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1. First‐in‐Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Author

Ullman, Julie C., Dick, Ryan A., Linzner, Daniela, Minga, Todd, Tep, Samnang, Satterfield, Terrence F., Xi, Yannan, Beattie, David T., Marmon, Tonya, Neutel, Joel M., Chung, Bernard, Leeds, Janet M., Noonberg, Sarah B., Green, Eric M., and Bernstein, Harold S.

Subjects
MONONUCLEAR leukocytes, GLYCOGEN storage disease, GLYCOGEN storage disease type II, ENZYME replacement therapy, INTRAVENOUS therapy
Abstract

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α‐glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first‐in‐human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well‐tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half‐life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose‐dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub‐study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Supplementary Data (Table S1, Figure S1, Figure S2, Figure S3) from Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies

Author

Coffey, Greg P., primary, Feng, Jiajia, primary, Betz, Andreas, primary, Pandey, Anjali, primary, Birrell, Matt, primary, Leeds, Janet M., primary, Der, Kenneth, primary, Kadri, Sabah, primary, Lu, Pin, primary, Segal, Jeremy, primary, Wang, Y. Lynn, primary, Michelson, Glenn, primary, Curnutte, John T., primary, and Conley, Pamela B., primary

Published
2023
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9. 2(sup)' -O-[2-(methylthio)-ethyl]-modified oligonucleotide: an analogueof 2(sup)'-O-[12-(methoxy)-ethyl]-modified oligonucleotides with improved proteinbiding properties and high binding affinity to target RNA

Author

Prakash, Thazha P., Manoharan, Muthiah, Kawasaki, Andrew, Fraser, Allister S., Lesnik, Elena A., Sioufi, Namir, Leeds, Janet M., Teplova, Marianna, and Egli, Martin

Subjects
Antisense DNA -- Research, Oligodeoxynucleotides, Protein binding -- Analysis, Biological sciences, Chemistry
Abstract

The crystal structure of a decamer DNA duplex containing 2(sup)' -O-[2-(methylthio)-ethyl] modification reveals the improved affinity for RNA binding, protein binding, and limited resistance of 2(sup)' -O-[2-(methylthio)-ethyl] modified oligonucleotides to exonuclease action.

Published
2002

10. Nuclease resistance of oligonucleotides containing the tricyclic cytosine analogues phenoxazine and 9-(2-aminoethoxy)-phenoxazine ('G-clamp') and origins of their nuclease resistance properties

Author

Maier, Martin A., Leeds, Janet M., Balow, Guity, Springer, Robert H., Bharadwaj, Ramesh, and Manoharan, Muthiah

Subjects
Antisense nucleic acids -- Research, Nucleic acid probes -- Physiological aspects, Nucleases -- Physiological aspects, Structure-activity relationships (Biochemistry) -- Analysis, Biological sciences, Chemistry
Abstract

The influence by a single modification at the 3'-terminus on the enzymatic stability of the phosphodiester backbone containing therapeutic oligonucleotides and by cytosine analogues of the phenoxazine and 9-(2-aminoethoxy)-phenoxazine are investigated. Data indicate that incorporation at the 3'-terminus completely protects the oligonucleotide against 3'-exonuclease attack.

Published
2002

12. Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Author

Smith, Stephen D., primary, Munoz, Javier, additional, Stevens, Don, additional, Smith, Sonali M., additional, Feldman, Tatyana A., additional, Ye, J Christine, additional, de Vos, Sven, additional, Hess, Brian T., additional, Miller, Carole B., additional, Khatcheressian, James L., additional, Birrell, Matt R., additional, Leeds, Janet M., additional, Coffey, Gregory P., additional, Conley, Pamela B., additional, Michelson, Glenn C., additional, Curnutte, John T., additional, and Hamlin, Paul A., additional

Published
2019
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13. A Phase 2 Study of the Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Author

