Additional biomarker, pharmacokinetics and anti-drug antibody data will be shown. Conclusions: Atezo + Imprime + bev was well tolerated; toxicities were consistent with the safety profiles of the individual agents. No efficacy signal was identified with atezo + Imprime + bev in pts with MSS refractory mCRC. Clinical trial information: NCT03555149.
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- 2021
20. Integrated Two-Analyte Population Pharmacokinetic Model of Polatuzumab Vedotin in Patients With Non-Hodgkin Lymphoma
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Jin Yan Jin, Jamie Hirata, Leonid Gibiansky, Rong Shi, Randall C. Dere, Sandhya Girish, Tong Lu, Priya Agarwal, Xiaobin Li, Chunze Li, Pascal Chanu, Dan Lu, Colby S. Shemesh, and Dale Miles
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Oncology ,medicine.medical_specialty ,Analyte ,Immunoconjugates ,Time Factors ,Population ,Models, Biological ,Article ,chemistry.chemical_compound ,Pharmacokinetics ,Internal medicine ,Covariate ,medicine ,Humans ,Pharmacology (medical) ,In patient ,education ,education.field_of_study ,Clinical Trials as Topic ,business.industry ,Lymphoma, Non-Hodgkin ,Research ,lcsh:RM1-950 ,Antibodies, Monoclonal ,Articles ,medicine.disease ,Lymphoma ,Polatuzumab vedotin ,lcsh:Therapeutics. Pharmacology ,Monomethyl auristatin E ,chemistry ,Modeling and Simulation ,Linear Models ,business - Abstract
A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.
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- 2019
21. Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study
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Lynley V. Marshall, Katherine E. Hutchinson, Jean Michon, Minlei Liao, H.N. Caron, Colby S. Shemesh, Michela Casanova, Gianluca Rossato, Mufiza Farid-Kapadia, Nadège Corradini, Francis Donaldson, C. Michel Zwaan, Tanya M. Trippett, Birgit Geoerger, Franck Bourdeaut, and Pediatrics
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Population ,Antineoplastic Agents ,Disease ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Atezolizumab ,Internal medicine ,Neoplasms ,medicine ,Humans ,Tissue Distribution ,Young adult ,Adverse effect ,education ,Child ,education.field_of_study ,business.industry ,Lymphoma, Non-Hodgkin ,medicine.disease ,Prognosis ,Hodgkin Disease ,Lymphoma ,Clinical trial ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Monoclonal ,Female ,business ,Follow-Up Studies - Abstract
Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.F Hoffmann-La Roche.
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- 2019
22. iMATRIX-Atezolizumab, a Phase 1/2 Study of the Safety, Pharmacokinetics, and Activity of Atezolizumab in Paediatric/Young Adult Patients with Previously Treated Solid Tumours
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Gianluca Rossato, Francis Donaldson, Jean Michon, Lynley V. Marshall, Nadège Corradini, C. Michel Zwaan, Colby S. Shemesh, H.N. Caron, Franck Bourdeaut, Katherine E. Hutchinson, Tanya M. Trippett, Michela Casanova, Minlei Liao, Birgit Geoerger, and Mufiza Farid-Kapadia
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Clinical trial ,medicine.medical_specialty ,Pharmacokinetics ,Informed consent ,Atezolizumab ,business.industry ,Internal medicine ,Good clinical practice ,medicine ,Young adult ,business ,Adverse effect ,Institutional review board - Abstract
Background: Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anticancer T-cell activity. The iMATRIX-atezolizumab study (phase 1/2, multicentre, open-label; NCT02541604) is the first trial to evaluate the safety, pharmacokinetics, and activity of atezolizumab in paediatric/young adult patients with refractory/relapsed solid tumours, with known or expected PD-L1 expression. Methods: Patients received atezolizumab on day 1 of each 3-week cycle until disease progression (PD)/loss of clinical benefit. Patients
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- 2019
23. 1315P Phase Ib/II open-label, randomised evaluation of atezolizumab (atezo) + CPI-444 vs docetaxel as second/third-line therapy in MORPHEUS-NSCLC (non-small cell lung cancer)
