Abstract
Background:
Sisunatovir is an investigational respiratory syncytial virus (RSV) antiviral that was effective in an adult human viral challenge study.
Methods:
In 2 multicenter studies, safety and pharmacokinetics of sisunatovir were evaluated in hospitalized individuals 1 month to 36 months of age (Study 1) and outpatient and hospitalized individuals 1 day to 60 months of age (Study 2) with RSV lower respiratory tract infection (RSV-LRTI). In Study 1 Part A, participants received single sisunatovir doses; in Part B, participants received placebo or multiple ascending sisunatovir doses every 12 hours for 5 days. In Study 2, participants received weight-based sisunatovir dosing or placebo every 12 hours for 5 days.
Results:
In Study 1 Part A, 19 participants received sisunatovir; 31 in Part B received sisunatovir (n = 22) or placebo (n = 9). Adverse events (AEs) were reported by 11 (57.9%) and 12 (38.7%) participants in Parts A and B, respectively. In Study 2, 10 participants received sisunatovir (n = 6) or placebo (n = 4). No treatment-related serious AEs were reported; all AEs were mild or moderate. In Study 1 Part A 12 hours post-dose, mean sisunatovir concentrations were within safety margins. In Part B, at the highest dose assessed for each group, steady-state trough concentrations surpassed those effective in the adult challenge study.
Conclusions:
In children with RSV-LRTI, sisunatovir was safe and well tolerated. The pediatric multiple-dose regimen achieved plasma concentrations effective at reducing viral load and symptoms in an adult challenge study; however, further studies are needed to identify doses providing comparable exposure across pediatric populations.
ClinicalTrials.gov registration number:
NCT04225897 (registered December 11, 2019); NCT06102174 (registered October 6, 2023)
Keywords: RSV, sisunatovir, pharmacokinetics, safety, pediatrics
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection (LRTI), including bronchiolitis and pneumonia, in children <5 years old.1–3 RSV-LRTI led to 3.6 million hospitalizations and 101,400 deaths in this pediatric age group worldwide in 2019.2 The burden of RSV-LRTI is highest in young infants, with nearly 60% of RSV-associated hospitalizations in infants <3 months of age.4 Additionally, RSV disease early in life may contribute to long-term sequelae, including episodes of recurrent wheeze and the development of asthma.5,6
Ribavirin, a nucleoside analog, is the only approved RSV antiviral and is specifically for the treatment of hospitalized pediatric patients with severe RSV-LRTI.7 However, ribavirin may be underutilized because of administration challenges and unclear efficacy; further studies are needed to confirm clinical benefit.7–9 Although antivirals are currently in development for the treatment of RSV disease,10,11 management of RSV disease in children and adults remains limited and primarily supportive.12
Recently, considerable progress has been made in the prevention of severe RSV disease in neonates and infants through the availability of maternal vaccination and monoclonal antibodies, nirsevimab and clesrovimab.13–20 Despite these developments, an ongoing unmet need remains for efficacious therapies in infants and young children who are ineligible for or cannot access preventive measures, and in pediatric patients with breakthrough infections and/or severe illness. Sisunatovir (RSV521, PF-07923568) is an orally available, small-molecule inhibitor of the RSV fusion (F) protein that has shown potency against RSV-A and RSV-B clinical isolates and against the RSV-A strain M37b in healthy adults.21 In a phase 2a human challenge study in healthy adults, sisunatovir demonstrated a significant reduction in viral load (VL) and RSV symptoms.22 The 2 early-phase studies reported here evaluated safety and pharmacokinetics (PK) of single or multiple sisunatovir doses in infants with RSV-LRTI.
METHODS
Study Designs
Study 1 was a multicenter, single-dose (Part A) and multiple-dose (Part B) trial conducted to evaluate safety and PK of single and multiple weight-based sisunatovir dosing in infants 1 month to 36 months of age hospitalized with RSV-LRTI (NCT04225897; REVIRAL 1; see Figure, Supplemental Digital Content 1, https://links.lww.com/INF/G546). Part A was an open-label, single-dose study conducted across 2 age groups. Part B was a randomized, double-blind, placebo-controlled study conducted across 3 cohorts in which participants received sisunatovir or placebo orally or via nasogastric tube every 12 hours (q12h) for 5 days (10 doses). The number of participants enrolled in Parts A and B and the dosing regimen in Part B depended on safety and PK data from participants enrolled in specified cohorts and the Data Safety Monitoring Committee (DSMC) recommendation.
Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in 1-day-old to 60-month-old infants and children with RSV-LRTI (NCT06102174). Up to 3 dosing cohorts (planned, cohort 1; optional, cohorts 2 and 3) were to be assessed, with each cohort divided into 4 age groups. Sisunatovir or placebo was administered orally or via nasogastric tube q12h in a 2:1 ratio for 5 days (10 doses). However, because of early study termination by the sponsor (due to business considerations, not safety concerns), only cohorts 1A (1 month−<6 months old), 1B (6−<12 months old) and 1C (12−60 months old) enrolled participants. Cohort 1D (age 1 day to ≤30 days) would only be open to enrollment following review of cohort 1A data by the DSMC. Sisunatovir doses expected to produce systemic steady-state exposures comparable to the 200-mg q12h adult dose were evaluated in and reported for cohorts 1A–1C.
Ethical study conduct is described in Text, Supplemental Digital Content 2, https://links.lww.com/INF/G547.
Study Populations
Study 1 included participants 1–36 months old weighing ≥3.5 kg, with a positive RSV test, LRTI diagnosis with active respiratory symptoms, and hospitalization for RSV-LRTI. For Study 1 Part B, RSV-LRTI symptoms must have been present for ≤7 days before the screening visit, and participants were required to be hospitalized for ≥3 days. Study 2 included participants 1 day–60 months old, weighing 2.5–23 kg, with a positive RSV test, evidence of LRTI (see Text, Supplemental Digital Content 2, https://links.lww.com/INF/G547), and with RSV-LRTI signs or symptoms for ≤7 days. Participants were excluded from both studies if they were born prematurely (gestational age: Study 1, <37 weeks; Study 2, <35 weeks) and were <1 year old at enrollment. In Study 2, preterm infants 35 to <37 weeks’ gestational age were permitted if they weighed ≥2.5 kg and were ≥2 months postnatal age at enrollment. Participants were excluded if they were known to have significant comorbidities, immunocompromised, concurrently infected with SARS-CoV-2 (Study 1), receiving an antiviral for another respiratory infection (Study 2) or suspected of having a clinically significant bacterial infection.
Safety
The primary objective of both studies was to describe the safety of sisunatovir. Safety endpoints included assessment of adverse events (AEs), laboratory tests, vital signs and electrocardiogram (ECG; ECG in Study 1 only). AE and serious AE (SAE) reports were collected from the time of informed consent through 7, 12 and 28 days after the last study intervention administration in Study 1 Part A, Study 1 Part B and Study 2, respectively. Treatment-emergent events are reported here. An external DSMC was to review all available safety and PK data, as specified for each study, and approve any dose escalation.
Pharmacokinetics
Secondary objectives of Studies 1 and 2 were the evaluation of PK parameters. The timings of PK samples are described in Text, Supplemental_Digital_Content_2 https://links.lww.com/INF/G547.
In Study 1, PK outcomes were assessed based on time to maximum plasma concentration (tmax), maximum observed plasma concentration (Cmax), area under the plasma concentration–time curve from time 0 to 12 hours (AUC0−12) and AUC from time 0 to last measurable plasma concentration (AUC0−t); Part B of Study 1 also included AUC from time 0 to end of last dosing interval and plasma trough concentration (Ctrough).
In Study 2, a population PK model that described adult and pediatric data was updated with nine studies, including data from Study 1 (see Text, Supplemental Digital Content 2, https://links.lww.com/INF/G547). Sisunatovir exposure in adults and pediatric patients was best described by a 1-compartment model with zero-order dose rate, first-order absorption and first-order elimination. This updated model was used to simulate plasma concentration–time curves for sisunatovir for individuals in Study 2 and to calculate post hoc estimates of PK parameters (Cmax at steady state, Ctrough at steady state and AUC0−12 at steady state) by age group. Because of the limited number of individuals enrolled, summaries of PK parameters from cohorts 1B and 1C were combined.
Other Assessments
An additional secondary endpoint in Study 1 Part B was to evaluate the effect of sisunatovir on the clinical course of RSV disease compared with placebo. Reduction in severity of symptoms was measured by a composite score over time. Clinical response was measured by investigators using the RSV clinical scoring system (Wang Bronchiolitis Severity Score [WBSS]; Table, Supplemental Digital Content 3, https://links.lww.com/INF/G548) and by parents using the adapted version of the ReSViNET Scale (Table, Supplemental_Digital_Content_4, https://links.lww.com/INF/G549).23,24
Another secondary endpoint was RSV VL analyzed by quantitative reverse transcriptase polymerase chain reaction from nasopharyngeal swab samples in Study 1 Part B and Study 2. See Text, Supplemental Digital Content 2, https://links.lww.com/INF/G547 for VL collection timepoints.
Statistics
In both studies, no formal sample size calculations were performed. Twenty-four participants in Study 1 Part B, receiving sisunatovir or placebo (2:1) at the same dose level and according to the same dosing regimen for their specified age group, were expected to be sufficient to assess safety and PK. In Study 2, 24 participants per cohort (6 participants per age group) were empirically chosen for randomization to provide adequate safety and PK information needed to inform dosing for future pediatric trials.
