WO2024252355A1

WO2024252355A1 - Pediatric dosing regimens comprising a fusion inhibitor for the treatment of rsv

Info

Publication number: WO2024252355A1
Application number: PCT/IB2024/055600
Authority: WO
Inventors: Arthur James BERGMAN; Ryan Michael FRANKE
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 2023-06-08
Filing date: 2024-06-07
Publication date: 2024-12-12
Anticipated expiration: 2025-12-08

Abstract

The invention relates to dosing regimens for the treatment of RSV infection comprising administering to a pediatric subject in need thereof a daily dose of a sisunatovir as a single agent or in combination with other RSV therapies.

Description

PEDIATRIC DOSING REGIMENS COMPRISING A FUSION INHIBITOR FOR THE TREATMENT OF RSV

Background of the Invention

Respiratory Syncytial Virus (RSV) is a negative-sense, single-stranded RNA virus of the Pneumoviridae family. RSV is readily transmitted by secretions from an infected person via surfaces or hand-to-hand transfer. Following successful inoculation, the incubation period is between four and six days during which time the virus spreads from the nasopharynx to the lower respiratory tract by fusion of infected with uninfected cells and by sloughing of the necrotic epithelium. In infants, coupled with increased mucus secretion and oedema, this can lead to mucus plugging causing hyper-inflation and collapse of distal lung tissue indicative of bronchiolitis. Hypoxia is common and the ability to feed is often impaired because of respiratory distress. In RSV pneumonia, inflammatory infiltration of the airways consists of mononuclear cells and is more generalized, with involvement of the bronchioles, bronchi and alveoli. The duration and degree of viral shedding has been found to correlate with the clinical signs and severity of disease.

RSV is the leading cause of serious respiratory tract infections in infants and young children throughout the world. The highest morbidity and mortality occur in those born prematurely and for those with chronic lung or heart disease, although many infants hospitalized for RSV infection are otherwise healthy. Severe RSV infection in infancy can lead to several years of recurrent wheezing and is linked to the later development of asthma.

RSV is also a major cause of morbidity and mortality in the elderly and in immunocompromised children and adults as well as those with chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).

Current anti-RSV treatment involves the use of ribavirin or a monoclonal antibody such as palivizumab or nirsevimab. Such use of monoclonal antibodies is usually as a prophylactic, rather than therapeutic, treatment of RSV. Although these antibodies are often effective, their use is restricted to preterm infants and infants at high risk. Indeed, its limited utility means that it is unavailable for many people in need of anti-RSV treatment. There is therefore an urgent need for effective alternatives to existing anti-RSV treatment.

Small molecules have also been proposed as inhibitors of RSV. These include benzimidazoles and benzodiazepines. For instance, benzimidazole inhibitors of RSV are disclosed in WO 02/062290 and WO 03/053344 (Squibb Bristol Myers Co); WO 2010/103306 (Astrazeneca UK Ltd); and WO 2013/068769, WO 2016/055780, WO 2019/016566 and WO 2019/122928 (ReViral Limited). The discovery and initial development of RSV604, a benzodiazepine compound having sub-micromolar anti-RSV activity, is described in Antimicrobial Agents and Chemotherapy, Sept. 2007, 3346-3353 (Chapman et al). Benzodiazepine inhibitors of RSV are also disclosed in publications including WO 2004/026843 and WO 2005/089770 (Arrow Therapeutics Limited); WO 2016/166546 and WO 2018/033714 (Durham University); WO 2017/015449, WO 2018/129287 and WO 2018/226801 (Enanta Pharmaceuticals, Inc.); and WO 2021/079121 , WO 2021/084280, WO 2021/032992, WO 2022/008911 and WO 2022/008912 (ReViral Limited).