Horwitz, Steven M., primary, Feldman, Tatyana A., primary, Hess, Brian T., primary, Khodadoust, Michael S., primary, Kim, Youn H., primary, Munoz, Javier, primary, Patel, Manish R., primary, Phillips, Tycel J., primary, Smith, Stephen D., primary, Smith, Sonali M., primary, Wilcox, Ryan A., primary, Birrell, Matt R., primary, Leeds, Janet M., primary, Conley, Pamela B., primary, Michelson, Glenn C., primary, Coffey, Gregory P., primary, Curnutte, John T., primary, and Hamlin, Paul A., primary

Published
2019
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14. Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies

Author

Coffey, Greg P., primary, Feng, Jiajia, additional, Betz, Andreas, additional, Pandey, Anjali, additional, Birrell, Matt, additional, Leeds, Janet M., additional, Der, Kenneth, additional, Kadri, Sabah, additional, Lu, Pin, additional, Segal, Jeremy, additional, Wang, Y. Lynn, additional, Michelson, Glenn, additional, Curnutte, John T., additional, and Conley, Pamela B., additional

Published
2019
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15. Efficacy and safety of the dual SYK/JAK inhibitor cerdulatinib in patients with relapsed or refractory B‐cell malignancies: Results of a phase I study

Author

Hamlin, Paul A., primary, Flinn, Ian W., additional, Wagner‐Johnston, Nina, additional, Burger, Jan A., additional, Coffey, Greg P., additional, Conley, Pamela B., additional, Michelson, Glenn, additional, Leeds, Janet M., additional, Der, Kenneth, additional, Kim, Yvonne, additional, Sabalvaro‐Torres, Alice, additional, Birrell, Matt, additional, Pandey, Anjali, additional, Curnutte, John T., additional, and Patel, Manish R., additional

Published
2019
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17. The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Author

Horwitz, Steven M., primary, Feldman, Tatyana A., additional, Hess, Brian T., additional, Khodadoust, Michael S, additional, Kim, Youn H., additional, Munoz, Javier, additional, Patel, Manish R, additional, Phillips, Tycel J., additional, Smith, Stephen D., additional, Smith, Sonali M., additional, Wilcox, Ryan A., additional, Steele, Andrew, additional, Pandey, Anjali, additional, Birrell, Matt R, additional, Leeds, Janet M., additional, Conley, Pamela B., additional, Michelson, Glenn, additional, Coffey, Gregory P., additional, Curnutte, John T, additional, and Hamlin, Paul A., additional

Published
2018
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19. The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