Study populations, including safety and modified intent-to-treat (mITT) population definitions, are summarized in Text, Supplemental_Digital_Content_2 https://links.lww.com/INF/G547. In both studies, safety outcomes were performed in the safety population; tabulated overall and by cohort, age group and treatment; and summarized using descriptive statistics (eg, frequencies, percentages). Similarly, PK analyses were performed in the PK populations and summarized descriptively by sampling time, treatment, cohort and age group.
All summaries and analyses of clinical outcomes were based on observed data in the mITT population of Study 1 Part B, which was not adequately powered to evaluate symptom endpoints, and neither tool used in this study (the WBSS for clinicians and the ReSViNET Scale for parental use) has been validated to evaluate the clinical course of RSV-LRTI in children. WBSS scores were summarized at baseline and at each post-baseline timepoint. Scores and changes from baseline were summarized by dose and time. Further details on efficacy analyses are provided in Text, Supplemental_Digital_Content_2, https://links.lww.com/INF/G547.
VL assessments were conducted in the mITT populations in Study 1 and the safety set in Study 2. The studies were not powered to compare VL differences between sisunatovir and placebo groups; all analyses were reported descriptively.
RESULTS
Participants
Study 1 was conducted between 13 November 2019 and 05 December 2022. In Part A, 19 participants were randomized and received sisunatovir; 3 withdrew and 16 completed the study (Fig. 1, Top panel). In Part B, 32 participants were randomized and received sisunatovir or placebo; 31 completed the study and 1 participant (cohort 3 sisunatovir 5.0-mg/kg group) withdrew on day 1 at parent/legal guardian request (Fig. 1 Center panel). Additional details are summarized in the Figure 1 footnote and Text, Supplemental_Digital_Content_5 https://links.lww.com/INF/G550.
FIGURE 1.
Participant disposition diagrams for Study 1 Parts A (top) and B (center) and Study 2 (bottom). mITT, modified intent-to-treat; PBO, placebo; PK, pharmacokinetics; SAE, serious adverse event. *Participant withdrew due to a non–treatment-related SAE of pyrexia on day 4. In Study 1 Part A, sisunatovir was suspended in water or formula/breast milk for oral administration (water was the suspending diluent for nasogastric tube administration). In Study 1 Part B, saline was the suspending diluent B, with water or milk used as alternative vehicles as needed. In Study 2, all cohorts were administered study drug with diluent of saline only. All 19 enrolled participants in Study 1 Part A were included in the safety population, the PK population and the mITT population. In Study 1 Part B, 96.9% (31 of 32) of participants were included in the safety population and the PK population, and 93.8% (30 of 32) were included in the mITT population. In Study 2, all participants were included in the safety population and 60.0% (6 of 10) were included in the PK population.
Study 2 was conducted between 15 February 2024 and 03 September 2024. Ten participants were randomized; 7 from the inpatient setting and 3 from the outpatient setting. Six participants received sisunatovir and 4 received placebo; all participants completed treatment and follow-up (Fig. 1, Bottom panel).
Demographics and baseline clinical characteristics of both studies are summarized for the overall populations in Table 1 and by individual cohorts in Tables, Supplemental_Digital_Content_6, https://links.lww.com/INF/G551 and Supplemental_Digital_Content_7 https://links.lww.com/INF/G552. RSV subtypes and viral coinfections are summarized in Text, Supplemental_Digital_Content_5, https://links.lww.com/INF/G550. Although Study 2 planned to enroll pediatric participants 1 day through 60 months old, the age range of participants enrolled at study termination was 4–29 months.
TABLE 1.
