Casirivimab/imdevimab for COVID-19: real-time analysis of all 35 studies

Casirivimab/imdevimab for COVID-19: real-time meta analysis of 24 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, hospitalization, progression, recovery, cases, and viral clearance. 17 studies from 12 independent teams in 4 different countries show statistically significant improvements in isolation (7 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 56% [37‑69%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and slightly worse for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment.

• Results are robust — in exclusion sensitivity analysis 13 of 24 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• Efficacy is variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, Tatham, VanBlargan]. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].

• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 29% of casirivimab/imdevimab studies show zero events with treatment.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 29 Sep 2022, preprint, 1 author.

Effectiveness of REGEN-COV combination monoclonal antibody infusion to reduce risk of COVID-19 hospitalization in pregnancy: A retrospective cohort study

Williams et al., American Journal of Obstetrics and Gynecology, doi:10.1016/j.ajog.2022.09.017

Retrospective 764 pregnant patients with COVID-19 in the USA, 88 treated with casirivimab/imdevimab, showing no significant difference in outcomes.

risk of oxygen therapy, 20.8% higher, RR 1.21, p = 0.87, treatment 1 of 88 (1.1%), control 6 of 676 (0.9%), OR converted to RR.

risk of severe case, 1.0% higher, RR 1.01, p = 0.99, treatment 1 of 88 (1.1%), control 7 of 676 (1.0%), OR converted to RR.

risk of hospitalization, 13.9% lower, RR 0.86, p = 0.90, treatment 1 of 88 (1.1%), control 8 of 676 (1.2%), NNT 2125, OR converted to RR.

Williams et al., 12 Sep 2022, retrospective, USA, peer-reviewed, 6 authors.

Outcome of lung transplant recipients infected with SARS-CoV-2/Omicron/B.1.1.529: a Nationwide German study

Kneidinger et al., Infection, doi:10.1007/s15010-022-01914-8

Retrospective 218 COVID+ lung transplant patients in Germany, showing no significant difference in severe cases with early casirivimab/imdevimab use.

risk of severe case, 97.2% lower, RR 0.03, p = 0.45, treatment 0 of 3 (0.0%), control 34 of 215 (15.8%), NNT 6.3, relative risk is not 0 because of continuity correction due to zero events.

Kneidinger et al., 9 Sep 2022, retrospective, Germany, peer-reviewed, 11 authors, study period 1 January, 2022 - 20 March, 2022, lung transplant patients.

Timing of REGEN-COV administration and progression to severe COVID-19

Kadowaki et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2022.07.002

Retrospective 342 patients in Japan, showing significantly greater efficacy of casirivimab/imdevimab with earlier treatment. The proportion of patients progressing to severe COVID-19 increased daily from symptom onset and increased sharply from day 5.

Kadowaki et al., 11 Jul 2022, retrospective, Japan, peer-reviewed, 5 authors, study period 19 July, 2021 - 30 September, 2021.

Outcomes of pregnant patients treated with REGEN-COV during the COVID-19 pandemic

Levey et al., American Journal of Obstetrics & Gynecology MFM, doi:10.1016/j.ajogmf.2022.100673

Retrospective 86 pregnant COVID-19 patients, 36 treated with casirivimab/imdevimab, showing no significant difference in COVID-19 outcomes with treatment.

risk of ICU admission, 30.6% lower, RR 0.69, p = 1.00, treatment 1 of 36 (2.8%), control 2 of 50 (4.0%), NNT 82.

risk of oxygen therapy, 7.4% lower, RR 0.93, p = 1.00, treatment 2 of 36 (5.6%), control 3 of 50 (6.0%), NNT 225.

risk of hospitalization, 108.3% higher, RR 2.08, p = 0.15, treatment 9 of 36 (25.0%), control 6 of 50 (12.0%).

Levey et al., 4 Jun 2022, retrospective, USA, peer-reviewed, 6 authors, study period March 2021 - October 2021.

Clinical efficacy of casirivimab-imdevimab antibody combination treatment in patients with COVID-19 Delta variant

Miyashita et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2022.05.012

Retrospective 461 patients treated with casirivimab/imdevimab in Japan, and 461 matched controls, showing lower oxygen requirements with treatment.

risk of mechanical ventilation, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 461 (0.4%), control 3 of 461 (0.7%), NNT 461.

risk of oxygen therapy, 46.4% lower, RR 0.54, p = 0.004, treatment 30 of 461 (6.5%), control 56 of 461 (12.1%), NNT 18.

