ABSTRACT
Background. There is a continued need for therapeutics for the treatment of COVID-19, including intramuscular (IM) agents, which will enable broader use across a variety of healthcare delivery settings. Methods. COMET-PEAK (NCT04779879) is a 3-part study evaluating the safety, tolerability, pharmacokinetics (Part A), and viral pharmacodynamics (PD) of sotrovimab as treatment in adults >= 18 years with early mild/moderate COVID-19. In Parts B and C, the safety, tolerability and viral PD of sotrovimab administered as a 500 mg intravenous (IV) infusion or as a 500 mg or 250 mg IM injection, respectively, was evaluated. The primary objective for Parts B and C was to compare the virologic response of sotrovimab IM to IV, with an endpoint of mean area under the curve (AUC) of SARS-CoV-2 viral load as measured by qRT-PCR from Day 1 to Day 8 (AUCD1-8) in nasopharyngeal swabs and predefined 90% confidence interval (CI) limits of 0.5-2.0 indicating equivalence. Results. A total of 167 and 157 participants were enrolled in Part B and C, respectively, from February-July 2021. The median age of participants was 47 and 42 years in Part B and C, respectively, and ~50% had >= 1 risk factor for progression to severe disease. The viral load at baseline and through Day 29 of follow-up for each arm is shown in Table 1 and Figure 1. The primary objective was met for both study parts: the ratio of the least square geometric mean viral load AUC(D1-8) of sotrovimab IM vs IV was 1.04 (90% CI, 0.98, 1.09) and 1.02 (90% CI, 0.94, 1.11), for Part B and C, respectively. Through Day 29 of follow-up, the most common adverse event was injection site reactions (ISRs) in the IM arms. A total of 10 (12%) participants in the 500 mg IM group and 4 (5%) participants in the 250 mg IM group experienced an ISR, all Grade 1. Serious adverse events were uncommon, and related to COVID-19 progression, including one death in the 250 mg IM arm (Table 2). ISRs aside, there were few treatment-related AEs (2/84 IV, 1/82 IM) in Part B, none serious. Conclusion. IM administration of sotrovimab 500 mg and 250 mg each demonstrated equivalence to 500 mg sotrovimab IV in viral load assessments. Overall, there were no treatment-related serious AEs and sotrovimab was well tolerated. An 500 mg IM formulation will allow for expanded treatment potential with sotrovimab.
ABSTRACT
Background: Sotrovimab is a pan-sarbecovirus neutralizing monoclonal antibody shown to be safe and effective for the treatment of early COVID-19 in high-risk patients and retains activity against variants of concern, including delta and omicron. To facilitate wider access to sotrovimab, it was formulated to allow for either intramuscular (IM) or intravenous (IV) administration. Methods: COMET-TAIL (NCT04913675) is a Phase III, randomized, multicenter, open-label, noninferiority (NI) study of IM vs IV sotrovimab for the treatment of mild/moderate COVID-19 in participants ≥12 years of age at high risk of disease progression. Participants were randomized to receive sotrovimab by single 500 mg IV infusion or IM injection (500 mg or 250 mg). The primary objective was to evaluate the efficacy of 500 mg IM vs 500 mg IV sotrovimab in preventing hospitalization for >24 hours for acute management of illness due to any cause or death. The 250 mg IM arm discontinued early due to a greater number of hospitalizations seen in that arm. A 3.5% NI margin on the risk difference scale was prespecified. Results: COMET-TAIL enrollment occurred from Jun-Aug 2021, coinciding with a surge in the SARS-CoV-2 delta variant in southern USA. The majority (∼85%) of participants were Hispanic or Latino and ∼25% were ≥65 years of age. In the 500 mg IM sotrovimab arm, 10/376 (2.7%) participants compared with 5/378 (1.3%) in the sotrovimab 500 mg IV arm met progression criteria for the primary endpoint (adjusted risk difference: 1.07% [95% CI:-1.25%, 3.39%]), meeting the NI margin of 3.5%. The overall rate of adverse events and injection/infusion-related reactions was low and similar between the 500 mg treatment arms. Most injection-site reactions were mild (grade 1), occurred shortly after dosing, and were limited in duration. Disease-related events (DREs) were balanced between the 500 mg IV and 500 mg IM arms. The most frequent DREs were COVID-19 pneumonia and pneumonia. There was a low percentage of participants (∼1%) with serious adverse events across all treatment arms, and none were considered related to treatment. Two participants (1 with BMI 69 mg/kg2 and an 82-year-old man) in the 500 mg IM arm died due to progression of COVID-19;no deaths occurred in the 500 mg IV arm. Conclusion: In the COMET-TAIL trial, sotrovimab given by 500 mg IM injection was found to be noninferior to IV infusion and was well tolerated. The option of IM administration will expand the potential for outpatient treatment with sotrovimab.