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Ben Solomon, Melissa Lynne Johnson, Simon Allen, Pakeeza Sayyed, Lorna Bailey, Mary O'Brien, J. Pintoffl, Bhumsuk Keam, A. Swalduz, Victor Moreno, J. Mazieres, Farah Louise Lim, E. Felip, H-J. Helms, N. Al-Sakaff, Sarah B. Goldberg, Colby S. Shemesh, Fabrice Barlesi, Byoung Chul Cho, and Valentina Boni
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Oncology ,medicine.medical_specialty ,business.industry ,Third-line therapy ,Hematology ,Docetaxel ,Atezolizumab ,Internal medicine ,medicine ,Non small lung cancer ,Open label ,business ,medicine.drug - Published
- 2020
24. SO-4 phase Ib/II, open-label, randomised evaluation of atezolizumab plus RO6874281 vs control in MORPHEUS–pancreatic ductal adenocarcinoma
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A. Alistar, A. Retiere, Kyu-Pyo Kim, Charles D. Lopez, Ben George, Xiaosong Zhang, Vincent Chung, Hedy L. Kindler, Colby S. Shemesh, D-Y. Oh, Hila Barak, Volker Teichgräber, Bo Ci, Janet Lau, and Simon Allen
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medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,Oncology ,Atezolizumab ,business.industry ,Urology ,medicine ,Hematology ,Open label ,business - Published
- 2020
25. Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + PEGPH20 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC)
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Anne-Cecile Retiere, Jill Lacy, Do-Youn Oh, Andrew H. Ko, Jens T. Siveke, N. Al-Sakaff, Colby S. Shemesh, Simon Allen, Jaffer A. Ajani, Kyu-Pyo Kim, Charles D. Lopez, Janet Lau, Hyun Cheol Chung, Maria Alsina, Xiaosong Zhang, Yung-Jue Bang, Hila Barak, Eileen M. O'Reilly, Jeeyun Lee, and S. Li
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,Atezolizumab ,business.industry ,Internal medicine ,Medicine ,Cancer ,Open label ,business ,medicine.disease - Abstract
4540 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti–PD-L1) was tested with PEGylated recombinant human hyaluronidase (PEGPH20), an anti–stromal and extracellular matrix modulator, in patients (pts) with metastatic (m) PDAC or advanced/mGC. Methods: In 2 separate randomized trials, eligible pts with 2L mPDAC or mGC received atezo (1200 mg IV q3w) + PEGPH20 (3 µg/kg IV on D1, 8, 15). Control tx for M-PDAC (NCT03193190) was mFOLFOX6 or gemcitabine + nab-paclitaxel. In M-GC (NCT03281369), control tx was ramucirumab + paclitaxel. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. Results: Pts were followed up for ≥ 18 wk in M-PDAC (data cutoff: Aug 5, 2019) and ≥ 24 wk in M-GC (data cutoff, Jul 11, 2019). In M-PDAC, 66 pts received atezo + PEGPH20 and 42 received control in both preliminary and expansion phases. Confirmed ORRs were 6.1% (95% CI: 1.7, 14.8) and 2.4% (95% CI: 0.06, 12.6), respectively. Duration of response ranged from 5.3 to 11.3 mo in tx arm and was 3.9 mo in control. Median PFS was 1.5 mo (95% CI: 1.4, 2.6) and 2.3 mo (95% CI: 1.6, 4.0), respectively. Median OS was 7.1 mo (95% CI: 4.6, 9.5) and 6.8 mo (95% CI: 5.6, 8.3). Updated survival data will be presented. Respectively, 62.2% and 59.5% of pts had Gr 3-4 AEs; Gr 5 AEs were seen in 4.5% and 2.4% of pts; serious AEs (SAEs) occurred in 45.5% and 45.2% of pts; 16.7% and 4.8% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were myalgia (65.2%) and peripheral edema (28.8%) in the combination arm. In M-GC, 13 pts received atezo + PEGPH20 and 12 received control. Confirmed ORRs were 0% (95% CI: 0, 24.7) and 16.7% (95% CI: 2.1, 48.4), respectively. Gr 3-4 AEs were seen in 30.8% and 75.0% of pts, respectively. No Gr 5 AEs occurred in either arm. SAEs occurred in 7.7% and 50.0% of pts, respectively. Only 1 pt in the control arm had a tx-related AE leading to tx withdrawal. While tumor hyaluronan (HA) appears to be associated with poor prognosis in the M-PDAC control, there was no clear association between HA levels and response to atezo + PEGPH20. PK data will also be presented. Conclusions: Limited efficacy was seen with the chemotherapy-free combination of atezo + PEGPH20 in PDAC. No efficacy was seen in GC. The safety of atezo + PEGPH20 was consistent with each agent’s known safety profile; no new safety signals were identified. Clinical trial information: NCT03193190 .
