Summary Basis of Decision for Xofluza

 

The clinical review of Xofluza was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Switzerland, and Singapore. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Clinical Pharmacology

Baloxavir marboxil (the medicinal ingredient in Xofluza) is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir acts on the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme, which is a component of the viral ribonucleic acid (RNA) polymerase complex. This inhibits the transcription of influenza virus genomes, thereby inhibiting replication of the influenza virus.

After oral administration of a single 40 mg dose, baloxavir marboxil is extensively converted to its active metabolite, baloxavir. In a human mass balance study, baloxavir accounted for 82.2% of the total exposure (as measured by the area under the concentration-time curve [AUC]) to baloxavir marboxil and its metabolites.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Xofluza have been well characterized in influenza patients and in healthy volunteers. In the pivotal studies, no differences were observed between otherwise healthy influenza patients (CAPSTONE-1) and those at high risk of developing complications (CAPSTONE-2) with respect to the pharmacokinetic parameters examined.

Body weight and race were identified as covariates in the oral clearance (CL/F) of baloxavir through a population pharmacokinetic analysis. Dose adjustment is required based on body weight, because exposure to baloxavir decreases as body weight increases, and the observed effects were significant. A single 40 mg dose is recommended for patients weighing 40 kg to <80 kg, and a single 80 mg dose is recommended for patients weighing ≥80 kg. Additionally, exposure to baloxavir was lower in non-Asian patients than in Asian patients. However, this difference was not considered clinically significant when the recommended dose was administered to patients.

At twice the expected exposure from recommended dosing, Xofluza did not prolong the corrected QT (QTc) interval in healthy subjects.

No dose adjustment is required due to mild or moderate hepatic impairment, based on the results of a clinical study in this patient population. However, the pharmacokinetics of Xofluza in patients with severe hepatic impairment has not been evaluated.

Renal excretion is a minor pathway for the elimination of both baloxavir marboxil and its active metabolite, baloxavir. Although there were no studies dedicated to examining the effects of renal impairment on the pharmacokinetics of Xofluza, some insights were obtained through the population pharmacokinetic analysis. The results of the population pharmacokinetic analysis did not reveal any clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with a creatinine clearance (CrCl) of 50 ml/min and above. Based on this information, no dose adjustment is required in patients with renal impairment.

The potential of both baloxavir marboxil and baloxavir for drug-drug interactions was appropriately characterized in vitro and in vivo. No clinically meaningful drug-drug interactions were identified with a strong cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor; the substrates of CYP 3A4, P-gp, and breast cancer resistance protein (BCRP), or the neuraminidase inhibitor oseltamivir. However, non-clinical data indicate that products containing polyvalent cations may decrease the plasma concentration of baloxavir. Therefore, Xofluza should not be taken with polyvalent cation-containing laxatives or antacids, or oral supplements containing iron, zinc, selenium, calcium, or magnesium. Additionally, Xofluza should not be taken with dairy products.

For further details, please refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Xofluza was evaluated in otherwise healthy patients as well as in patients at high risk for developing complications related to influenza infection. The studies described were all randomized, double-blind, and placebo-controlled.

The pivotal studies (CAPSTONE-1 and CAPSTONE-2) evaluated the safety and efficacy of a single oral dose of Xofluza administered within 48 hours of the onset of symptoms, without regard to meals. The dose administered to each patient was dependent on body weight. Patients weighing 40 kg to <80 kg were given a single 40 mg dose, and patients weighing ≥80 kg were given a single 80 mg dose. Both pivotal studies also included a third treatment group (in addition to the groups receiving Xofluza or a placebo) in which patients received a 75 mg dose of oseltamivir, an active comparator, twice daily for five days.

CAPSTONE-1 (Pivotal Phase III study in otherwise healthy patients)

CAPSTONE-1 (Study 1601T0831) was a pivotal Phase III study in patients 12-64 years of age. Patients enrolled in this study had uncomplicated influenza infection, and were otherwise healthy.

The primary efficacy endpoint of this study was the median time to alleviation of influenza symptoms (TTAS). The TTAS endpoint has been commonly used as a measure of the efficacy of anti-influenza virus drugs, with a reduction of 24 hours accepted as a clinically meaningful benefit for the approved NAIs.

A statistically significant improvement was observed in the median TTAS in patients who received Xofluza (number of patients [n] = 455) compared to those who received the placebo (n = 230). In the intent-to-treat infected (ITTI) population, the median TTAS was 54 hours in patients who received Xofluza (95% confidence interval [CI]: 50, 59) and 80 hours in patients who received the placebo (95% CI: 73, 87; p<0.0001).