1 '-{[5-(Aminomethyl)-1 -(4,4,4-trif luorobutyl)- 1 H-1 ,3-benzodiazol-2-yl]methyl}- 6'-fluoro- 1 ',2'-dihydrospiro[cyclopropane-1 ,3'-indole]-2'-one, also known as sisunatovir, is a respiratory syncytial virus fusion inhibitor currently in phase 2 clinical trials for the treatment of RSV infections and has the following structure:

Sisunatovir and preparation thereof is described in international publication WO 2016/055780. Clinical studies in adults have investigated the pharmacokinetics of sisunatovir (DeVincenzo et aL, Antimicrobial Agents and Chemotherapy Feb. 2020 Vol. 64 issue 2). The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

There is however a need for appropriate pediatric dosing regimens of sisunatovir and pharmaceutically acceptable salts thereof, as a single agent or in combination therapies for treating RSV infection, to improve benefit and convenience to pediatric patients while minimizing adverse events and risks to them.

Based on what is currently known, sisunatovir hydrochloride salt (HCI) adult dosing is expected to be 200 mg twice daily (DeVincenzo et al). Based on allometric scaling, pediatric doses with comparable exposure to adults was predicted to be approximately 2 mg/kg for pediatric patients aged 1 month to < 6 months and 2.5 mg/kg for pediatric patients aged 6 months to 36 months. However, it was unexpectedly found these doses resulted in unacceptably low exposures compared to adults and that the dose to pediatric patients aged 1 to 60 months should be much higher to achieve comparable exposure to adult patients. Summary of the Invention

The present invention provides, in part, dosing regimens for administering sisunatovir, or a pharmaceutically acceptable salt thereof, to a subject as a single agent, and in combination therapies, for treating RSV infection in pediatric populations. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

According to an embodiment of the invention, there is provided a method for treating RSV infection comprising administering to a 1- to 60-month-old subject in need thereof a dose of from about 4.0 mg/kg to about 8.0 mg/kg of sisunatovir HCI, wherein the dose is administered twice per day (BID or Q12h).

Described below are embodiments of the invention, where for convenience Embodiment 1 (E1 ) is identical to the embodiment provided above.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

Brief Description of Drawing

FIG. 1 shows the results of a Phase 2 Open-Label Study in Infants with Respiratory Syncytial Virus Lower Respiratory Tract Infection, followed by a Double-blind, Placebo Controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (sisunatovir).

Detailed Description of the Invention

The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

E1 A method for treating RSV infection, as defined above.

E2 A method of embodiment E1 , wherein the dose is from about 4.0 mg/kg to about 7 mg/kg of sisunatovir HCI.

E3 A method of embodiment E1 , wherein the dose is from about 4.0 mg/kg to about 6.5 mg/kg of sisunatovir HCI.

E4 A method of embodiment E1 , wherein the dose is from about 4.2 mg/kg to about 6.5 mg/kg of sisunatovir HCI. E5 A method of embodiment E1 , wherein the dose is from about 4.5 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

E6 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

E7 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

E8 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 5.5 mg/kg of sisunatovir HCI.

E9 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 5.0 mg/kg of sisunatovir HCI.

E10 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.2 mg/kg to about 4.8 mg/kg of sisunatovir HCI.

E11 A method of embodiment E1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.5 mg/kg of sisunatovir HCI.

E12 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

E13 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 4.0 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

E14 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 4.5 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

E15 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 5.0 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

E16 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 5.2 mg/kg to about 5.8 mg/kg of sisunatovir HCI. E17 A method of embodiment E1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 5.5 mg/kg of sisunatovir HCL

E18 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCL

E19 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 4.5 mg/kg to about 7 mg/kg of sisunatovir HCL

E20 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 5.0 mg/kg to about 7.0 mg/kg of sisunatovir HCL

E21 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 5.5 mg/kg to about 6.5 mg/kg of sisunatovir HCL

E22 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 5.7 mg/kg to about 6.3 mg/kg of sisunatovir HCL

E23 A method of embodiment E1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 6.0 mg/kg of sisunatovir HCL

E24 A method for treating RSV infection comprising administering to a 1- to 60-month-old subject in need thereof a total daily dose of from about 8.0 mg/kg to about 16.0 mg/kg of sisunatovir HCL

E25 A method of embodiment E24 wherein the total daily dose is from about 8.0 mg/kg to about 13 mg/kg.