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- 2020
26. Thermosensitive Liposome Formulated Indocyanine Green for Near-Infrared Triggered Photodynamic Therapy: In Vivo Evaluation for Triple-Negative Breast Cancer
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Delaram Moshkelani, Hailing Zhang, and Colby S. Shemesh
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Indocyanine Green ,medicine.medical_treatment ,Mice, Nude ,Pharmaceutical Science ,Triple Negative Breast Neoplasms ,Photodynamic therapy ,chemistry.chemical_compound ,Breast cancer ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Photosensitizer ,Breast ,Triple-negative breast cancer ,Fluorescent Dyes ,Pharmacology ,Liposome ,Photosensitizing Agents ,business.industry ,Optical Imaging ,Organic Chemistry ,Near-infrared spectroscopy ,Temperature ,medicine.disease ,eye diseases ,Photochemotherapy ,chemistry ,Delayed-Action Preparations ,Liposomes ,Cancer research ,Molecular Medicine ,Female ,business ,Indocyanine green ,Biotechnology - Abstract
The focus of this research was to formulate and evaluate a theranostic liposomal delivery system using indocyanine green (ICG) as a photosensitizer, triggered by near infrared (NIR) irradiation, for in vivo photodynamic therapy (PDT) of breast cancer.Cytotoxicity of PDT using liposomal ICG (LPICG) as well as free ICG (FRICG) was evaluated in the human MDA-MB-468 triple-negative breast cancer (TNBC) cell line. NIR irradiation-induced increase in temperature was also monitored both in vitro and in vivo. Quantitative pharmacokinetic profile and fluorescence imaging-based biodistribution patterns of both formulations were obtained using the human TNBC xenograft model in nude mice. Overall safety, tolerability, and long-term anti-tumor efficacy of LPICG versus FRICG-mediated PDT was evaluated.Significant loss of cell viability was achieved following photoactivation of LPICG via NIR irradiation. Temperatures of irradiated LPICG increased with increasing concentrations of loaded ICG, which correlated with significant rise of temperature compared to PBS in vivo (p 0.01). Pharmacokinetic assessment revealed a significant increase in systemic distribution and circulation half-life of LPICG, and NIR fluorescence imaging demonstrated enhanced accumulation of liposomes within the tumor region. Tumor growth in mice treated with LPICG followed by NIR irradiation was significantly reduced compared to those treated with FRICG, saline, and irradiation alone.In vivo photodynamic therapy using LPICG demonstrated targeted biodistribution and superior anti-tumor efficacy in a human TNBC xenograft model compared to FRICG. In addition, this unique delivery system exhibited a promising role in NIR image-guided delivery and real-time biodistribution monitoring of formulation with ICG serving as the fluorescent probe.
