Therapeutics for COVID-19.

Vaccines and monoclonal antibody treatments to prevent severe coronavirus disease 2019 (COVID-19) illness were available within a year of the pandemic being declared but there remained an urgent need for therapeutics to treat patients who were not vaccinated, were immunocompromised or whose vaccine immunity had waned. Initial results for investigational therapies were mixed. AT-527, a repurposed nucleoside inhibitor for hepatitis C virus, enabled viral load reduction in a hospitalized cohort but did not reduce viral load in outpatients. The nucleoside inhibitor molnupiravir prevented death but failed to prevent hospitalization. Nirmatrelvir, an inhibitor of the main protease (Mpro), co-dosed with the pharmacokinetic booster ritonavir, reduced hospitalization and death. Nirmatrelvir-ritonavir and molnupiravir received an Emergency Use Authorization in the United States at the end of 2021. Immunomodulatory drugs such as baricitinib, tocilizumab and corticosteroid, which target host-driven COVID-19 symptoms, are also in use. We highlight the development of COVID-19 therapies and the challenges that remain for anticoronavirals.

Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment.

Nirmatrelvir coadministered with ritonavir is highly efficacious in reducing the risk of coronavirus disease 2019 (COVID-19) adverse outcomes among patients at increased risk of progression to severe disease, including patients with chronic kidney disease. Because nirmatrelvir is eliminated by the kidneys when given with ritonavir, this phase I study evaluated the effects of renal impairment on pharmacokinetics, safety, and tolerability of nirmatrelvir/ritonavir. Participants with normal renal function (n = 10) or mild, moderate, or severe renal impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose with 100 mg ritonavir given 12 hours before, together with and 12 and 24 hours after the nirmatrelvir dose. Systemic nirmatrelvir exposure increased with increasing renal impairment, with mild, moderate, and severe renal impairment groups having respective adjusted geometric mean ratio areas under the plasma concentration-time profile from time 0 extrapolated to infinite time of 124%, 187%, and 304% vs. the normal renal function group. Corresponding ratios for maximum plasma concentration were 130%, 138%, and 148%. Apparent clearance was positively correlated with estimated glomerular filtration rate, and geometric mean renal clearance values were particularly lower for the moderate (47% decrease) and severe (80% decrease) renal impairment groups vs. the normal renal function group. Nirmatrelvir/ritonavir exhibited an acceptable safety profile; treatment-related adverse events were mild in severity, and there were no significant findings regarding laboratory measurements, vital signs, or electrocardiogram assessments. These findings led to a dose reduction recommendation for nirmatrelvir/ritonavir in patients with moderate renal impairment (150/100 mg nirmatrelvir/ritonavir instead of 300/100 mg twice daily for 5 days). NCT04909853.

Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.

Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase I study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a three-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well-tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials' initiation (NCT04756531).