E26 A method of embodiment E24 wherein the subject is a 1- to 6-month-old and the total daily dose is from about 8 mg/kg to about 10 mg/kg.

E27 A method of embodiment E24 wherein the subject is a 6- to 12-month-old and the total daily dose is from about 10 mg/kg to about 12 mg/kg.

E28 A method of embodiment E24 wherein the subject is a 12- to 60-month-old and the total daily dose is from about 11 mg/kg to about 13 mg/kg. E29 A method according to any of embodiments E1 to E28 and E30 to E40 wherein sisunatovir HCI is administered orally.

E30 A method according to embodiment E1 wherein the dose is about 5 mg/kg to about 6.0 of sisunatovir HCI.

E31 A method for treating RSV infection according to any of the embodiments E1 to E30 and E32 to E40 wherein the dosage of sisunatovir HCI is replaced by an equivalent dosage of sisunatovir free base.

E32 A method for treating RSV infection comprising administering to a 6- to 36-month-old subject in need thereof a dose of from about 4.0 mg/kg to about 5.5 mg/kg of sisunatovir HCI, or a pharmaceutically acceptable salt thereof, wherein the dose is administered twice per day (BID).

E33 A method of embodiment E32, wherein the dose is from about 4.0 mg/kg to about 5.0 mg/kg.

E34 A method of embodiment E32, wherein the dose is from about 4.25 mg/kg to about 5.0 mg/kg.

E35 A method of embodiment E32, wherein the dose is from about 4.25 mg/kg to about 4.75 mg/kg.

E36 A method of embodiment E32, wherein the dose is from about 4.3 mg/kg to about 4.6 mg/kg.

E37 A method of embodiment E32, wherein the dose is from about 4.4 mg/kg to about 4.6 mg/kg.

E38 A method of embodiment E32, wherein the dose is about 4.5 mg/kg.

E39 A method of any of the embodiments E1 to E38, wherein sisunatovir is administered as a single agent.

E40 A method of any of the embodiments E1 to E38, wherein sisunatovir is administered in combination with another RSV treatment. Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined.

Definitions

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a sisunatovir) means that the parameter may vary by as much as 20% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg means 5 mg/kg ± 20%, i.e., it may vary between 4 mg/kg and 6 mg/kg.

As used herein, the term “combination”, unless otherwise indicated, means a fixed-dose combination or a combination of agents that is administered intermittently, concurrently, or sequentially, according to the same or different route of administration and according to the same or different dosage schedules.

As used herein, the terms "treating", "treat" or "treatment", unless otherwise indicated, embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s RSV infection or any tissue damage associated with the RSV infection.

Administration and Dosing

As used herein, the phrase “effective dose” refers to the amount of sisunatovir that elicits the biological or medicinal response in the 1 - to 60-month-old subject, which may include one or more of the following:

(1 ) preventing the disease; for example, preventing the RSV infection in a 1 - to 60- month-old subject that may have been exposed to RSV but does not yet experience or display the pathology or symptomatology of the RSV infection;

(2) inhibiting the disease; for example, inhibiting the RSV infection in a 1 - to 60- month-old subject that is experiencing or displaying the pathology or symptomatology of the RSV infection (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

(3) ameliorating the disease; for example, ameliorating the pathology or symptomatology of the RSV infection (i.e., reversing the pathology or symptomatology or both). The use of sisunatovir to treat RSV infection is administered in an amount effective to treat a condition as described herein. Sisunatovir may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.

In one embodiment, sisunatovir may be administered as a hydrochloride salt (HCI). For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds described herein are known to one of skill in the art.