Demographics and Clinical Characteristics of Participants Receiving Sisunatovir or Placebo in Study 1 Parts A and B (Safety Population) and Study 2 (Full Analysis Population)
| Study 1 Part A | Study 1 Part B | Study 2 | |||||
|---|---|---|---|---|---|---|---|
| Total | Overall PBO | Overall treated | Total | Overall PBO | Overall treated | Total | |
| (N = 19) | (n = 9) | (n = 22) | (N = 31) | (n = 4) | (n = 6) | (N = 10) | |
| Age at screening, mo | |||||||
| Mean (SD) | 13.4 (10.3) | NA | NA | 8.4 (9.5) | 14.2 (8.2) | 14.0 (9.3) | 14.06 (8.387) |
| Median (range) | 11.5 (1–34) | NA | NA | 3.8 (1–34) | 15.0 (4.0–22.7) | 10.9 (5.1–29.0) | 12.10 (4.0, 29.0) |
| Female sex, n (%) | 7 (36.8) | 1 (11.1) | 11 (50.0) | 12 (38.7) | 2 (50.0) | 3 (50.0) | 5 (50.0) |
| Race, n (%) | |||||||
| White | 10 (52.6) | 4 (44.4) | 14 (63.6) | 18 (58.1) | 0 | 1 (16.7) | 1 (10.0) |
| Asian | 8 (42.1) | 2 (22.2) | 6 (27.3) | 8 (25.8) | 4 (100.0) | 4 (66.7) | 8 (80.0) |
| Other*/unknown | 1 (5.3) | 3 (33.3) | 2 (9.0) | 5 (16.1) | 0 | 1 (16.7) | 1 (10.0) |
| Ethnicity, n (%) | |||||||
| Hispanic/Latino | 4 (21.1) | 3 (3.33)† | 2 (9.1) | 5 (16.1) | 0 | 1 (16.7) | 1 (10.0) |
| Not Hispanic/Latino | 15 (78.9) | 5 (55.6) | 20 (90.9) | 25 (80.6) | 4 (100.0) | 5 (83.3) | 9 (90.0) |
| RSV-A+, n (%) | 10 (52.6) | 4 (44.4) | 14 (63.6)‡ | 18 (58.1) | 2 (50.0) | 3 (50.0) | 5 (50.0) |
| RSV-B+, n (%) | 9 (47.4) | 4 (44.4) | 9 (40.9)‡ | 13 (41.9) | 2 (50.0) | 3 (50.0) | 5 (50.0) |
| Viral coinfection, n/N (%) | 3/13 (23.1) | 3 (33.3) | 3 (13.6) | 6 (19.4) | 1 (25.0) | 3 (50.0) | 4 (40.0) |
| Time from symptom onset to first dose, d | |||||||
| Mean (SD) | NA | 2.8 (2.11) | 3.9 (1.70) | 3.6 (1.87) | 5.0 (1.63) | 3.2 (2.14) | 3.9 (2.08) |
| Median (range) | NA | 3.1 (0–6) | 4.3 (0.3–6) | 4.1 (0–6) | 5.0 (3–7) | 3.0 (1–6) | 4.5 (1–7) |
mo, month; NA, not available; PBO, placebo; RSV, respiratory syncytial virus.
Demographics for individual cohorts are in Tables, Supplemental Digital Content 6 and 7.
Full analysis population in Study 2 included all randomly assigned participants who received ≥1 dose of study intervention.
Includes Native Hawaiian or other Pacific Islander for Study 2.
Ethnicity was unknown for one participant in the cohort 5 placebo group.
One participant in the cohort 5 placebo group tested positive for both RSV-A and RSV-B.
Safety
In Study 1 Part A, 13 AEs were reported by 11 participants (57.9%), with 5 AEs (26.3%) considered treatment related (Table 2). All AEs in Part A were mild or moderate; no deaths or treatment-related SAEs occurred. One participant in cohort 1 experienced a moderate SAE of pyrexia on day 1 (11.9 hours after a single dose of sisunatovir) with a fever duration of <2 hours, which was considered serious because it prolonged hospitalization; the participant withdrew. Five treatment-related AEs (TRAEs) occurred in 5 individuals: 3 mild cases of vomiting, 1 report of moderate thrombocytosis and 1 report of mild sinus arrhythmia; all participants were in cohort 1. The participant experiencing sinus arrhythmia of mild intensity on day 3 (47.9 hours post-dose) following a single dose of sisunatovir was 18.9 months old, remained asymptomatic and had normal vital signs. The infant was concurrently receiving a short-acting beta-2-adrenergic agonist, salbutamol. The same ECG was reviewed by a pediatric cardiologist and reported as normal. Three participants in cohort 1 who vomited after dosing were administered doses diluted in water, and vomiting was attributed to poor palatability of sisunatovir when dosed via this method; vomiting was not observed in subsequent participants in cohorts 1 and 2 who received oral dosing using formula or breast milk as the suspending diluent.
TABLE 2.