Author

Raymuno, S., Ramacciotti, E., Manenti, E., Freire, A., Fiss, E., Bizzacchi, J. Annichino, Lienart, F., Dive, A., Delforge, M., Blockmans, D., Soroka, N., Kamenova, Z., Kostadinova, M., Milanova, M., Pencheva, G., Runev, N., Stoeva, N., Stoyanov, M., Syulemzova, S., Todorov, G., Polonetsy, L., Pimanov, S., Mitkovskaya, N., Tokmakova, M., Dhar, A., Mikhailova, E., Koryk, V., Adzerikho, I., Schoenerr, H., Mathies, R., Douketis, J., Konig, J., Le Gal, G., Pearce, M., Provencher, S., Verreault, S., Alarcon, M. Arias, Lazcano, M. Opazo, Cardenas, S. Potthoff, Butkovic-Soldo, S., Car, S., Ciglenecki, N., Francetic, I., Jakopovic, M., Kalinic-Grgorinic, H., Knezevic, A., Marusic, S., Vagic, J. Sikic, Skerk, V., Cermak, O., Gibson, C. Michael, Halaby, Rim, Korjian, Serge, Daaboul, Yazan, Arbetter, Douglas F., Yee, Megan K., Chlumsky, J., Chochola, J., Cizek, V., Goldhaber, Samuel Z., Hull, Russel, Hernandez, Adrian F., Huber, K., Lu, Shiao-ping, Dunaj, M., Dusek, J., Francek, L., Havelka, J., Herold, M., Holaj, R., Nazliel, BİJEN, Bandman, Olga, Leeds, Janet M., Gold, Alex, Harrington, Robert A., Bello, F., Ferrari, A. E., Jure, H., Macin, S., Oliva, M., Parody, M., Horny, I., Hubac, J., Jajtner, P., Kolman, P., Poy, C., Baker, R., Lang, P., Mikulova, J., Podpera, I., Reiterer, P., Spacek, R., Vejvoda, J., Vyhnanek, M., Christensen, H., Lassen, M., Storgaard, M., Tuxen, C., Urhammer, S., Lember, M., Uuetoa, T., Airaksinen, J., Honkaniemi, J., Kaaja, R., Saarinen, J., Tatlisumak, T., Vikman, S., Agraou, B., Aquilanti, S., Belhassane, A., Brisot, D., De Geeter, G., Coughlin, P., Finfer, S., Debourdeau, P., Decoulx, E., El Kouri, D., Falvo, N., Grange, C., Rubinfeld, A., Lacroix, P., Messas, E., Mismetti, P., Montaclair, K., Paleiron, N., Payot, L., Zakai, N., Yousef, K., Wichman, T., Whitman, B., Welker, J., Welch, M., Warner, A., Updegrove, J., Tuck, M., Stoltz, S., Sokol, S., Sharma, S., Shammas, N., Saba, F., Rodriguez, W., Rastogi, P., Rajan, R., Quintana, O., Pullman, J., Pratt, R., Pineda, L., Pernod, G., Pearl, R., Parthiban, K., Ortel, T., Ohaju, V., Pottier, P., Proust, A., Quere, I., Roy, P-M., Schmidt, J., Simoneau, G., Datikashvili-David, I., Khabeishvili, G., Khintibidze, I., Nadar, V., Mittal, M., Milling, T., McLaren, G., Margolis, B., Mahal, S., Macchiavelli, A., Lopez, J., Lerner, R., Kung, M., Kouras, F., Kazimir, M., Kao, C-K., Kabler, H., Ioachimescu, O., Hazelrigg, M., Hamad, A., Haidar, A., Hahn, B., Goytia-Leos, D., Gaggin, H., Fulmer, J., Fraiz, J., Fermann, G., Farley, B., Doshi, A., Dhingra, R., Cornell, J., Concha, M., Clark, C., Chang, H., Carman, T., Bidair, M., Bercz, P., Bastani, A., Barney, J., Baker, S., Anderson, C., Amin, M., Almasri, E., Natarajan, I., McCollum, C., MacCallum, P., Davis, M., Body, R., Yagensky, A., Voronkov, L., Vishnivestsky, I., Vakaliuk, I., Ursol, G., Tseluyko, V., Svyshchenko, Y., Svyridova, I., Ryabichenko, T., Rudenko, L., Reshotko, D., Perepeliuk, M., Parkhomenko, O., Nikonov, V., Maslovaskyi, V., Malynovsky, Y., Legkonogov, O., Kyrychenko, I., Krakhmalova, O., Koshlia, V., Kopytsya, M., Karpenko, O., Gryb, V., Goncharova, Y., Goloborodko, B., Goloborodko, A., Godlevska, O., Burmak, I., Brozhyk, J., Batushkin, V., Abrahamovych, O., Tuncay, E., Topcuoglu, M., Tigen, K., Okumus, G., Kutluk, H., Kirma, C., Kilichesmez, K., Guneri, S., Akgul, O., Villalta, J., Vargas