Sisunatovir may administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

Sisunatovir may be administered orally. Oral administration may involve swallowing, so that sisunatovir enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

In a preferred embodiment, the daily dose of sisunatovir or a pharmaceutically acceptable salt thereof, is administered orally twice a day.

Sisunatovir, or a pharmaceutically acceptable salt, may be present in a pharmaceutical composition which includes at least one pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject. The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The amount of sisunatovir, or a pharmaceutically acceptable salt, in the pharmaceutical compositions can be any amounts disclosed herein.

The formulation will preferably be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.

Examples

In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner. Example 1 : Phase 2 Sisunatovir Clinical Trial In Pediatric Population

Overview

Sisunatovir was investigated in a Phase 2 Open-Label Study in Infants with Respiratory Syncytial Virus Lower Respiratory Tract Infection, followed by a Double-blind, Placebo Controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (sisunatovir).

Study Design: The overall study design is detailed in FIG. 1 . The study contains two parts, Part A and Part B: To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalized with RSV lower respiratory tract infection (LRTI).

Selection of Starting Single Dose of Sisunatovir HCI in Pediatrics

The starting doses were estimated using a population pharmacokinetic (PK) approach according to the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) requirements (FDA CDER/CBER Guidance for Industry; EMEA/CHMP Guideline). PK data from healthy adult subjects who had received sisunatovir during clinical studies: C5241001 (formerly referenced as REVC001 ) and C5241002 (formerly referenced as REVC002) were used to build a population PK model using Phoenix nonlinear mixed effects (NLME) software. The model was verified using standard checks, such as Visual Predictive Check plots, bootstrap analysis, and goodness-of-fit plots (EMA, 2007), which compared the predicted concentration values to actual observed concentrations as well as showed the residual differences between predicted and actual concentrations as an assessment of model validity. The terms for allometric scaling and maturation factors in an infant population, depending on postnatal age and body weight, were added to the model to simulate PK profiles and resulting exposure in infants. The model was informed with the available demographic covariates to allow the incorporation of a nonlinear dose effect, formulation, and/or food effect, and available body weight and age data to support extrapolation to infants.

The simulated exposure was restricted by the lower bound for efficacy, using the EC90 for RSV inhibition, applied to the unbound concentration after the first dose (Dose 1 ) at the end of the dosing interval of 12 hours (minimum concentration [Cmin]). This equated to a total sisunatovir concentration of 7.3 ng/mL (converted from unbound). Initial target was Cmin of ~21 ng/mL in Part A. In Part B, exposure (Cmin, Cmax, and area under the curve from time zero to tau [the dosing interval] [AUCtau]) targets were comparable to 200 mg Q12h in adults. 200 mg Q12h in adults was found to be efficacious in C5241002 (viral challenge study). To assess where the upper limit of the exposure could be set, the Cmax and AUCtau for the last dose (Dose 10) of the BID dosing regimen in adult subjects dosed at 350 mg of sisunatovir (Clinical Study C5241002 [formerly referenced as REVC002])) were used as a guideline and are presented in a separate report (Syneos Health, 2018). Therefore, the upper limit for dose levels was selected such that the peak plasma exposure levels did not exceed the group mean values observed in Clinical Study C5241002 [formerly referenced as REVC002]) (Cmax of 294 ng/mL) and total exposure (AUCtau 2500 ngxh/mL).

The resulting proposed starting doses for Part A from Phoenix NLME population PK model, Cohort 2, was 2 mg/kg for infants >1 month to <6 months of age and for Part A, Cohort 1, was 2.5 mg/kg for infants >6 months to <36 months of age for actual doses and dose adjustments.