Summary of AEs in Participants Receiving Sisunatovir or Placebo in Study 1 Parts A and B and Study 2 (Safety Populations)
| Study 1 | Part A | Part B* | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort 1 Age ≥6 to ≤36 months† |
Cohort 2 Age ≥1 to ≤6 months† |
Total* | Cohort 3 Age ≥6 to ≤36 months† |
Cohorts 4 and 5 Age ≥1 to <6 months† |
Total† | ||||||||||||
| 1.0 mg/kg (n = 3) |
2.0 mg/kg (n = 7) |
2.5 mg/kg (n = 3) |
2.0 mg/kg (n = 6) |
N = 19 | PBO (n = 3) | 2.5 mg/kg (n = 3) | 3.5 mg/kg (n = 4) | 5 mg/kg (n = 3) | PBO (n = 6) | 2.5 mg/kg (n = 12) | N = 31 | ||||||
| AE type, n (%); events | |||||||||||||||||
| Any AE | 2 (66.7); 2 | 5 (71.4); 5 | 3 (100); 5 | 1 (16.7); 1 | 11 (57.9); 13 | 1 (33); 3 | 2 (66.7); 6 | 1 (25.0); 1 | 1 (33.3); 1 | 4 (66.7); 17 | 3 (25.0); 10 | 12 (38.7); 38 | |||||
| Treatment-related AEs | 0 | 2 (28.6); 2 | 3 (100); 3 | 0 | 5 (26.3); 5‡ | 0 | 1 (33.3); 1 | 0 | 1 (33.3); 1§ | 0 | 1 (8.3); 1 | 3 (9.7); 3‖ | |||||
| SAEs | 0 | 1 (14.3); 1¶ | 0 | 0 | 1 (5.3); 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| Treatment-related SAEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| AEs leading to sisunatovir discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3); 1§ | 0 | 0 | 1 (3.2); 1 | |||||
| Fatal AEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| Cohort 1A >30 d to <6 months |
Cohort 1B 6 to <12 months |
Cohort 1C 12 to 60 months |
Overall | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study 2 | PBO (n = 1) | Sisunatovir (n = 1) | PBO (n = 1) | Sisunatovir (n = 2) | PBO (n = 2) | Sisunatovir (n = 3) | PBO (n = 4) | Sisunatovir (n = 6) | Total (N = 10) | ||||||||
| AE type, n (%); events | |||||||||||||||||
| Any AE | 1 (100); 1 | 0 | 1 (100); 4 | 1 (50.0); 2 | 1 (50.0); 2 | 3 (100); 8 | 3 (75.0); 7 | 4 (66.7); 10 | 7 (70.0); 17 | ||||||||
| Treatment-related AEs | 1 (100); 1# | 0 | 0 | 0 | 0 | 0 | 1 (25.0); 1 | 0 | 1 (10.0); 1 | ||||||||
| SAEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||
| Treatment-related SAEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||
| AEs leading to sisunatovir discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||
| Fatal AEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||
AE, adverse event; ECG, electrocardiogram; PBO, placebo; SAE, serious adverse event.
Sisunatovir or placebo suspended in saline or formula milk for oral administration every 12 hours for 5 days.
All data are presented as n (%) of participants with an event; number of events.
Treatment-related AEs were vomiting (n = 3 [all mild] in the cohort 1 sisunatovir 2.5-mg/kg group), thrombocytosis (n = 1 [moderate] in the cohort 1 sisunatovir 2.0-mg/kg group) and sinus arrhythmia (n = 1 [mild] in the cohort 1 sisunatovir 2.0-mg/kg group). The participant who experienced mild sinus arrhythmia on day 3 following a single dose of sisunatovir was asymptomatic with normal vital signs; the same ECG was reviewed by a pediatric cardiologist and reported as normal.
Participant discontinued study drug due to AE of moderate vomiting with first dose based on parent/legal guardian request.
Treatment-related AEs: vomiting (n = 1 [moderate] in the cohort 3 sisunatovir 5-mg/kg group), diarrhea (n = 1 [mild] in the cohort 4 sisunatovir 2.5-mg/kg.
One participant experienced a moderate SAE of pyrexia with a duration of <2 hours that was considered serious because it prolonged hospitalization.
One participant reported a treatment-related AE of constipation.
In Study 1 Part B, 38 AEs were reported by 12 participants (38.7%), with 3 AEs in 3 participants (9.7%) considered TRAEs (Table 2). All AEs in Part B were mild or moderate, and no deaths or SAEs occurred. The 3 TRAEs all occurred in participants who received sisunatovir and included 1 report of moderate vomiting (cohort 3), one of mild thrombocytosis (cohort 3), and one of mild diarrhea (cohort 4). The participant in cohort 3, experiencing moderate vomiting with dose 1 (day 1), was subsequently withdrawn at parent/guardian request.
In Study 2, 17 AEs were reported in 7 participants (70.0%), with 1 TRAE (constipation) reported in a placebo recipient (Table 2). All AEs were mild; no SAEs, severe AEs or deaths were reported. Two mild AEs of vomiting were reported (sisunatovir, n = 1; placebo, n = 1); neither were considered TRAEs.
