BackgroundType 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein.MethodsWe report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.ResultsA total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.ConclusionsIn infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.)The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status were reported.

Baranello, G., Darras, B. T., Day, J. W., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Rose, K., El-khairi, M., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Seabrook, T., Fontoura, P., Servais, L., Firefish Working Group: Joseph, J. V., John, P., Armin, K., Ulrich, K., Rosaline, Q., Irina, B., Patricia, D., Inge, J., Valentine, T., Sylvia, W., Elke De Vos,, Edmar, Z., Rodrigo De Holanda Mendonça,, Ciro Matsui Jr,, Ana Letícia Fornazieri Darcie,, Cleide, M., Maria Kiyoko Oyamada,, Daniel De Souza Costa,, Joyce, M., Graziela, P., Juliana Rodrigues Iannicelli,, Juliana Caires De Oliveira Achili Ferreira,, Wang, Y., Chaoping, H., Yiyun, S., Shuizhen, Z., Xiaomei, Z., Chen, Q., Shen, L., Ying, X., Zhenxuan, Z., Hui, L., Sujuan, W., Hui, X., Tian, S., Cuijie, W., Jing, W., Yiwen, C., Wenzhu, L., Lun, Q., Nina, B., Ivan, C., Martina Galiot Delic,, Petra Kristina Ivkić,, Nenad, V., Ivana, K., Boris, N., Marin, S., Odile, B., Teresa, G., Andrea, S., Emmanuel, B., Elodie Da Cunha,, Céline, L., Nabila, M., Helene, P., Stephanie, G., Allison, G., Charlotte, L., Darko, M., Ariadna, P., Shotaro, T., Emanuela, P., Bianchi Marzoli, S., Diletta, S., Myriam Garcia Sierra,, Gemma, T., Maria Teresa Arnoldi,, Marta, V., Riccardo, Z., Claudio, B., Noemi, B., Marina, P., Enrico, P., Giuseppe, R., Enrica, S., Lorenza, S., Elisa, T., Simone, M., Paola, T., Giacomo Pietro Comi,, Alessandra, G., Silvia Gabriella Osnaghi,, Valeria, M., Francesca, A., Federica, F., Michaela, F., Amalia, L., Elisa, M., Pane, M., Concetta, P., Pera, M. C., Amorelli, G. M., Costanza, B., Gugliemo, D., Orazi, L., Coratti, G., De Sanctis, R., Yasuhiro, T., Fumi, G., Naoki, K., Takanobu, M., Mana, O., Toru, F., Maria, M., Mateusz, K., Natalia, K., Urszula, S., Agnieszka, W., Jagoda, K., Agnieszka, S., Dmitry, V., Svetlana, A., Evgenia, M., Natalya, L., Nataliya, Y., Elena, L., Anastasya, M., Yulia, P., Olga, S., Cornelia, E., Elea, G., Konstantin, G., Patricia, S., Verena, K., Christine Wondrusch Haschke,, Haluk, T., Ibrahim, O., Didem, A., Nesibe Eroglu Ertugrul,, Hizal, G., Ceren, G., Bahadir, K., Selen Serel Arslan,, Elams Ebru Yalcin,, Fatma Gokcem Yildiz Sarikaya,, Bora, E., Sibel, K., Ipek, A., Aynur Ayse Karaduman,, Oznur Tunca Yilmaz,, Lucia, A., Anne, F., Anna Maria Baglieri,, Courtney, D., Elizabeth, M., Elizabeth, M., Amy, P., Shannon, B., Tina, D., Richard, G., Sally, Y., Risdiplam in Type 1 Spinal Muscular Atrophy, <<NEW ENGLAND JOURNAL OF MEDICINE>>, 2021; 384 (10): 915-923. [doi:10.1056/NEJMoa2009965] [http://hdl.handle.net/10807/213685]

Risdiplam in Type 1 Spinal Muscular Atrophy

Baranello, Giovanni;Mercuri, Eugenio;Bianchi Marzoli, Stefania;Claudio, Bruno;Pane, Marika;Pera, Maria Carmela;Amorelli, Giulia Maria;Orazi, Lorenzo;Coratti, Giorgia;De Sanctis, Roberto;
2021

