Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-CoV-2 Antiviral, in Adults With COVID-19

Mortezavi et al., Clinical Infectious Diseases, doi:10.1093/cid/ciae529, NCT05799495

Nov 2024

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RCT 240 outpatients showing significant viral load reduction with ibuzatrelvir (an oral SARS-CoV-2 M^pro inhibitor) compared to placebo. The study enrolled non-hospitalized adults aged 18-65 with symptomatic COVID-19 (≤5 days) and positive rapid antigen test, excluding those with obesity, smoking, chronic conditions, or immunocompromised status. Patients were randomized 1:1:2:2 to receive 100mg, 300mg, or 600mg ibuzatrelvir or placebo twice daily for 5 days. There were dose-dependent decreases in viral load at days 3 and 5 compared to placebo. The trial has limited generalizability due to strict exclusion criteria that eliminated many high-risk patients who would typically be candidates for antiviral therapy.

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viral load, 27.3% lower, relative load 0.73, p < 0.001, treatment 66, control 60, 600mg, day 5.

viral load, 20.0% lower, relative load 0.80, p = 0.01, treatment 24, control 60, 300mg, day 5.

viral load, 17.9% lower, relative load 0.82, p = 0.02, treatment 34, control 60, 100mg, day 5.

viral load, 48.0% lower, relative load 0.52, p < 0.001, treatment 70, control 63, 600mg, day 3.

viral load, 48.0% lower, relative load 0.52, p < 0.001, treatment 27, control 63, 300mg, day 3.

viral load, 35.0% lower, relative load 0.65, p = 0.01, treatment 35, control 63, 100mg, day 3.

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Mortezavi et al., 2 Nov 2024, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 13 authors, study period 24 May, 2023 - 8 September, 2023, trial NCT05799495 (history). Contact: mahta.mortezavi@pfizer.com, niki.alami@pfizer.com.

This Paper Ibuzatrelvir All

Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-cov-2 Antiviral, in Adults With COVID-19

MD Mahta Mortezavi, PhD Abigail Sloan, Ravi Shankar, PhD P Singh, MBBS Luke F Chen, PhD Jin Hyang Kim, PhD Negin Shojaee, MD Sima S Toussi, PhD John Prybylski, PhD Mary Lynn Baniecki, PhD Arthur Bergman, PhD Anindita Banerjee, MPhil Charlotte Allerton, MD Negar Niki Alami, Dr Niki Negar, Alami, Head

doi:10.1093/cid/ciae5291

Background: Despite effective vaccines and treatments for COVID-19, clinical burden persists. An unmet need exists for additional effective agents with safety profiles allowing use across a broad population. Ibuzatrelvir is an orally bioavailable SARS-CoV-2 M pro inhibitor that has demonstrated in vitro antiviral activity and low potential for safety concerns, including drug-drug interactions. Methods: This phase 2b, double-blind, randomized clinical trial enrolled US adults aged 18-<65 years with symptomatic COVID-19 and no risk factors for severe disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or placebo orally twice daily for 5 days. Nasopharyngeal specimens were collected on Days 1 (baseline), 3, 5, 10, 14, and 21; adverse

Conflict of Interest Disclosures: All authors are employees of Pfizer and may hold stock or stock options.

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Ibuzatrelvir is an orally bioavailable SARS-CoV-2 ' 'Mpro inhibitor that has demonstrated in vitro antiviral activity and low potential for safety ' 'concerns, including drug-drug interactions.\n' ' \n' ' \n' ' Methods\n' ' This phase 2b, double-blind, randomized clinical trial enrolled US ' 'adults aged 18‒&lt;65 years with symptomatic COVID-19 and no risk factors for severe ' 'disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or ' 'placebo orally twice daily for 5 days. Nasopharyngeal specimens were collected on Days 1 ' '(baseline), 3, 5, 10, 14, and 21; adverse events (AEs) were recorded through Day 33. The ' 'primary endpoint was change in SARS-CoV-2 RNA level (viral load [VL]) from baseline to Day 5 ' 'among participants with baseline VL ≥4 log10 copies/mL.\n' ' \n' ' \n' ' Results\n' ' Of 240 enrollees, 237 received ≥1 dose and 199 were included in the ' 'primary analysis. Placebo-adjusted least squares mean (80% CI) change from baseline in VL at ' 'Day 5 was significant across all doses: 100 mg, ‒0.7 (‒1.1, ‒0.3) log10 copies/mL, P=0.02; ' '300 mg, ‒0.8 (‒1.3, ‒0.3) log10 copies/mL, P=0.01; and 600 mg, ‒1.2 (‒1.5, ‒0.8) log10 ' 'copies/mL, P&lt;0.0001. AEs occurred in similar percentages of participants across ' 'groups. 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