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- 2014
27. Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice
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Yanfeng Wang, Hans Gaus, Richard S. Geary, Frank C. Bennett, Punit P. Seth, Scott P. Henry, Colby S. Shemesh, Eric E. Swayze, and Rosie Z. Yu
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0301 basic medicine ,Enzyme-Linked Immunosorbent Assay ,Plasma protein binding ,Pharmacology ,Biochemistry ,alpha-2-Macroglobulin ,03 medical and health sciences ,Subcutaneous injection ,Mice ,Pharmacokinetics ,Drug Discovery ,Genetics ,Animals ,Humans ,Scavenger receptor ,Molecular Biology ,Gel electrophoresis ,Mice, Knockout ,Messenger RNA ,biology ,Oligonucleotide ,Chemistry ,Genetic Therapy ,Oligonucleotides, Antisense ,Scavenger Receptors, Class B ,Pregnancy-Associated alpha 2-Macroglobulins ,030104 developmental biology ,Gene Expression Regulation ,Liver ,biology.protein ,Hepatocytes ,Molecular Medicine ,Serum Globulins - Abstract
To investigate the pharmacokinetics (PKs) and pharmacodynamics (PDs) for ION-353382, an antisense oligonucleotide (ASO) targeting scavenger receptor class B type I (SRB1) mRNA, using alpha-2-macroglobulin (A2M), murinoglobulin double-knockout (DKO), and wild-type mice. Wild-type and DKO homozygous mice were administered a single subcutaneous injection of ION-353382 at 0, 5, 15, 30, and 60 mg/kg. Mice were sacrificed at 72 h with plasma and organs harvested. Both liquid chromatography-mass spectrometry (LC-MS) and enzyme-linked immunosorbent assay (ELISA) were used to determine ASO exposure with real-time PCR for SRB1 expression. Immunohistochemistry was evaluated to explore hepatic uptake of ASOs. The total plasma protein binding and profiling was assessed. Finally, two-dimensional gel electrophoresis identified protein expression differences. PK exposures were comparable between wild-type and DKO mice in plasma, liver, and kidney, yet a near twofold reduction in EC50 was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology.
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- 2016
28. Near-Infrared Image-Guided Delivery and Controlled Release Using Optimized Thermosensitive Liposomes
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Hailing Zhang, Colby S. Shemesh, David C. Turner, Delaram Moshkelani, and David Luc
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Indocyanine Green ,Materials science ,Surface Properties ,Pharmacology toxicology ,Pharmaceutical Science ,Thermosensitive liposomes ,Cell Line ,Polyethylene Glycols ,Mice ,Phagocytosis ,Neoplasms ,Animals ,Tissue Distribution ,Pharmacology (medical) ,Tissue distribution ,Coloring Agents ,Pharmacology ,Mice, Inbred BALB C ,Macrophages ,Organic Chemistry ,Temperature ,technology, industry, and agriculture ,Dextrans ,Controlled release ,Neoplasms diagnosis ,Delayed-Action Preparations ,Liposomes ,Molecular Medicine ,Biotechnology ,Biomedical engineering - Abstract
To engineer optimized near-infrared (NIR) active thermosensitive liposomes to potentially achieve image-guided delivery of chemotherapeutic agents.Thermosensitive liposomes were surface-coated with either polyethylene glycol or dextran. Differential scanning calorimetry and calcein release studies were conducted to optimize liposomal release, and flow cytometry was employed to determine the in vitro macrophage uptake of liposomes. Indocyanine green (ICG) was encapsulated as the NIR dye to evaluate the in vivo biodistribution in tumor-bearing mice.The optimized thermosensitive liposome formulation consists of DPPC, SoyPC, and cholesterol in the 100:50:30 molar ratio. Liposomes with dextran and polyethylene glycol demonstrated similar thermal release properties; however in vitro macrophage uptake was greater with dextran. Non-invasive in vivo NIR imaging showed tumor accumulation of liposomes with both coatings, and ex vivo NIR imaging correlated well with actual ICG concentrations in various organs of healthy mice.The optimized thermosensitive liposome formulation demonstrated stability at 37 °C and efficient burst release at 40 and 42 °C. Dextran exhibited potential for application as a surface coating in thermosensitive liposome formulations. In vivo studies suggest that liposomal encapsulation of ICG permits reliable, real-time monitoring of liposome biodistribution through non-invasive NIR imaging.