Miyashita et al., 26 May 2022, retrospective, Japan, peer-reviewed, 6 authors, average treatment delay 4.0 days.

REGEN-COV antibody cocktail (casirivimab/imdevimab) for the treatment of inpatients with early hospital-acquired COVID-19: a single center experience

Faraone et al., Research Square, doi:10.21203/rs.3.rs-1170976/v1 (Preprint)

Retrospective 34 patients with hospital-acquired COVID-19, showing lower mortality and oxygen requirements with early casirivimab/imdevimab treatment.

risk of death, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 11 (0.0%), control 8 of 23 (34.8%), NNT 2.9, relative risk is not 0 because of continuity correction due to zero events.

risk of oxygen therapy, 94.5% lower, RR 0.06, p = 0.02, treatment 0 of 11 (0.0%), control 15 of 23 (65.2%), NNT 1.5, OR converted to RR, relative risk is not 0 because of continuity correction due to zero events.

Faraone et al., 5 May 2022, retrospective, Italy, preprint, 12 authors, study period 25 October, 2020 - 30 April, 2021, average treatment delay 2.3 days.

Real World Outcomes of Cancer Patients With SARS-CoV-2 Infection Receiving Monoclonal Antibodies

Wilden et al., Journal of the National Comprehensive Cancer Network, doi:10.6004/jnccn.2021.7309

Retrospective 395 patients in the USA receiving casirivimab/imdevimab or bamlanivimab, showing lower risk of hospitalization with treatment, statistically significant for casirivimab/imdevimab.

risk of hospitalization, 82.0% lower, OR 0.18, p = 0.004, adjusted, multivariable, RR approximated with OR.

Wilden et al., 31 Mar 2022, retrospective, USA, peer-reviewed, 9 authors, study period December 2020 - July 2021.

Real-world Effectiveness of Casirivimab and Imdevimab in Patients With COVID-19 in the Ambulatory Setting: An Analysis of Two Large US National Claims Databases

Wei et al., medRxiv, doi:10.1101/2022.02.28.22270796 (Preprint)

Retrospective 4,396 casirivimab/imdevimab patients in the USA, showing lower combined mortality/hospitalization (CDM database) and lower hospitalization (PMTX+ database) with treatment.

risk of death/hospitalization, 61.0% lower, HR 0.39, p < 0.001, treatment 23 of 1,116 (2.1%), control 27 of 5,291 (0.5%), Optum CDM, Cox proportional hazards.

risk of hospitalization, 61.0% lower, HR 0.39, p < 0.001, treatment 59 of 3,280 (1.8%), control 75 of 16,284 (0.5%), IQVIA PMTX+, Cox proportional hazards.

Wei et al., 28 Feb 2022, retrospective, database analysis, USA, preprint, 8 authors, study period December 2020 - June 2021.

SARS-CoV-2 Omicron BA.2 Variant Evades Neutralization by Therapeutic Monoclonal Antibodies

Zhou et al., bioRxiv, doi:10.1101/2022.02.15.480166 (Preprint) (In Vitro)

In Vitro study showing that omicron BA.2 evades all monoclonal antibodies tested, including sotrovimab and tixagevimab/cilgavimab which retained activity for omicron BA.1.

Zhou et al., 16 Feb 2022, preprint, 4 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Clinical Prognosis of Patients With Mild COVID-19 Treated With Casirivimab/Imdevimab in Japan

Osugi et al., Cureus, doi:10.7759/cureus.21882

Retrospective 104 outpatients in Japan, 30 treated with casirivimab/imdevimab, showing no significant difference in hospitalization.

risk of hospitalization, 24.0% lower, HR 0.76, p = 0.65, treatment 4 of 30 (13.3%), control 15 of 74 (20.3%), adjusted, multivariable, Cox proportional hazards.

Osugi et al., 3 Feb 2022, retrospective, Japan, peer-reviewed, mean age 47.8, 5 authors, study period 31 August, 2021 - 27 September, 2021.