Pharmacokinetics
Table 3 summarizes plasma PK parameters of sisunatovir for Study 1 Part A. In cohort 1, the sisunatovir 1.0-mg/kg and 2.5-mg/kg groups exhibited limited exposure to sisunatovir (Fig. 2, Top panel). In the 2.5-mg/kg group, this limited exposure was attributed to the poor palatability of sisunatovir when administered by oral syringe using pharmacopeia-grade water as the suspending diluent. Reducing the dose to 1.0 mg/kg (suspended in water) did not have the same palatability issues but resulted in plasma levels below the limit of quantitation. In the sisunatovir 2.0-mg/kg group in cohort 1 and cohort 2, all but 1 participant exhibited exposure to sisunatovir after oral administration when dosed by oral syringe using formula or breast milk as the suspending diluent. Sisunatovir was absorbed into systemic circulation with a median tmax of approximately 4.6–4.8 hours (Table 3).
TABLE 3.
Plasma Sisunatovir Pharmacokinetic Parameters Among Participants Receiving Sisunatovir in Study 1 Parts A and B and Study 2 (Pharmacokinetic Populations)
| Study 1 Part A | Cohort 1* | Cohort 2* | |||
|---|---|---|---|---|---|
| 1.0 mg/kg (n = 3) | 2.0 mg/kg (n = 7) | 2.5 mg/kg (n = 3) | 2.0 mg/kg (n = 6) | ||
| Parameter | |||||
| tmax, h† | 4.2 (4.0–4.5) [n = 3] |
4.6 (4.4–6.2) [n = 7] |
7.0 (4.9–48.3) [n = 3] |
4.8 (2.0–6.7) [n = 6] |
|
| Cmax, ng/mL | 1.6 (2.8) [n = 3] |
8.1 (7.9) [n = 7] |
3.0 (3.1) [n = 3] |
28.0 (17.5) [n = 6] |
|
| AUC0-12, h·ng/mL | 9.2 (16.0) [n = 3] |
45.0 (48.0) [n = 7] |
6.5 (9.1) [n = 2] |
201.0 (143.0) [n = 6] |
|
| AUC0-t, h·ng/mL | 23.1 (NA) [n = 1] |
48.1 (49.9) [n = 6] |
14.0 (1.5) [n = 2] |
287.0 (217.0) [n = 6] |
|
| Cohort 3* | Cohorts 4 and 5 Combined* | ||||
|---|---|---|---|---|---|
| Study 1 Part B | 2.5 mg/kg (n = 3) |
3.5 mg/kg (n = 4) |
5 mg/kg (n = 3) |
2.5 mg/kg (n = 12) |
|
| Parameter | |||||
| tmax, h†: dose 1 | 4.6 (4.3–4.6) [n = 3] |
4.3 (3.6–11.6) [n = 4] |
4.2 (2.5–4.2) [n = 3] |
4.3 (3.8–12.0) [n = 12] |
|
| tmax, ss, h†: dose 6 | 4.4 (4.4–4.5) [n = 3] |
4.0 (3.7–4.9) [n = 3] |
4.5 (4.1–5.0) [n = 2] |
4.4 (0–11.8) [n = 11] |
|
| Cmax, ng/mL: dose 1 | 43.2 (36.7) [n = 3 |
24.9 (20.0) [n = 4] |
115.0 (182.0) [n = 3] |
50.7 (72.1) [n = 12] |
|
| Cmax, ss, ng/mL: dose 6 | 30.9 (31.3) [n = 3] |
67.8 (86.3) [n = 3] |
212.0 (157.0) [n = 2] |
165.0 (131.0) [n = 11] |
|
| AUC0-12, h·ng/mL: dose 1 | NA [n = 0] |
NA [n = 0] |
1170 (1460) [n = 2] |
153 (105) [n = 5] |
|
| AUC0-12, ss, h·ng/mL: dose 6 | 87.9 (NA) [n = 1] |
184.0 (NA) [n = 1] |
NA [n = 0] |
1360.0 (346.0) [n = 2] |
|
| AUC0-t, h·ng/mL: dose 1 | 288.0 (251.0) [n = 3] |
163.0 (132.0) [n = 4] |
1170.0 (1460.0) [n = 2] |
324.0 (332.0) [n = 12] |
|
| AUC0-t, ss, h·ng/mL: dose 6 | 225.0 (233.0) [n = 3] |
477.0 (594.0) [n = 3] |
1560.0 (1010.0) [n = 2] |
1180.0 (797.0) [n = 11] |
|
| Cavg, ss, ng/mL: dose 6 | 7.3 (NA) [n = 1] |
15.3 (NA) [n = 1] |
NA [n = 0] |
113.0 (28.8) [n = 2] |
|
| Ctrough, SS, ng/mL (pre-dose 6) | 8.5 (9.9) [n = 3] |
24.3 (24.7) [n = 4] |
70.8 (20.9) [n = 3] |
69.7 (61.6) [n = 12] |
|
| Study 2 | Cohort 1A 2.5 mg/kg (n = 1) Age 5 months |
Cohort 1B + 1C 4.5 mg/kg (n = 5) Age 7–29 months |
|||
|---|---|---|---|---|---|
| Parameter | |||||
| AUC0-12,SS, h·ng/mL†: Last dose |
65.3 [n = 1] |
332 (207-480) [n = 5] |
|||
| Cmax,SS, ng/mL†: Last dose |
8.8 [n = 1] |
42.9 (26.9-57.7) [n = 5] |
|||
| Ctrough,SS, ng/mL†: Last dose | 2.76 [n = 1] |
13.9 (8.59-21.7) [n = 5] |
|||
AUC0-12, area under the plasma concentration–time curve from 0 to 12 hours; AUC0-t, area under the plasma concentration–time curve from 0 to the last measurable concentration; Ctrough, observed trough plasma concentration; Cavg, average plasma concentration over the dosing interval; Cmax, maximum observed plasma concentration; NA, not applicable; PK, pharmacokinetic; ss, parameter at steady state; tmax, time to maximum plasma concentration.