Part A (single dose)

As per protocol, the first group of 3 subjects enrolled into Cohort 1 (age: >6 months to <36 months) received a single dose of 2.5 mg/kg sisunatovir suspended in pharmacopoeial- grade water administered by oral syringe. At the initial dose of 2.5 mg/kg sisunatovir suspended in pharmacopoeial-grade water, only 2 out of 3 subjects had 1 post-Dose sample collected, only

1 of which was quantifiable for sisunatovir. The third subject exhibited quantifiable concentration of sisunatovir until at least 12 hours post-Dose. The reduced number of PK samples taken from

2 subjects dosed at 2.5 mg/kg was likely due to poor palatability of sisunatovir when suspended in pharmacopoeial-grade water, which resulted in one subject being withdrawn from the study. Dose adjustments for sisunatovir in Cohort 1 were made as follows: 1 .0 mg/kg. Three subjects were dosed at 1 .0 mg/kg via oral syringe with sisunatovir suspended in pharmacopoeial-grade water. At the next dose level of 1 .0 mg/kg sisunatovir suspended in pharmacopoeial-grade water, most of the PK samples analysed were below the limit of quantification (BLQ), except for 2 quantifiable concentrations for 1 of the 3 subjects.

Dose adjustments for sisunatovir in Cohort 1 were made as follows: and then 2.0 mg/kg. At a dose of 2.0 mg/kg suspended in formula milk for oral administration, 6 out 7 subjects had quantifiable concentrations of sisunatovir through the 6-to-8-hour post-Dose timepoint, with 2 out of 7 subjects remaining quantifiable for sisunatovir until at least 12 hours post-Dose. Approval of protocol version 4.0 and country-specific amendments permitted the use of either formula milk or breast milk as a suspending diluent for dose administration via oral syringe (pharmacopeial-grade water was still recommended for dose administration via nasogastric tube). All 7 subjects in Cohort 1 were dosed with 2.0 mg/kg via oral syringe with sisunatovir suspended in formula milk.

Subjects in Cohort 2 (age: >1 month to <6 months) were dosed with 2.0 mg/kg sisunatovir suspended in either formula milk or pharmacopeial-grade water depending on the route of administration. Three of the subjects were dosed via oral syringe using formula milk as the suspending diluent, and 3 were dosed via nasogastric tube using pharmacopeial-grade water as the suspending diluent. Part B

The Phoenix NLME Population PK model was updated with data from Part A and used to predict doses for Part B. The Phoenix NLME popPK model was built with C5241001 , C5241002 adult data and Part A (single dose) pediatric data from C5241003.

As per protocol, the first group of 3 subjects enrolled into Cohort 3 (age: >6 months to <36 months) received 10 doses of 2.5 mg/kg sisunatovir suspended in 0.9% weight per volume (w/v) sodium chloride (saline) administered by oral syringe.

Dose adjustments for sisunatovir in Cohort 3 was made as follows: 3.5 mg/kg, because the Phoenix NLME Population PK prediction for 2.5 mg/kg too low. Two subjects were dosed at 3.5 mg/kg via oral syringe with sisunatovir suspended in saline. One subject was dosed at 3.5 mg/kg via nasogastric tube using pharmacopoeial-grade water as the suspending diluent for doses 1 -7 and via oral syringe with sisunatovir suspended in saline for doses 8-10. One subject was dosed at 3.5 mg/kg via oral syringe with sisunatovir suspended in saline for doses 1 -3 and with sisunatovir suspended in formula milk for doses 4-10. Exposures from 3.5 mg/kg were too low.

Dose adjustments for sisunatovir in Cohort 3 was as follows: 5.0 mg/kg, because exposures from 3.5 mg/kg were too low. One subject was dosed at 5 mg/kg sisunatovir suspended in formula milk via oral syringe for doses 1 and 10, and via nasogastric tube for doses 2-9. One subject was dosed at 5 mg/kg via oral syringe with sisunatovir suspended in formula milk via oral syringe.

