ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients

Jens Gottlieb, Martin R. Zamora, Tony Hodges, A. W. Musk, Urte Sommerwerk, Daniel Dilling, Selim Arcasoy, John Devincenzo, Verena Karsten, Shaily Shah, Brian R. Bettencourt, Jeffrey Cehelsky, Sara Nochur, Jared Gollob, Akshay Vaishnaw, Amy R. Simon, Allan R. Glanville

Research output: Contribution to journalArticle

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Abstract

Background Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. Methods We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. Results Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. Conclusions These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalJournal of Heart and Lung Transplantation
Volume35
Issue number2
DOIs
StatePublished - Feb 1 2016

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Bronchiolitis Obliterans
Respiratory Syncytial Virus Infections
Respiratory Syncytial Viruses
Placebos
Lung
Incidence
Ribavirin
Virus Replication
Small Interfering RNA
Transplant Recipients
Cohort Studies
Transplants
Therapeutics

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients. / Gottlieb, Jens; Zamora, Martin R.; Hodges, Tony; Musk, A. W.; Sommerwerk, Urte; Dilling, Daniel; Arcasoy, Selim; Devincenzo, John; Karsten, Verena; Shah, Shaily; Bettencourt, Brian R.; Cehelsky, Jeffrey; Nochur, Sara; Gollob, Jared; Vaishnaw, Akshay; Simon, Amy R.; Glanville, Allan R.

In: Journal of Heart and Lung Transplantation, Vol. 35, No. 2, 01.02.2016, p. 213-221.

Research output: Contribution to journalArticle

Gottlieb, J, Zamora, MR, Hodges, T, Musk, AW, Sommerwerk, U, Dilling, D, Arcasoy, S, Devincenzo, J, Karsten, V, Shah, S, Bettencourt, BR, Cehelsky, J, Nochur, S, Gollob, J, Vaishnaw, A, Simon, AR & Glanville, AR 2016, 'ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients', Journal of Heart and Lung Transplantation, vol. 35, no. 2, pp. 213-221. https://doi.org/10.1016/j.healun.2015.08.012
Gottlieb, Jens ; Zamora, Martin R. ; Hodges, Tony ; Musk, A. W. ; Sommerwerk, Urte ; Dilling, Daniel ; Arcasoy, Selim ; Devincenzo, John ; Karsten, Verena ; Shah, Shaily ; Bettencourt, Brian R. ; Cehelsky, Jeffrey ; Nochur, Sara ; Gollob, Jared ; Vaishnaw, Akshay ; Simon, Amy R. ; Glanville, Allan R. / ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients. In: Journal of Heart and Lung Transplantation. 2016 ; Vol. 35, No. 2. pp. 213-221.
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abstract = "Background Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. Methods We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. Results Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6{\%} vs 30.3{\%}, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. Conclusions These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.",
author = "Jens Gottlieb and Zamora, {Martin R.} and Tony Hodges and Musk, {A. W.} and Urte Sommerwerk and Daniel Dilling and Selim Arcasoy and John Devincenzo and Verena Karsten and Shaily Shah and Bettencourt, {Brian R.} and Jeffrey Cehelsky and Sara Nochur and Jared Gollob and Akshay Vaishnaw and Simon, {Amy R.} and Glanville, {Allan R.}",
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T1 - ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients

AU - Gottlieb, Jens

AU - Zamora, Martin R.

AU - Hodges, Tony

AU - Musk, A. W.

AU - Sommerwerk, Urte

AU - Dilling, Daniel

AU - Arcasoy, Selim

AU - Devincenzo, John

AU - Karsten, Verena

AU - Shah, Shaily

AU - Bettencourt, Brian R.

AU - Cehelsky, Jeffrey

AU - Nochur, Sara

AU - Gollob, Jared

AU - Vaishnaw, Akshay

AU - Simon, Amy R.

AU - Glanville, Allan R.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. Methods We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. Results Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. Conclusions These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.

AB - Background Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. Methods We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. Results Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. Conclusions These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.

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