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.

Standard of Care (SOC): SOC for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

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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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1. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

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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DOI record: { "DOI": "10.1093/cid/ciae529", "ISSN": [ "1058-4838", "1537-6591" ], "URL": "http://dx.doi.org/10.1093/cid/ciae529", "abstract": "Abstract\n \n Background\n 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 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. No deaths from any cause or treatment-related serious AEs occurred through Day 33, and no participants reported dysgeusia.\n \n \n Conclusions\n All 3 ibuzatrelvir doses were associated with robust antiviral activity and an acceptable safety profile, supporting continued clinical development.\n \n \n Trial Registration\n Clinicaltrials.gov identifier: NCT05799495\n ", "author": [ { "affiliation": [ { "name": "Pfizer Inc , New York, NY ,", "place": [ "USA" ] } ], "family": "Mortezavi", "given": "Mahta", "sequence": "first" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Sloan", "given": "Abigail", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Singh", "given": "Ravi Shankar P", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Chen", "given": "Luke F", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Collegeville, PA ,", "place": [ "USA" ] } ], "family": "Kim", "given": "Jin Hyang", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Shojaee", "given": "Negin", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Pearl River, NY ,", "place": [ "USA" ] } ], "family": "Toussi", "given": "Sima S", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Groton, CT ,", "place": [ "USA" ] } ], "family": "Prybylski", "given": "John", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Baniecki", "given": "Mary Lynn", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Groton, CT ,", "place": [ "USA" ] } ], "family": "Bergman", "given": "Arthur", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Banerjee", "given": "Anindita", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , Cambridge, MA ,", "place": [ "USA" ] } ], "family": "Allerton", "given": "Charlotte", "sequence": "additional" }, { "affiliation": [ { "name": "Pfizer Inc , New York, NY ,", "place": [ "USA" ] } ], "family": "Alami", "given": "Negar Niki", "sequence": "additional" } ], "container-title": "Clinical Infectious Diseases", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2024, 11, 1 ] ], "date-time": "2024-11-01T22:22:57Z", "timestamp": 1730499777000 }, "deposited": { "date-parts": [ [ 2024, 11, 1 ] ], "date-time": "2024-11-01T22:22:57Z", "timestamp": 1730499777000 }, "indexed": { "date-parts": [ [ 2024, 11, 2 ] ], "date-time": "2024-11-02T04:14:23Z", "timestamp": 1730520863973, "version": "3.28.0" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2024, 11, 2 ] ] }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "content-version": "am", "delay-in-days": 0, "start": { "date-parts": [ [ 2024, 11, 1 ] ], "date-time": "2024-11-01T00:00:00Z", "timestamp": 1730419200000 } } ], "link": [ { "URL": "https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciae529/60298252/ciae529.pdf", "content-type": "application/pdf", "content-version": "am", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciae529/60298252/ciae529.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2024, 11, 2 ] ] }, "published-online": { "date-parts": [ [ 2024, 11, 2 ] ] }, "publisher": "Oxford University Press (OUP)", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciae529/7863440" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-CoV-2 Antiviral, in Adults With COVID-19", "type": "journal-article" }

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