Xofluza Drug Information

Treatment of Acute Uncomplicated Influenza—Otherwise Healthy Subjects (12 Years of Age and

Older) Two randomized, controlled, double-blinded clinical trials conducted in two different influenza seasons evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated influenza. In Trial T0821, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial T0821 were Asian, the majority of subjects were male (62%), and the mean age was 38 years.

In this trial, among subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%). In Trial T0831 (NCT02954354), a phase 3, randomized, double-blind, active- and placebo-controlled trial, XOFLUZA was studied in 1,436 otherwise healthy adults and adolescents with signs and symptoms of influenza in the U.S. and Japan. Subjects were 12 to 64 years of age and weighed at least 40 kg. Adults aged 20 to 64 years received weight-based XOFLUZA (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=612) or placebo as a single oral dose on day 1 (N=310) or oseltamivir twice a day for 5 days (N=514). Subjects in the XOFLUZA and placebo arms received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm.

Adolescent subjects 12 to less than 20 years of age received weight-based XOFLUZA or placebo as a single oral dose. Seventy-eight percent of subjects in Trial T0831 were Asian, 17% were White, and 4% were Black or African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of subjects were male and 46% female.

In Trial T0831, 1,062 of 1,436 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=455, placebo N=230, or oseltamivir N=377). Among subjects who received XOFLUZA and had influenza virus typed, influenza A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%). In both Trials T0821 and T0831, eligible subjects had an axillary temperature of at least 38˚C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. The primary efficacy population was defined as those with a positive rapid influenza diagnostic test (Trial T0821) or positive influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial T0831) at trial entry.

The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours. In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter time to alleviation of symptoms compared with placebo in the primary efficacy population ( Tables 10 and 11 ). Table 10 Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Adults with Acute Uncomplicated Influenza in Trial T0821 (Median Hours) XOFLUZA 40 mg (95% CI CI: Confidence interval ) N=100 Placebo (95% CI ) N=100 Adults (20 to 64 Years of Age) 50 hours XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Gehan-Breslow's generalized Wilcoxon test (p-value: 0.014, adjusted for multiplicity using the Bonferroni method). The primary analysis using the Cox Proportional Hazards Model did not reach statistical significance (p-value: 0.165). 78 hours Table 11 Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Subjects 12 Years of Age and Older with Acute Uncomplicated Influenza in Trial T0831 (Median Hours) XOFLUZA 40 mg or 80 mg (95% CI CI: Confidence interval ) N=455 Placebo (95% CI ) N=230 Subjects (≥ 12 Years of Age) 54 hours XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Peto-Prentice's generalized Wilcoxon test (p-value: < 0.001). 80 hours In Trial T0831, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20 years) who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent subjects (12 to 17 years of age) in Trial T0831, the median time to alleviation of symptoms for subjects infected with influenza and who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to 93 hours (95% CI of 64, 118) in the placebo arm (N=27). The number of subjects who received XOFLUZA at the recommended dose and who were infected with influenza type B virus was limited, including 24 subjects in Trial T0821 and 38 subjects in Trial T0831. In the influenza B subset in Trial T0821, the median time to alleviation of symptoms in subjects who received 40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects who received placebo. In the influenza B subset in Trial T0831, the median time to alleviation of symptoms in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77 hours (95% CI of 47, 189) in subjects who received placebo.

Treatment of Acute Uncomplicated Influenza—High Risk Subjects (12 Years of Age and

Older) Trial T0832 (NCT02949011) was a randomized, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo or oseltamivir in adult and adolescent subjects 12 years of age or older with influenza who were at high risk of developing influenza-related complications. A total of 2,182 subjects with signs and symptoms of influenza were randomized to receive a single oral dose of 40 mg or 80 mg of XOFLUZA according to body weight (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=729), oseltamivir 75 mg twice daily for 5 days (N=725), or placebo (N=728). Twenty-eight percent of subjects were Asian, 59% were White, and 10% were Black or African American. The mean age was 52 years, and 3% of subjects were less than 18 years of age; 43% of subjects were male and 57% female.

High risk factors were based on the Centers for Disease Control and Prevention definition 1 of health factors known to increase the risk of developing serious complications from influenza. The majority of subjects had underlying asthma or chronic lung disease, diabetes, heart disease, morbid obesity, or were 65 years of age or older. In Trial T0832, 1,158 of the 2,182 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=385, placebo N=385, or oseltamivir N=388). Among subjects in whom only one type/subtype of influenza virus was identified, 50% were infected with subtype A/H3N2, 43% were infected with type B, and 7% were infected with subtype A/H1N1. Eligible subjects had an axillary temperature of at least 38°C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset.

Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. A total of 215 subjects (19%) had preexisting symptoms (cough, muscle or joint pain, or fatigue) associated with their underlying high-risk condition that were worsened due to influenza infection. The primary efficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). This endpoint included alleviation of new symptoms and improvement of any preexisting symptoms that had worsened due to influenza.