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- 2012
29. Indocyanine green loaded liposome nanocarriers for photodynamic therapy using human triple negative breast cancer cells
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Brian Fernandez, Colby S. Shemesh, David S. Yu, Hailing Zhang, and Claire W. Hardy
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Indocyanine Green ,medicine.medical_specialty ,Radiation-Sensitizing Agents ,DNA damage ,Cell Survival ,medicine.medical_treatment ,Biophysics ,Photodynamic therapy ,Apoptosis ,Triple Negative Breast Neoplasms ,Dermatology ,Diffusion ,chemistry.chemical_compound ,Nanocapsules ,Cell Line, Tumor ,medicine ,Humans ,Pharmacology (medical) ,Photosensitizer ,Viability assay ,Clonogenic assay ,Cytotoxicity ,Liposome ,Chemistry ,eye diseases ,Surgery ,Treatment Outcome ,Oncology ,Photochemotherapy ,Liposomes ,Cancer research ,Indocyanine green - Abstract
Summary Background The goal of the current research is to evaluate the potential of photodynamic therapy (PDT) in the treatment of triple negative breast cancer (TNBC) with the development of a theranostic thermosensitive liposome platform to deliver indocyanine green (ICG) as the near-infrared (NIR) photosensitizer excited by an 808 nm diode laser. Methods In the PDT protocol, an optimized thermosensitive liposome formulation is investigated to formulate ICG as the photosensitizer, which is exited by laser light at the wavelength of 808 nm delivered by a fiber-coupled laser system. ICG in both free solution and thermosensitive liposomal formulation were evaluated as the NIR photosensitizer and compared in the PDT treatment on a panel of triple negative breast cancer cell lines along with the nontumorigenic mammary epithelial cell line MCF-10A. In addition to cytotoxicity, and clonogenic survival assessment, the role of DNA double strand break damage was evaluated. Results Both MTT and clonogenic assays revealed that PDT using ICG inhibited the growth of several TNBC cell lines as well as the non-tumorigenic human breast epithelial cell line MCF-10A; and the liposomal formulation of ICG did not compromise the in vitro treatment potency, though free ICG performed slightly more effective in certain cell lines, but was not statistically significant. Cell viability was dose dependent in regards to ICG concentration and irradiation energy. Interestingly, PDT using the described protocol was more potent to inhibit the growth of MDA-MB-468 and HCC-1806 cells, coinciding with the observation that these cells are more sensitive toward DNA damaging agents. In comparison, cell lines HCC-70, BT-549, and MCF-10A were found to have less of an inhibitory effect. Furthermore, substantial DNA double strand breaks (DSBs) were observed 30 min after the PDT treatment via a γ-H2AX staining assay. PDT induced DNA damage has the potential to lead to mutagenicity, which may have various responses depending on the repair capabilities of the cells. Conclusion Our results suggest that PDT using indocyanine green loaded liposomes were effective in inhibiting tumor cell growth to varying extents with higher responses observed for MDA-MB-468 and HCC-1806 cells.
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- 2013
30. Disposition and Pharmacology of a GalNAc3-conjugated ASO Targeting Human Lipoprotein (a) in Mice
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Colby S Shemesh, Thazha P. Prakash, Punit P. Seth, Mark J. Graham, Richard S. Geary, Jennifer Burkey, Yanfeng Wang, Stan Riney, Shannon Hall, Rosie Z. Yu, Eric E. Swayze, Noah Post, Thomas A. Zanardi, and Scott P. Henry
- Subjects
0301 basic medicine ,Genetically modified mouse ,antisense oligonucleotide ,mice ,endocrine system diseases ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,Drug Discovery ,Potency ,biology ,Oligonucleotide ,lcsh:RM1-950 ,nutritional and metabolic diseases ,Lipoprotein(a) ,Blood proteins ,humanities ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Galactosamine ,disposition ,biology.protein ,Molecular Medicine ,Original Article ,pharmacokinetics ,hormones, hormone substitutes, and hormone antagonists - Abstract
Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency via receptor-mediated uptake. In the present study, the in vivo pharmacology of a 2′-O-(2-methoxyethyl)-modified ASO conjugated with GalNAc3 (ISIS 681257) together with its unmodified congener (ISIS 494372) targeting human apolipoprotein (a) (apo(a)), were studied in human LPA transgenic mice. Further, the disposition kinetics of ISIS 681257 was studied in CD-1 mice. ISIS 681257 demonstrated over 20-fold improvement in potency over ISIS 494372 as measured by liver apo(a) mRNA and plasma apo(a) protein levels. Following subcutaneous (SC) dosing, ISIS 681257 cleared rapidly from plasma and distributed to tissues. Intact ISIS 681257 was the major full-length oligonucleotide species in plasma. In tissues, however, GalNAc sugar moiety was rapidly metabolized and unconjugated ISIS 681257 accounted > 97% of the total exposure, which was then cleared slowly from tissues with a half-life of 7–8 days, similar to the half-life in plasma. ISIS 681257 is highly bound to plasma proteins (> 94% bound), which limited its urinary excretion. This study confirmed dose-dependent exposure to the parent drug ISIS 681257 in plasma and rapid conversion to unconjugated ASO in tissues. Safety data and the extended half-life support its further development and weekly dosing in phase 1 clinical studies.
