Exploring Clinical and Antiviral Efficacy of Baloxavir Marboxil in a Phase 3, Randomized, Double-blind, Placebo- and Active-controlled Study of Otherwise Healthy Adults/Adolescents in Seasonal Influenza: Impact on Regional Participants, Treatment Time and Influenza Type B Virus Infection (CAPSTONE-1 Study)

Background: Baloxavir marboxil (BXM), a selective cap-dependent endonuclease inhibitor, has demonstrated efficacy + safety for influenza in otherwise healthy patients (pts). We present subgroup analyses for (i) US vs Japan (J), (ii) time (t) of treatment (early: ≥0 to ≤24 hrs, vs. late: >24 to ≤48 hrs), and (iii) influenza type B infections from the global Ph 3 trial (16/17 season).

Methods: A multicenter, randomized, double-blind, placebo (PLC)- and oseltamivir (OV)-controlled study, recruited pts in Japan (n=846) and US (n=590). Inclusion criteria: age 12-64 yrs, fever + flu symptoms, and ≤48 hrs from symptom onset. Pts (20-64 yrs) randomized (2:2:1) to a single oral dose of BXM, PLC, or 75 mg OV BID for 5 d; pts 12-19 yrs were randomized (2:1) to receive BXM or PLC. BXM dose: 40/80 mg for BW </≥ 80 kg. Primary endpoint: time to alleviation of symptoms (TTAS) in ITTI population (pop). Viral titers measured from pre-/post-dose nasal swabs.

Results: BXM reduced the median TTAS by 30.6 hrs vs PLC (87.3 vs 117.9 hrs, p=0.1373) in the US pop and t to cessation of viral shedding: 24 vs 72 hrs for PLC (p<.0001). Median TTAS in the US vs. J pop was longer, due to imbalances between groups. In both early/late treatments from symptom onset, BXM reduced TTAS vs PLC (Tbl. 1). Regardless of the t to treatment from symptom onset, BXM reduced virus titer significantly from BL vs PLC and OV (Tbl. 2). No significant reduction in TTAS was seen, while BXM reduced virus titer vs PLC and OV in type B virus infection.

Conclusion: Outcomes for US were aligned with the Ph 3 results. Early treatment with BXM leads to a significantly faster TTAS vs. PLC. BXM caused significant viral titer reduction regardless of treatment time vs. OV. BXM reduced virus titer vs PLC and OV in type B virus infection.

Tbl. 1: Median TTAS (hrs) to TTAS

t to treatment from symptom onset	BXM	PLC	Strat. Gen. Wilcoxon test [a]
early	49.3 (N=238)	82.1 (N=120)	P<0.0001
late	66.2 (N=217)	79.4 (N=110)	P=0.0080

[a] Stratification factors: region and composite symptom scores at baseline

Tbl. 2: Mean change (log₁₀ [TCID₅₀/mL]) from BL of viral titer at 1 day after start of treatment (age ≥20)

t to treatment from symptom onset	BXM	OV	Strat. Gen. Wilcoxon test [a]
early	-4.46 (n=180)	-2.57 (n=187)	P<0.0001
late	-4.32 (n=160)	-2.48 (n=161)	P<0.0001

[a] Same with tbl. 1