For Study 1, individual PK parameters were calculated based on the noncompartmental analysis. For Study 2, individual PK parameters after the last dose (dose 10) were calculated based on the empirical Bayes parameter estimates given a population PK model (Text, Supplemental Digital Content 2, https://links.lww.com/INF/G546).
All data are presented as mean (SD) [n] unless otherwise indicated.
Median (range) data are presented.
FIGURE 2.
Mean sisunatovir plasma concentration over time for Study 1 Part A (single dose; top) and Part B (multiple doses; bottom). PK, pharmacokinetics. Plasma sisunatovir concentrations below the limit of quantification were treated as 0 µg/L. Baseline results were imputed as 0 µg/L for all individuals in the PK population. Samples were not taken before dose. Lower SD bars were truncated at 0 µg/L.
Table 3 summarizes plasma PK parameters of sisunatovir for Study 1 Part B. In all cohorts, sisunatovir was absorbed into systemic circulation with a median tmax ranging from 4.0 to 4.6 hours. At steady state, repeat dosing of sisunatovir produced a mean Ctrough,ss (pre-dose 6) of 70.8 ng/mL in the cohort 3 5.0-mg/kg group and 69.7 ng/mL in the cohorts 4 and 5 2.5-mg/kg groups (Table 3; Fig. 2, bottom panel).
Table 3 summarizes population PK model-derived plasma PK parameters of sisunatovir for Study 2. The steady-state predictions based on the sparse sampling of very few participants (cohort 1A, n = 1; cohorts 1B + 1C, n = 5), produced a median (range) Ctrough,ss (before last dose) of 2.8 ng/mL in cohort 1A 2.5-mg/kg group and 13.9 ng/mL (8.59–21.7) in combined cohorts 1B and 1C 4.5-mg/kg groups.
Other Assessments
Clinical and Parental Assessments
In Study 1 Part B, median (range) time from symptom onset to first dose was shorter in the placebo group (cohort 3: 1.9 days [1–6]; cohorts 4 and 5: 3.1 days [0–5]) than all sisunatovir cohorts (cohort 3: 2.5 mg/kg, 4.5 days [3–6]; 3.5 mg/kg, 3.5 days [2–5]; 5.0 mg/kg, 4.0 days [0.3–5]; cohorts 4 and 5: 2.5 mg/kg, 4.6 days [1–6]; Table, Supplemental_Digital_Content_6 https://links.lww.com/INF/G551). The WBBS (RSV clinical score) was reported as mild or moderate for all participants and time points except one participant who reported a severe score (WBSS) at the pre-dose 5 visit. Change from baseline in WBBS and the mixed-effects analysis of covariance change from baseline are presented in Figure, Supplemental_Digital_Content_8, https://links.lww.com/INF/G553 and Table, Supplemental_Digital_Content_9, https://links.lww.com/INF/G554, respectively.
At baseline, the mean ReSViNET Scale completed by parents in Part B cohorts 4 and 5 was higher in the sisunatovir 2.5-mg/kg group (11.8) compared with the placebo group (8.7; analysis of covariance change from baseline, −9.5; Table, Supplemental_Digital_Content_10 https://links.lww.com/INF/G555). Overall, the ReSViNET score reduced from baseline to 40–48 hours post-Dose 10 for cohorts 4 and 5, with a higher reduction in sisunatovir groups compared with the placebo group, with a between-group difference of −1.6 (95% CI, −4.4, 1.2).
Viral Load
In Study 1 Part B and Study 2, the mean RSV VL decreased gradually after treatment, with no meaningful differences between treatment groups (Figure, Supplemental_Digital_Content_11 https://links.lww.com/INF/G556).