Abstract

BackgroundType 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein.MethodsWe report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.ResultsA total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.ConclusionsIn infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.)The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status were reported.
Inglese
Baranello, G., Darras, B. T., Day, J. W., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Rose, K., El-khairi, M., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Seabrook, T., Fontoura, P., Servais, L., Firefish Working Group: Joseph, J. V., John, P., Armin, K., Ulrich, K., Rosaline, Q., Irina, B., Patricia, D., Inge, J., Valentine, T., Sylvia, W., Elke De Vos,, Edmar, Z., Rodrigo De Holanda Mendonça,, Ciro Matsui Jr,, Ana Letícia Fornazieri Darcie,, Cleide, M., Maria Kiyoko Oyamada,, Daniel De Souza Costa,, Joyce, M., Graziela, P., Juliana Rodrigues Iannicelli,, Juliana Caires De Oliveira Achili Ferreira,, Wang, Y., Chaoping, H., Yiyun, S., Shuizhen, Z., Xiaomei, Z., Chen, Q., Shen, L., Ying, X., Zhenxuan, Z., Hui, L., Sujuan, W., Hui, X., Tian, S., Cuijie, W., Jing, W., Yiwen, C., Wenzhu, L., Lun, Q., Nina, B., Ivan, C., Martina Galiot Delic,, Petra Kristina Ivkić,, Nenad, V., Ivana, K., Boris, N., Marin, S., Odile, B., Teresa, G., Andrea, S., Emmanuel, B., Elodie Da Cunha,, Céline, L., Nabila, M., Helene, P., Stephanie, G., Allison, G., Charlotte, L., Darko, M., Ariadna, P., Shotaro, T., Emanuela, P., Bianchi Marzoli, S., Diletta, S., Myriam Garcia Sierra,, Gemma, T., Maria Teresa Arnoldi,, Marta, V., Riccardo, Z., Claudio, B., Noemi, B., Marina, P., Enrico, P., Giuseppe, R., Enrica, S., Lorenza, S., Elisa, T., Simone, M., Paola, T., Giacomo Pietro Comi,, Alessandra, G., Silvia Gabriella Osnaghi,, Valeria, M., Francesca, A., Federica, F., Michaela, F., Amalia, L., Elisa, M., Pane, M., Concetta, P., Pera, M. C., Amorelli, G. M., Costanza, B., Gugliemo, D., Orazi, L., Coratti, G., De Sanctis, R., Yasuhiro, T., Fumi, G., Naoki, K., Takanobu, M., Mana, O., Toru, F., Maria, M., Mateusz, K., Natalia, K., Urszula, S., Agnieszka, W., Jagoda, K., Agnieszka, S., Dmitry, V., Svetlana, A., Evgenia, M., Natalya, L., Nataliya, Y., Elena, L., Anastasya, M., Yulia, P., Olga, S., Cornelia, E., Elea, G., Konstantin, G., Patricia, S., Verena, K., Christine Wondrusch Haschke,, Haluk, T., Ibrahim, O., Didem, A., Nesibe Eroglu Ertugrul,, Hizal, G., Ceren, G., Bahadir, K., Selen Serel Arslan,, Elams Ebru Yalcin,, Fatma Gokcem Yildiz Sarikaya,, Bora, E., Sibel, K., Ipek, A., Aynur Ayse Karaduman,, Oznur Tunca Yilmaz,, Lucia, A., Anne, F., Anna Maria Baglieri,, Courtney, D., Elizabeth, M., Elizabeth, M., Amy, P., Shannon, B., Tina, D., Richard, G., Sally, Y., Risdiplam in Type 1 Spinal Muscular Atrophy, <<NEW ENGLAND JOURNAL OF MEDICINE>>, 2021; 384 (10): 915-923. [doi:10.1056/NEJMoa2009965] [http://hdl.handle.net/10807/213685]
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