Nunez, J. A., Trujillo, J., Riera, A., Richart, C., Mellibovsky, L., Jimenez, D., Grandes, J., Gonzales-Porras, J. R., Gomez Cerezo, J., Ferrer, R., Diaz Santos, E., Cereto, F., Cepeda, J. M., Castro Guardiola, A., Bisbe, J., Barbagelata Lopez, C., Alvarez Sala, L. A., Van Dyk, C., Mitha, I., Engelbrecht, J., Breedt, J., Basson, M., Adler, D., Spisakova, M., Payer, J., Krastev, G., Kokles, M., Hrubon, A., Herman, O., Dvorak, M., Cervenakova, A., Bodikova, S., Miloradovic, V., Kovacevic-Kuzmanovic, A., Ilic, S., Celic, V., Apostolovic, S., Vishnevskiy, A., Vishneva, E., Solovyov, O., Simanenkov, V., Shvarts, Y., Shpagina, L., Shapovalova, Y., Sergeeva, E., Reshetko, O., Privalova, E., Popov, D., Nilk, R., Nikolaev, K., Mordovin, V., Maslova, N., Martynenko, V., Martynenko, T., Malygin, A., Kostenko, V., Kosmacheva, E., Kobalava, Z., Klein, G., Khachatryan, N., Ershova, O., Dovgalevskiy, Y., Chefranova, Z., Boldueva, S., Bogdanov, E., Belskaya, G., Barbarash, O., Averkov, O., Arkhipov, M., Apartsin, K., Andreev, D., Abashev, A., Vida-Simiti, L., Stanciulescu, G., Stamate, S., Kobulia, B., Megreladze, I., Pagava, Z., Paposhvili, K., Amann, B., Beyer-Westendorf, J., Blessing, E., Bott, M., Dengler, T., Dziewas, R., Genth-Zotz, S., Hamann, F., Horacek, T., Klimpe, S., Kroning, R., Lapp, H., Lawall, H., Licka, M., Rizos, T., Tiefenbacher, C., Weimar, C., Alkonyi, B., Falukozy, J., Futo, L., Katona, A., Kirschner, R., Kristof, P., Lakatos, F., Lupkovics, G., Merkely, B., Andras, C. Nagy, Nemeth, L., Papp, A., Soltesz, P., Sudar, Z., Szabo, G., Szegedi, N., Timar, G., Valco, J., Vertes, A., Efrati, S., Elias, M., Gafter, A., Hayek, T., Hussein, O., Lishner, M., Lugassy, G., Cerveri, I., D'Angelo, A., De Pellegrin, A., Imberti, D., Landolfi, R., Lembo, G., Lodigiani, C., Moia, M., Molteni, M., Mumoli, N., Novo, S., Orlandini, F., Parisi, R., Pizzini, A., Pomero, F., Salvi, A., Schenone, A., Visona, A., Martinova, V., Pontaga, N., Rozitis, V., Stukena, I., Alekniene, B., Basijokiene, V., Butkiene, Z., Griskeviciene, V., Naudziunas, A., Norvaisiene, R., Norviliene, R., Petrauskiene, R., Poskiene, R., Susinskiene, D., Valavicius, A., Castillo Leon, R., Pereyra, R. Cotrina, Karlo, L. Farjardo, Horna, M., Salas, M., Yanez, L. Toche, Fryze, W., Gaciong, Z., Gniot, J., Gorecka, D., Gruenpeter, P., Grzelakowski, P., Jastrzebski, D., Kucharski, L., Mirek-Bryniarska, E., Pulkowski, G., Sobkowicz, B., Sulik, P., Walasek, L., Waldemar, K., Wrzesinski, K., Balogh, Z. E., Bojinca, M., Marin, I., Musetescu, R., Podoleanu, C., Popescu, M., Kalpachki, R., Grigorov, M., Dimov, B., Rocha, A., Goloshchekin, B., Berrouschot, J., Laszlo, Z., Rees, C., Overcash, J., Prokop, D., and Cohen, Alexander T.

