15 results on '"Colby S. Shemesh"'
Search Results
2. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations
- Author
-
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
-
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.
- Published
- 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
-
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
-
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.
- Published
- 2020
- Full Text
- View/download PDF
6. Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer
- Author
-
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
- Published
- 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
-
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
-
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. Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer
- Author
-
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
10. Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region
- Author
-
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
11. Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden
- Author
-
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
12. Assessment of the Drug Interaction Potential of Unconjugated and GalNAc3-Conjugated 2′-MOE-ASOs
- Author
-
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
13. Disposition and Pharmacology of a GalNAc3-conjugated ASO Targeting Human Lipoprotein (a) in Mice
- Author
-
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
14. 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
15. 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
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.