Table 1 below compares key simulation data for pediatric patients aged 1 to 6 months, 6 to 12 months, and 12 to 60 months from a NONMEM population pharmacokinetic model to data from sisunatovir studies in adults (DeVincenzo et aL). The table included values obtained for steady-state trough concentration (CtroughSS), steady-state maximum concentration (CmaxSS), and area under the curve from time zero to time tau (the dosing interval) (AUCtauSS) predicted to achieve a comparable exposure to adults receiving 200 mg twice daily. Therefore, seeking at least an equivalent exposure as in the adult study, at least 4.5 mg/kg is the predicted appropriate dosage for 1 - to 6-month-old patients BID (twice daily), at least 5.5 mg/kg is the predicted appropriate dosage for 6- to 12-month-old patients BID (twice daily), and at least 6 mg/kg is predicted appropriate dosage for 12- to 60-month-old patients BID (twice daily). Doses could increase up to the limit of impurity specification (8 mg/kg BID [twice daily]). TABLE 1

After the completion of C5241003, a population PK model was developed using nonlinear mixed-effect modeling (NONMEM) software that include a CYP3A4 maturation. This refined NONMEM population PK model included data from C5241001 , C5241002, C5241003, and C5241006. This NONMEM population PK model was used to simulate pediatric exposures across a range of ages and weight-based dosing to identify doses that were predicted to have exposures at least comparable to adults receiving 200 mg twice-daily (Table 1 ). Pediatric doses were targeting exposures greater than or equal to 200 mg Q12h (twice daily, every 12 hours) in adults (Ctroughss 38 ng/mL, C_maxss 87 ng/mL, AUC_tauss 561 h. ng/mL).

Thus, based on the results of Part B, it was unexpectedly discovered that pediatric patients 1- to 60-months of age will require a much higher dosing compared to what was initially expected. It was found that dosing in pediatric patients aged 1 to 6 months would require at least 4.5 mg/kg, pediatric patients aged 6 to 12 months would require at least 5.5 mg/kg, pediatric patients 12 to 60 months would require at least 6 mg/kg twice daily (BID). These pediatric patients should receive a weight-based dose until the calculated dose is equal to the adult flat dose of 200 mg in adults. Based on standard growth charts it is anticipated that most adolescents will receive the adult flat dose.

Claims

CLAIMS We claim:

1. A method for treating RSV infection comprising administering to a 1- to 60-month-old subject in need thereof a dose of from about 4.0 mg/kg to about 8.0 mg/kg of sisunatovir HCI, wherein the dose is administered twice per day (BID).

2. The method of claim 1 , wherein the dose is from about 4.5 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

3. The method of claim 1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

4. The method of claim 1 , wherein the subject is a 1 - to 6-month-old and wherein the dose is from about 4.0 mg/kg to about 5.0 mg/kg of sisunatovir HCI.

5. The method of claim 1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

6. The method of claim 1 , wherein the subject is a 6- to 12-month-old and wherein the dose is from about 5.0 mg/kg to about 6.0 mg/kg of sisunatovir HCI.

7. The method of claim 1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 4.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

8. The method of claim 1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 5.0 mg/kg to about 7.0 mg/kg of sisunatovir HCI.

9. The method of claim 1 , wherein the subject is a 12- to 60-month-old and wherein the dose is from about 5.5 mg/kg to about 6.5 mg/kg of sisunatovir HCI.

10. The method of claim 1 , wherein sisunatovir HCI is administered orally.

11 . A method for treating RSV infection comprising administering to a 1- to 60-month-old subject in need thereof a total daily dose of from about 8.0 mg/kg to about 16.0 mg/kg of sisunatovir HCI.

12. The method of claim 11 , wherein the total daily dose is from about 8.0 mg/kg to about 13 mg/kg.

13. The method of claim 11 , wherein the subject is a 1- to 6-month-old and the total daily dose is from about 8 mg/kg to about 10 mg/kg.

14. The method of claim 11 , wherein the subject is a 6- to 12-month-old and the total daily dose is from about 10 mg/kg to about 12 mg/kg.

15. The method of claim 11 , wherein the subject is a 12- to 60-month-old and the total daily dose is from about 11 mg/kg to about 13 mg/kg.

16. The method of claim 11 , wherein sisunatovir HCI is administered orally.