Subjects
Relative risk reduction, Male, Pyridines, Population, Hemorrhage, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Randomized controlled trial, Double-Blind Method, law, Medicine, Humans, 030212 general & internal medicine, Dosing, Enoxaparin, education, Aged, Aged, 80 and over, Venous Thrombosis, education.field_of_study, business.industry, Absolute risk reduction, Anticoagulants, Venous Thromboembolism, Hospitalization, chemistry, Concomitant, Betrixaban, Anesthesia, Benzamides, Female, Cardiology and Cardiovascular Medicine, business, Pulmonary Embolism, Factor Xa Inhibitors
Abstract

The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor.This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial.The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin.The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

Published
2016

20. Andexanet Alfa for the Management of Acute Major Bleeding Associated with FXa Inhibitors (P5.059)

Author

Connolly, Stuart J., primary, Milling, Truman J., additional, Eikelboom, John W., additional, Gibson, C. Michael, additional, Curnutte, John T., additional, Gold, Alex, additional, Lu, Genmin, additional, Conley, Pamela B., additional, Verhamme, Peter, additional, Schmidt, Jeannot, additional, Middeldorp, Saskia, additional, Cohen, Alexander T., additional, Beyer-Westendorf, Jan, additional, Albaladejo, Pierre, additional, Lopez-Sendon, Jose, additional, Goodman, Shelly, additional, Leeds, Janet M., additional, Siegal, Deborah M., additional, Zotova, Elena, additional, Nakamya, Juliet, additional, Lim, W. Ting, additional, and Crowther, Mark, additional

Published
2017
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21. Reversal of Anticoagulation Effects of Rivaroxaban and Associated Bleeding in a Rabbit Acute Hemorrhage Model by Andexanet Alfa vs. Coagulation Replacement Factors (P5.054)

Author

Lu, Genmin, primary, Pine, Polly, additional, DeGuzman, Francis, additional, Canivel, Deogracias, additional, Malinowski, John, additional, Pratikhya, Pratikhya, additional, Lin, Joyce, additional, Leeds, Janet M., additional, Curnutte, John T., additional, and Conley, Pamela B., additional

Published
2017
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26. Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Author

Hamlin, Paul A, primary, Flinn, Ian, additional, wagner-Johnston, Nina, additional, Burger, Jan A, additional, Michelson, Glenn, additional, Pandey, Anjali, additional, Birrell, Matt, additional, Coffey, Greg P., additional, Leeds, Janet M, additional, Curnutte, John T., additional, and Patel, Manish R., additional

Published
2015
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29. A Phase I Open-Label, Multi-Dose Escalation Study of the Dual Syk/Jak Inhibitor PRT062070 (Cerdulatinib) in Patients with Relapsed/Refractory B Cell Malignancies

Author

Patel, Manish, primary, Hamlin, Paul, additional, Strickland, Donald K, additional, Pandey, Anjali, additional, Coffey, Greg, additional, Leeds, Janet M, additional, Levy, Gallia G., additional, Curnutte, John T., additional, Wagner-Johnston, Nina, additional, and Flinn, Ian W., additional

Published
2014
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31. Novel Benzoxazole Inhibitor of Dengue Virus Replication That Targets the NS3 Helicase

Author

Byrd, Chelsea M., primary, Grosenbach, Douglas W., additional, Berhanu, Aklile, additional, Dai, Dongcheng, additional, Jones, Kevin F., additional, Cardwell, Kara B., additional, Schneider, Christine, additional, Yang, Guang, additional, Tyavanagimatt, Shanthakumar, additional, Harver, Chris, additional, Wineinger, Kristin A., additional, Page, Jessica, additional, Stavale, Eric, additional, Stone, Melialani A., additional, Fuller, Kathleen P., additional, Lovejoy, Candace, additional, Leeds, Janet M., additional, Hruby, Dennis E., additional, and Jordan, Robert, additional

Published
2013
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32. Pharmacokinetic and Pharmacodynamic Modeling To Determine the Dose of ST-246 To Protect against Smallpox in Humans

Author

Leeds, Janet M., primary, Fenneteau, Frederique, additional, Gosselin, Nathalie H., additional, Mouksassi, Mohamad-Samer, additional, Kassir, Nastya, additional, Marier, J. F., additional, Chen, Yali, additional, Grosenbach, Doug, additional, Frimm, Annie E., additional, Honeychurch, Kady M., additional, Chinsangaram, Jarasvech, additional, Tyavanagimatt, Shanthakumar R., additional, Hruby, Dennis E., additional, and Jordan, Robert, additional

Published
2013
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33. Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

Author

Chinsangaram, Jarasvech, primary, Honeychurch, Kady M., additional, Tyavanagimatt, Shanthakumar R., additional, Leeds, Janet M., additional, Bolken, Tove' C., additional, Jones, Kevin F., additional, Jordan, Robert, additional, Marbury, Thomas, additional, Ruckle, Jon, additional, Mee-Lee, Denis, additional, Ross, Eric, additional, Lichtenstein, Israel, additional, Pickens, Margaret, additional, Corrado, Michael, additional, Clarke, Jean M., additional, Frimm, Annie M., additional, and Hruby, Dennis E., additional