- Published
- 2016
31. Elucidation of the Biotransformation Pathways of a Galnac3-conjugated Antisense Oligonucleotide in Rats and Monkeys
- Author
-
Hans Gaus, Noah Post, Scott P. Henry, Colby S. Shemesh, Rosie Z. Yu, Punit P. Seth, Thazha P. Prakash, Karsten Schmidt, Michael T. Migawa, Thomas A. Zanardi, Eric E. Swayze, Yanfeng Wang, and Sarah Greenlee
- Subjects
antisense oligonucleotide ,0301 basic medicine ,Metabolite ,Aldehyde dehydrogenase ,targeted drug delivery ,03 medical and health sciences ,chemistry.chemical_compound ,Biotransformation ,In vivo ,Drug Discovery ,N-acetyl galactosamine ,biology ,lcsh:RM1-950 ,Metabolism ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Biochemistry ,Galactosamine ,biology.protein ,Molecular Medicine ,Alkaline phosphatase ,Original Article ,Asialoglycoprotein receptor ,biotransformation ,metabolism - Abstract
Triantennary N-acetyl galactosamine (GalNAc3) is a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors. Conjugation with GalNAc3 via a trishexylamino (THA)-C6 cluster significantly enhances antisense oligonucleotide (ASO) potency. Herein, the biotransformation, disposition, and elimination of the THA cluster of ION-681257, a GalNAc3-conjugated ASO currently in clinical development, are investigated in rats and monkey. Rats were administered a single subcutaneous dose of (3)H-radiolabeled ((3)H placed in THA) or nonradiolabeled ION-681257. Mass balance included radiometric profiling and metabolite fractionation with characterization by mass spectrometry. GalNAc3-conjugated ASOs were extensively distributed into liver. The THA-C6 triantenerrary GalNAc3 conjugate at the 5'-end of the ASO was rapidly metabolized and excreted with 25.67 ± 1.635% and 71.66 ± 4.17% of radioactivity recovered in urine and feces within 48 hours postdose. Unchanged drug, short-mer ASOs, and linker metabolites were detected in urine. Collectively, 14 novel linker associated metabolites were discovered including oxidation at each branching arm, initially by monooxidation at the β-position followed by dioxidation at the α-arm, and lastly, tri and tetra oxidations on the two remaining β-arms. Metabolites in bile and feces were identical to urine except for oxidized linear and cyclic linker metabolites. Enzymatic reaction phenotyping confirmed involvement of N-acetyl-β-glucosaminidase, deoxyribonuclease II, alkaline phosphatase, and alcohol + aldehyde dehydrogenases on the complex metabolism pathway for THA supplementing in vivo findings. Lastly, excreta from monkeys treated with ION-681257 revealed the identical series as observed in rat. In summary, our findings provide an improved understanding of GalNAc3-conjugated-ASO metabolism pathways which facilitate similar development programs.