The primary endpoint was further supported by a faster resolution of fever in patients treated with Xofluza compared to those who received the placebo, which was considered clinically relevant.

Study 1518T0821 (Supportive Phase II study in otherwise healthy patients)

Study 1518T0821 was a supportive proof-of-concept and dose-finding Phase II study conducted in Japanese adults. Patients enrolled in this study had uncomplicated influenza infection, and were otherwise healthy.

The results from this supportive study were supportive of the results from the pivotal study, CAPSTONE-1. The median TTAS was 50 hours in patients who were treated with 40 mg Xofluza (95% CI: 45, 64), and 78 hours in patients who received the placebo (95% CI: 68, 89).

CAPSTONE-2 (Pivotal Phase III study in high-risk patients)

In the high-risk patient population, evidence of clinical efficacy came primarily from the results of CAPSTONE-2 (Study 1602T0832); a pivotal, randomized, double-blind and placebo-controlled Phase III study. This study enrolled patients 12 years of age and older with uncomplicated influenza infection, who were at high risk for developing influenza-related complications.

The primary efficacy endpoint of this study was the median time to improvement of influenza symptoms (TTIS), a novel efficacy endpoint which includes both the alleviation of new symptoms and the improvement of any pre-existing symptoms that had worsened in patients with influenza due to the infection. A statistically significant improvement was observed in the median TTIS in patients who received Xofluza (n = 385) compared to those who received the placebo (n = 385).

In the intent-to-treat infected (ITTI) population, the median TTIS was 73 hours in patients who received Xofluza (95% CI: 68, 85) and 102 hours in patients who received the placebo (95% CI: 93, 113; p<0.0001). The primary endpoint was supported by a faster resolution of fever, as well as a reduction in the overall incidence of influenza-related complications. However, the overall incidence of complications was low, and the lower overall incidence in patients who received Xofluza was mainly driven by lower incidences of bronchitis and sinusitis. There were no significant treatment differences for the other complications of death, hospitalization, otitis media and pneumonia.

Overall Efficacy Analysis

Xofluza was determined to be effective against influenza viruses A and B based on the clinical data. There is no clinical evidence for efficacy of Xofluza in any illness caused by agents other than influenza viruses A and B.

Influenza virus types and subtypes characteristically vary from one season to the next, and the efficacy of anti-influenza virus drugs may vary based on the strain. In CAPSTONE-1 subgroup analyses, efficacy was observed for Xofluza compared with placebo for type A/H3 virus, detected in the vast majority of patients, but not for type B virus, detected in less than 10% of patients. In CAPSTONE-2, in which type A/H3 (predominant strain) and type B viruses were more evenly represented, the median TTIS was observed to be shorter with Xofluza compared with placebo in both subgroups.

The potential for the emergence and dissemination of viral resistance generally depends on both the incidence of treatment-emergent resistance mutations and the ability of the resistant strains to transmit resistance. Treatment-emergent mutations have been identified in influenza virus isolates from the clinical studies, which have been associated with reduced susceptibility to the active metabolite, baloxavir. The fitness of these mutations remains unclear. Potential risks were mitigated through the communication of available results pertinent to resistance monitoring in the Xofluza Product Monograph. Additionally, a recommendation was included reminding health professionals to consider the available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.

In each of the pivotal studies, no statistically significant differences were identified (in a secondary analysis) between Xofluza and oseltamivir with respect to the primary endpoints. However, the pivotal studies have not demonstrated that Xofluza and oseltamivir are equivalent to one another.

While significant reductions in the median time to cessation of viral shedding by virus titer and by reverse transcription polymerase chain reaction were observed, reduced transmission of influenza virus, a clinically relevant measure of efficacy, has not been established.

Efficacy has not been established in the following settings:

• Pediatric patients with acute uncomplicated influenza who are <12 years of age or who weigh <40 kg;
• Geriatric patients with acute uncomplicated influenza who weigh <40 kg;
• Patients who begin treatment after 48 hours of symptoms;
• For the treatment of complicated influenza (i.e. patients requiring hospitalization); or
• For the prevention of influenza.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Xofluza (baloxavir marboxil) is indicated for: the treatment of influenza in patients aged 12 and above who have been symptomatic for no more than 48 hours, the treatment of influenza in patients aged 12 and above who have been symptomatic for no more than 48 hours, and are at high risk of developing influenza complications.

Xofluza (baloxavir marboxil tablets) is indicated for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza complications. Health professionals should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza. Efficacy is based on significant reduction in the time to alleviation or improvement of influenza symptoms with Xofluza compared with placebo.