DISCUSSION
In the 2 studies evaluating safety and PK of sisunatovir in infants and young children with RSV-LRTI, oral sisunatovir was safe and well tolerated, with all AEs mild or moderate and no treatment-related SAEs or deaths reported. In Study 1 Part A, 12 hours after dose administration, the mean sisunatovir concentrations were within safety margins. In Study 1 Part B, exposures were within safety margins at the highest dose assessed for each age group, and steady-state trough concentrations surpassed those found to be effective at reducing VL and clinical symptoms in an adult viral challenge study.22 Study 2 was subsequently conducted to optimize dose selection and expand the ages enrolled (allowing neonates and children up to 5 years old) to inform future pediatric trials evaluating clinical efficacy. However, because of the small sample size in Study 2 at study termination, the study was not powered to establish the PK of sisunatovir in this population. Pediatric simulations based on the current population PK model indicate that further dose optimization is needed for pediatric patients to ensure that sisunatovir achieves comparable exposures to those achieved with the 200-mg twice-daily dose in the adult challenge study.
Certain study limitations should be noted. First, the results should be interpreted with caution because of the small sample size in each treatment cohort of both studies. The PK data from these studies are sparse, and the pediatric exposure simulations have limitations because of the small dataset. Additionally, sisunatovir exposure prediction in younger age groups is sensitive to assumptions for ontogeny maturation.
Antiviral effect could not be evaluated for sisunatovir given the study design limitations and small sample sizes. The symptom scores used in Study 1, the WBSS clinical score and the ReSViNET parental score are not validated tools for the evaluation of children with RSV disease. Additionally, Study 1 Part B was not designed or powered to evaluate changes in symptoms across treatment groups, and Study 1 Part B and Study 2 were not powered to evaluate changes in VL across treatment groups; thus, clinically meaningful differences between groups regarding symptoms or VL change could not be evaluated.
In a recently completed pediatric phase 2 RSV study, despite the N-inhibitor zelicapavir showing antiviral effect, no difference in symptom reduction was observed with the parental ReSViNET tool.25 However, subsequent ad hoc analyses showed reduced time to complete symptom resolution in the zelicapavir vs placebo group using the ReSViNET scale.26 Additionally, a phase 3 study evaluating ziresovir, an F-inhibitor, in children hospitalized with RSV disease achieved the primary endpoint of reduced clinical symptoms at day 3 using the WBSS.10 Further research is needed to build on these recent developments, to move closer to validating clinically meaningful tools needed for pediatric RSV clinical trials.
In conclusion, single and multiple doses of sisunatovir in infants and young children with RSV-LRTI were safe and well tolerated in these 2 studies. However, the small sample size limits the ability to recommend doses to achieve adequate exposures across the pediatric age spectrum. Thus, further evaluation and dose optimization are needed in pediatric participants to identify doses that would provide comparable exposure in children with RSV-LRTI to the exposures effective in the adult challenge study, and with potential to show efficacy in a pivotal pediatric trial.
ACKNOWLEDGMENTS
We thank all the participants and families who volunteered in these 2 studies. We also thank all the study site personnel for their contributions. Additionally, we are grateful to all Pfizer colleagues for their contribution to the development and conduct of this study, including Mary Lynn Baniecki, Ogert Fisniku, Justin Smith and Lucy Williams. Medical writing support was provided by Erin O’Keefe, PhD, and Chris Kirk, PhD, of ICON (Blue Bell, PA) and was funded by Pfizer Inc.
Supplementary Material
Footnotes
Sponsored by Pfizer Inc.
C.C. has participated in RSV clinical trials with Sanofi, ENANTA and Janssen. S.S.T., B.H., E.T., R.M.F., M.K., A.B., S.R., S.S., H.W., I.O., S.Z. and N.N.A. are current or former employees of Pfizer Inc and may hold stock or stock options. I.J. is an advisor to Pfizer. K.S. is employed as a lecturer at Naresuan University in Phitsanulok, Thailand. M.D. is a current employee of the Malaysian Ministry of Health. A.N., S.O., K.A. and J.N. have no disclosures to report. P.R. has participated in RSV clinical trials with Pfizer, Sanofi, ENANTA and Janssen. T.-H.T. has participated in RSV clinical trials with Ark Biosciences, Ablynx NV, Janssen and Merck, and Sharp & Dohme Corp. W.T. has received research grants paid to Institution from Pfizer, Merck, Moderna, GSK, Janssen, AstraZeneca, Gilead and Lumen.
S.S.T. and C.C. contributed equally. B.H., S.R., and H.W. affiliation at time of study conduct.
C.C., I.J., K.S., M.D., A.N., P.R., T.-H.T., S.O., K.A., W.T. and J.N. were involved in enrollment and data collection. S.S.T., B.H., R.M.F., A.B. and S.Z. were involved in study concept and design and data analysis. S.S. and I.O. were involved in data analysis. All authors drafted, edited, or critically reviewed the manuscript. All authors approved the final draft.
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).
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