- Published
- 2016
32. Disposition and Pharmacology of a GalNAc3-conjugated ASO Targeting Human Lipoprotein (a) in Mice
- Author
-
Rosie Z Yu, Mark J Graham, Noah Post, Stan Riney, Thomas Zanardi, Shannon Hall, Jennifer Burkey, Colby S Shemesh, Thazha P Prakash, Punit P Seth, Eric E Swayze, Richard S Geary, Yanfeng Wang, and Scott Henry
- Subjects
antisense oligonucleotide ,disposition ,mice ,pharmacokinetics ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency via receptor-mediated uptake. In the present study, the in vivo pharmacology of a 2′-O-(2-methoxyethyl)-modified ASO conjugated with GalNAc3 (ISIS 681257) together with its unmodified congener (ISIS 494372) targeting human apolipoprotein (a) (apo(a)), were studied in human LPA transgenic mice. Further, the disposition kinetics of ISIS 681257 was studied in CD-1 mice. ISIS 681257 demonstrated over 20-fold improvement in potency over ISIS 494372 as measured by liver apo(a) mRNA and plasma apo(a) protein levels. Following subcutaneous (SC) dosing, ISIS 681257 cleared rapidly from plasma and distributed to tissues. Intact ISIS 681257 was the major full-length oligonucleotide species in plasma. In tissues, however, GalNAc sugar moiety was rapidly metabolized and unconjugated ISIS 681257 accounted > 97% of the total exposure, which was then cleared slowly from tissues with a half-life of 7–8 days, similar to the half-life in plasma. ISIS 681257 is highly bound to plasma proteins (> 94% bound), which limited its urinary excretion. This study confirmed dose-dependent exposure to the parent drug ISIS 681257 in plasma and rapid conversion to unconjugated ASO in tissues. Safety data and the extended half-life support its further development and weekly dosing in phase 1 clinical studies.
- Published
- 2016
- Full Text
- View/download PDF
33. Elucidation of the Biotransformation Pathways of a Galnac3-conjugated Antisense Oligonucleotide in Rats and Monkeys
- Author
-
Colby S Shemesh, Rosie Z Yu, Hans J Gaus, Sarah Greenlee, Noah Post, Karsten Schmidt, Michael T Migawa, Punit P Seth, Thomas A Zanardi, Thazha P Prakash, Eric E Swayze, Scott P Henry, and Yanfeng Wang
- Subjects
antisense oligonucleotide ,biotransformation ,metabolism ,N-acetyl galactosamine ,targeted drug delivery ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Triantennary N-acetyl galactosamine (GalNAc3) is a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors. Conjugation with GalNAc3 via a trishexylamino (THA)-C6 cluster significantly enhances antisense oligonucleotide (ASO) potency. Herein, the biotransformation, disposition, and elimination of the THA cluster of ION-681257, a GalNAc3-conjugated ASO currently in clinical development, are investigated in rats and monkey. Rats were administered a single subcutaneous dose of 3H-radiolabeled (3H placed in THA) or nonradiolabeled ION-681257. Mass balance included radiometric profiling and metabolite fractionation with characterization by mass spectrometry. GalNAc3-conjugated ASOs were extensively distributed into liver. The THA-C6 triantenerrary GalNAc3 conjugate at the 5′-end of the ASO was rapidly metabolized and excreted with 25.67 ± 1.635% and 71.66 ± 4.17% of radioactivity recovered in urine and feces within 48 hours postdose. Unchanged drug, short-mer ASOs, and linker metabolites were detected in urine. Collectively, 14 novel linker associated metabolites were discovered including oxidation at each branching arm, initially by monooxidation at the β-position followed by dioxidation at the α-arm, and lastly, tri and tetra oxidations on the two remaining β-arms. Metabolites in bile and feces were identical to urine except for oxidized linear and cyclic linker metabolites. Enzymatic reaction phenotyping confirmed involvement of N-acetyl-β-glucosaminidase, deoxyribonuclease II, alkaline phosphatase, and alcohol + aldehyde dehydrogenases on the complex metabolism pathway for THA supplementing in vivo findings. Lastly, excreta from monkeys treated with ION-681257 revealed the identical series as observed in rat. In summary, our findings provide an improved understanding of GalNAc3-conjugated-ASO metabolism pathways which facilitate similar development programs.
- Published
- 2016
- Full Text
- View/download PDF
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