A statistically significant improvement in the primary endpoint was observed for XOFLUZA when compared with placebo (see Table 12 ). Table 12 Time to Improvement of Symptoms After Single Dose in High-Risk Subjects 12 Years of Age and Older with Acute Uncomplicated Influenza in Trial T0832 (Median Hours) XOFLUZA 40 mg or 80 mg The dosage of XOFLUZA was based on subject's weight. (95% CI CI: Confidence interval ) N=385 Placebo (95% CI ) N=385 73 hours XOFLUZA treatment resulted in a significant reduction in Time to Improvement of Influenza Symptoms compared to placebo using Peto-Prentice's generalized Wilcoxon test (p-value: < 0.001). 102 hours There was no statistically significant difference in the median time to improvement of influenza symptoms in the subjects who received XOFLUZA (73 hours) and those who received oseltamivir (81 hours). The median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to 17 years infected with influenza virus was similar for subjects who received XOFLUZA (188 hours) or placebo (191 hours) (N=13 and N=12, respectively). For subjects infected with type B virus, the median time to improvement of influenza symptoms was 75 hours in the XOFLUZA group (95% CI of 67, 90) compared to 101 hours in the placebo group (95% CI of 83, 116).

Treatment of Acute Uncomplicated Influenza—Otherwise Healthy and High-Risk Pediatric Subjects (5 to

< 12 Years of Age) Trial CP40563 (NCT03629184) was a randomized, double-blind, multicenter, active-controlled trial, designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of XOFLUZA compared with oseltamivir in otherwise healthy pediatric subjects (including subjects aged 5 to < 12 years of age) with influenza-like symptoms. Eligible subjects had a tympanic temperature of at least 38°C and at least one respiratory symptom of either cough or nasal congestion. A total of 118 subjects 5 to less than 12 years of age were randomized and received a single one-time oral dose of XOFLUZA (N=79) based on body weight (2 mg/kg for subjects weighing < 20 kg or 40 mg for subjects weighing ≥ 20 kg) or oseltamivir (N=39) for 5 days (dose based on body weight). Subjects at high risk of developing complications associated with influenza were included in the trial.

The primary objective was to compare the safety of a single one-time dose of XOFLUZA with 5 days of oseltamivir administered twice daily. The secondary efficacy endpoint included time to alleviation of influenza signs and symptoms, which was defined as the time when all of the following were met for at least 21.5 hours: cough and nasal symptoms were assessed by the caregiver as no problem or minor problem, subject was able to return to normal daily activity, and subject was afebrile (temperature ≤ 37.2°C). However, the trial was not powered to detect statistically significant differences in this secondary endpoint. Of the 118 randomized subjects 5 to less than 12 years of age in Trial CP40563, 94 subjects had influenza confirmed by RT-PCR at baseline or during the trial; 89% percent of subjects were White, 3% Black or African American and 8% Other/unknown/multiple races.

The mean age was 8 years ; 56% of subjects were female and 44% male. The predominant influenza virus strain in this trial was the A/H3N2 subtype (67%), followed by A/H1N1 (20%) and type B (9%). The median time to alleviation of influenza signs and symptoms was 138 hours in the XOFLUZA arm (95% CI of 117, 163) and 126 hours in the oseltamivir arm (95% CI of 96, 166).

Post-Exposure Prophylaxis of Influenza (5 Years of Age and Older) Trial T0834

was a phase 3, randomized, double-blind, multicenter, placebo-controlled trial designed to evaluate the efficacy of a single oral dose of XOFLUZA compared with placebo in the prevention of influenza in subjects who were household contacts of influenza-infected patients in Japan. Influenza-infected index patients were required to have onset of symptoms for ≤ 48 hours, and subjects (household contacts) were required to have lived with the influenza-infected index patient for ≥ 48 hours. A total of 715 subjects (XOFLUZA N=360, placebo N=355) 5 years of age and older were randomized and received a single oral dose of XOFLUZA according to body weight and age, or placebo, on Day 1. Subjects received a single dose of XOFLUZA according to body weight.

The primary efficacy endpoint was the proportion of household subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10. Influenza infection was confirmed by RT-PCR, fever was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a symptom of "cough" or "nasal discharge/nasal congestion" with a severity of moderate or severe as assessed by the subject. The mean age of subjects that were ≥ 5 years of age in Trial T0834 was 35 years; 108 (15%) were 5 to < 12 years, 33 (5%) were ≥ 12 to < 18 years of age, 551 (77%) were ≥ 18 to < 65 years of age, and 23 (3%) were ≥ 65 years of age. All subjects were Asian, 80% were female, and 20% were male.

In subjects that were 5 years of age and older, there was a statistically significant reduction in the proportion of household contacts (subjects) with laboratory-confirmed clinical influenza from 13% in the placebo group to 2% in the XOFLUZA group (see Table 13 ). Table 13 Proportion of Household Contacts (Subjects 5 Years of Age and Older) Infected with Influenza Virus with Fever and at Least One Respiratory Symptom (Trial T0834) XOFLUZA (95% CI CI: Confidence interval (%) XOFLUZA treatment resulted in a significant reduction in the risk ratio of patients who were infected with influenza virus and presented with fever compared to placebo using modified Poisson regression for a binary response (p-value: < 0.0001). ) N=360 Placebo (95% CI ) N=355 6 (2%) 47 (13%) (1%, 4%) (10%, 17%) In the 108 pediatric subjects 5 to less than 12 years of age enrolled in Trial T0834, 57 subjects received XOFLUZA and 51 received placebo. In this age group, the proportion of subjects with laboratory-confirmed clinical influenza was 4% in the XOFLUZA group and 14% in the placebo group.