Published
2012
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34. Comparison of the Safety and Pharmacokinetics of ST-246® after IV Infusion or Oral Administration in Mice, Rabbits and Monkeys

Author

Chen, Yali, primary, Amantana, Adams, additional, Tyavanagimatt, Shanthakumar R., additional, Zima, Daniela, additional, Yan, X. Steven, additional, Kasi, Gopi, additional, Weeks, Morgan, additional, Stone, Melialani A., additional, Weimers, William C., additional, Samuel, Peter, additional, Tan, Ying, additional, Jones, Kevin F., additional, Lee, Daniel R., additional, Kickner, Shirley S., additional, Saville, Bradley M., additional, Lauzon, Martin, additional, McIntyre, Alan, additional, Honeychurch, Kady M., additional, Jordan, Robert, additional, Hruby, Dennis E., additional, and Leeds, Janet M., additional

Published
2011
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36. Synthesis of 2‘,3‘-Dideoxynucleoside 5‘-α-P-Borano-β,γ-(difluoromethylene)triphosphates and Their Inhibition of HIV-1 Reverse Transcriptase

Author

Boyle, Nicholas A., primary, Rajwanshi, Vivek K., additional, Prhavc, Marija, additional, Wang, Guangyi, additional, Fagan, Patrick, additional, Chen, Fu, additional, Ewing, Gregory J., additional, Brooks, Jennifer L., additional, Hurd, Tiffany, additional, Leeds, Janet M., additional, Bruice, Thomas W., additional, and Cook, P. Dan, additional

Published
2005
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37. Synthesis of AZT 5‘-Triphosphate Mimics and Their Inhibitory Effects on HIV-1 Reverse Transcriptase

Author

Wang, Guangyi, primary, Boyle, Nicholas, additional, Chen, Fu, additional, Rajappan, Vasanthakumar, additional, Fagan, Patrick, additional, Brooks, Jennifer L., additional, Hurd, Tiffany, additional, Leeds, Janet M., additional, Rajwanshi, Vivek K., additional, Jin, Yi, additional, Prhavc, Marija, additional, Bruice, Thomas W., additional, and Cook, P. Dan, additional

Published
2004
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39. 2‘-O-[2-(Methylthio)ethyl]-Modified Oligonucleotide: An Analogue of 2‘-O-[2-(Methoxy)-ethyl]-Modified Oligonucleotide with Improved Protein Binding Properties and High Binding Affinity to Target RNA

Author

Prakash, Thazha P., primary, Manoharan, Muthiah, additional, Kawasaki, Andrew M., additional, Fraser, Allister S., additional, Lesnik, Elena A., additional, Sioufi, Namir, additional, Leeds, Janet M., additional, Teplova, Marianna, additional, and Egli, Martin, additional

Published
2002
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46. Pharmacokinetic and Pharmacodynamic Modeling To Determine the Dose of ST-246 To Protect against Smallpox in Humans

Author

Leeds, Janet M., Fenneteau, Frederique, Gosselin, Nathalie H., Mouksassi, Mohamad-Samer, Kassir, Nastya, Marier, J. F., Chen, Yali, Grosenbach, Doug, Frimm, Annie E., Honeychurch, Kady M., Chinsangaram, Jarasvech, Tyavanagimatt, Shanthakumar R., Hruby, Dennis E., and Jordan, Robert

Abstract

ABSTRACTAlthough smallpox has been eradicated, the United States government considers it a “material threat” and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.

Published
2012
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47. Pharmacokinetics of an Antisense Oligonucleotide Injected Intravitreally in Monkeys

Author

Leeds, Janet M., Henry, Scott P., Bistner, Steve, Scherrill, Scott, Williams, Kevin, and Levin, Arthur A.