Patients with certain conditions associated with high risk for the development of influenza-related complications were excluded from CAPSTONE-2 in order to prevent exposure in utero or unnecessary potential risk to patients from receiving the placebo rather than an active antiviral drug. This rationale is acceptable in the context of a clinical trial. Additionally, the size of some high-risk groups was too small for statistical comparisons. However, some patients meeting the exclusion criteria are also considered to be among those at highest risk for developing influenza-related complications. It was determined that generalizing the available data from the study in high-risk patients to the wider high-risk population is reasonable. The authorized indication of Xofluza is therefore broad enough to encompass all high-risk conditions.

For more information, refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall safety profile of Xofluza was based on data from 2,109 patients who had been exposed to at least one dose of Xofluza in the completed Phase I, II, and III studies. This patient group included 1,640 adults and adolescents (12 years of age and older) with acute uncomplicated influenza who received Xofluza in CAPSTONE-1, CAPSTONE-2, or Study 1518T0821, which are described in detail in the Clinical Efficacy section. Approximately 81% of patients were 18-64 years of age, 13% were 65 years of age and older, and 6% were adolescents 12 to 17 years of age. All patients enrolled in the pivotal studies (CAPSTONE-1 and CAPSTONE-2) weighed 40 kg or more, and the vast majority of patients in the supportive study (1518T0821) weighed 45 kg or more.

Xofluza was generally well-tolerated, and the safety profile was similar in high-risk and otherwise healthy patients. There were no apparent safety concerns in either group of patients, and no relevant differences in safety were observed based on age.

The incidence of treatment-related adverse events in patients treated with Xofluza was consistent between the pooled studies in otherwise healthy patients (CAPSTONE-1 and Study 1518T0821) and the study in patients at high risk of developing influenza-related complications (CAPSTONE-2), 5% and 6%, respectively. The incidence of treatment-related adverse events was also consistent between patients who were treated with Xofluza (5% and 6%, respectively) and patients who received placebo in the pooled otherwise healthy studies and the high risk study (5% and 8%, respectively).

The incidence of serious adverse events in patients treated with Xofluza was low across CAPSTONE-1, CAPSTONE-2, and Study 1518T0821 (0.7% in total). No treatment-related serious adverse events were identified, and no fatalities occurred among Xofluza-treated patients across all three studies.

Overdoses with Xofluza have been reported from clinical trials and in the post-market setting. Adverse events of vomiting, some of which may be clinically significant, have been reported following overdoses of Xofluza. However, no adverse events were reported following overdose in the majority of cases.

A safety signal was identified during the review of the Xofluza submission related to prescribing and dispensing errors associated with different dose packs. This led to medication errors, including overdosage and underdosage. This risk was mitigated by limiting the number of packaging configurations and clearly communicating the dosing instructions and available packaging configurations in the Xofluza Product Monograph.

Influenza infection is associated with neuropsychiatric adverse events (NPAEs), with a relative risk of NPAEs approximately twice that of the general population within 30 days of infection. Post-marketing data for NPAEs in Xofluza-treated patients appear consistent with the complications of influenza, and the incidence of NPAEs in the three clinical studies was generally similar across treatment groups, including the placebo group. Baloxavir marboxil does not cross the blood-brain barrier, which limits the potential for NPAEs. Additionally, it is a substrate for the drug transporter P-glycoprotein (expressed at the blood-brain barrier), which would further restrict brain penetration.

A Serious Warnings and Precautions box is included in the Xofluza Product Monograph to highlight the risk of clinically significant hypersensitivity reactions. Xofluza has been associated with Type I immediate hypersensitivity reactions, based on the review of post-marketing data. Clinically significant hypersensitivity reactions to Xofluza have included anaphylaxis, urticaria, and angioedema. There were some reports of erythema multiforme (EM) and one case of acute generalized exanthematous pustulosis (AGEP). However, these reports were considered to be actually more consistent with an acute allergic-like reaction characterized by urticaria and rash, and these events have been communicated in the Xofluza Product Monograph.

A warning was included in the Xofluza Product Monograph to recommend that health professionals should be alert to the potential for secondary bacterial infections and treat with antibiotics as appropriate. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza.

Events of bloody diarrhea, melena, and ischemic colitis were reported during post-marketing use of Xofluza. While the evidence reviewed to date does not provide compelling evidence of an association between Xofluza and these gastrointestinal events, the establishment of causality is not a pre-requisite to inclusion within Post-Market Adverse Reactions. The communication of these events was considered a risk mitigation measure.

For more information, refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.