Abstract

The kinetics of an intravitreally administered phosphorothioate oligonucleotide, ISIS 2922, were studied in cynomolgus monkeys. Vitreal and retinal concentrations were measured after administration of 11, 57, or 115 μg/eye. ISIS 2922 concentrations in vitreous and retina were compared, after single, weekly, or biweekly doses, for potential accumulation. ISIS 2922 levels were quantified using solid-phase extraction followed by capillary gel electrophoresis. Concentrations of ISIS 2922 in the vitreous were proportional to the dose and were nearly linear with respect to the dose. The ISIS 2922 concentrations 3 days after dosing ranged from 80 nM to approximately 1.5 μM. By 14 days after intravitreal injection, the concentrations were below the limit of quantitation (<10 nM) for all dose groups. There was no accumulation in the vitreous after multiple weekly or biweekly doses. The concentrations of ISIS 2922 in the retina 2 days after a single intravitreal injection ranged from 50 nM to 1.1 μM. The uptake and disposition of ISIS 2922 in the retina appeared to have been saturated between the 57- and 115-μg doses; the average concentrations were 0.71 ± 0.24 μM (N= 4) and 0.88 ± 0.27 μM (N= 3) for the two doses, respectively. Electrophoretic profiles of extracts revealed multiple chain-shortened oligonucleotides in the vitreous and retina, suggesting extensive metabolism in both compartments. Analyses from the multiple-dose study suggested that accumulation was dependent on the total administered dose, with accumulation occurring after biweekly dosing in the 115-μg dose group and only after weekly dosing in the 57-μg dose group.

Published
1998
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48. Pharmacokinetics and Metabolism in Mice of a Phosphorothioate Oligonucleotide Antisense Inhibitor of C-raf-1 Kinase Expression

Author

Geary, Richard S., Leeds, Janet M., Fitchett, Jon, Burckin, Todd, Truong, Loanne, Spainhour, Charles, Creek, Moire, and Levin, Arthur A.

Abstract

The plasma and tissue disposition of CGP 69846A (ISIS 5132) was characterized in male CD-1 mice following iv bolus injections administered every other day for 28 days (total of 15 doses). The doses ranged from 0.8 mg/kg to 100 mg/kg. Urinary excretion of oligonucleotide was also monitored over a 24-hr period following single dose administration over the same dose range. Pharmacokinetic plasma profiles were determined following single dose administration (dose 1) and after multiple doses (dose 15) at doses of 4 and 20 mg/kg. Concentrations in kidney, liver, spleen, heart, lung, and lymph nodes were characterized following doses 1, 8, and 15 for all doses. Capillary gel electrophoresis was used to quantitate intact (full-length) oligonucleotide and its metabolites (down to N− 11 base deletions) in both plasma and tissue at all time points. The plasma and tissue disposition of CGP 69846A was characterized by a rapid distribution into all tissues analyzed. Rapid plasma clearance of the parent oligonucleotide (9.3–14.3 ml/min/kg) was predominantly the result of distribution to tissue and, to a lesser extent, metabolism. Appearance and pattern of chain-shortened metabolites seen in plasma and tissue were consistent with predominantly exonuclease-mediated base deletion. No measurable accumulation of oligonucleotide was observed in plasma following multiple-dose administration, but both the liver and the kidney exhibited 2–3-fold accumulations. In general, the tissues exhibited half-lives for the elimination of parent oligonucleotide of 16–60 hr compared with plasma half-lives of 30–45 min. After repeated administrations, significant decreases in plasma clearance and volume of distribution at steady state (Vss) were observed following dose 15 at the dose of 20 mg/kg but not at the dose of 4 mg/kg. Changes in tissue accumulation and evidence for saturation of tissue distribution at the high doses may explain the plasma disposition changes observed in the absence of alteration of metabolism or plasma accumulation. Urinary excretion was a minor pathway for elimination of oligonucleotide over the 24-hr period immediately following iv administration. However, the amount of oligonucleotide excreted in the urine increased as a function of dose from less than 1% to approximately 13% of the administered dose over a dose range of 0.8 mg/kg to 100 mg/kg.

Published
1997
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