Doubtful Clinical Benefit of Casirivimab-Imdevimab Treatment for Disease Severity Outcome of High-Risk Patients with SARS-CoV-2 Delta Variant Infection

Shopen et al., medRxiv, doi:10.1101/2022.01.29.22270090 (Preprint)

Retrospective 359 COVID+ patients in Israel, 116 treated with casirivimab/imdevimab, showing no significant difference with treatment in multivariable analysis.

risk of severe case, 45.6% higher, RR 1.46, p = 0.26, treatment 24 of 116 (20.7%), control 26 of 243 (10.7%), adjusted, OR converted to RR.

Shopen et al., 31 Jan 2022, retrospective, Israel, preprint, 11 authors, study period June 2021 - September 2021.

Lack of Ronapreve (REGN-CoV; casirivimab and imdevimab) virological efficacy against the SARS-CoV 2 Omicron variant (B.1.1.529) in K18-hACE2 mice

Tatham et al., bioRxiv, doi:10.1101/2022.01.23.477397 (Preprint)

K18-hACE2 mouse study showing that casirivimab/imdevimab was not effective for omicron at doses 2x higher than those effective for previous variants.

Tatham et al., 24 Jan 2022, preprint, 15 authors.

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial

O'Brien et al., JAMA, doi:10.1001/jama.2021.24939768

RCT 204 asymptomatic COVID+ patients, 100 treated with subcutaneous casirivimab/imdevimab, showing lower development of symptoms, lower hospitalization, and faster viral clearance with treatment. Study conducted prior to widespread circulation of delta and omicron in the study locations.

risk of hospitalization, 85.5% lower, RR 0.15, p = 0.25, treatment 0 of 100 (0.0%), control 3 of 104 (2.9%), NNT 35, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization/ER, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 100 (0.0%), control 6 of 104 (5.8%), NNT 17, relative risk is not 0 because of continuity correction due to zero events.

risk of symptomatic case, 33.0% lower, RR 0.67, p = 0.04, treatment 29 of 100 (29.0%), control 44 of 104 (42.3%), NNT 7.5, OR converted to RR, day 14, primary outcome.

relative weeks with high viral load, 39.7% better, RR 0.60, p = 0.001, treatment 100, control 104.

O'Brien et al., 14 Jan 2022, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 38 authors, study period 13 July, 2020 - 28 January, 2021.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic

Suzuki et al., medRxiv, doi:10.1101/2021.12.19.21268078 (Preprint)

Retrospective 949 patients in Japan, 314 treated with casirivimab/imdevimab showing significantly lower risk of deterioration with treatment.

risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 222 (0.5%), control 0 of 222 (0.0%), continuity correction due to zero event, propensity score matching.

risk of death, 59.6% lower, RR 0.40, p = 0.67, treatment 1 of 314 (0.3%), control 5 of 635 (0.8%), NNT 213, unadjusted.

risk of progression, 45.2% lower, RR 0.55, p = 0.02, treatment 17 of 222 (7.7%), control 31 of 222 (14.0%), NNT 16, propensity score matching.

risk of progression, 49.9% lower, RR 0.50, p = 0.002, treatment 34 of 314 (10.8%), control 70 of 365 (19.2%), NNT 12, OR converted to RR, multivariate.

Suzuki et al., 21 Dec 2021, retrospective, Japan, preprint, 49 authors, study period 24 July, 2021 - 30 September, 2021.

Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron)

Sheward et al., bioRxiv, doi:10.1101/2021.12.19.473354 (Preprint) (In Vitro)

In Vitro study showing that omicron is substantially resistant to neutralization by monoclonal antibodies REGN10933, REGN10987, Ly-CoV016 and Ly-CoV555. S309 (the parent of Sotrovimab) had only 2-fold loss in potency.

Sheward et al., 20 Dec 2021, preprint, 11 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The effect of casirivimab with imdevimab on disease progression in nonsevere COVID‐19 patients in a single hospital in Japan

Komagamine et al., Journal of General and Family Medicine, doi:10.1002/jgf2.516

Combined retrospective/prospective study in Japan with 53 casirivimab/imdevimab patients and 75 control patients, showing significantly lower progression with treatment.

risk of mechanical ventilation, 77.3% lower, RR 0.23, p = 0.51, treatment 0 of 53 (0.0%), control 2 of 75 (2.7%), NNT 38, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 92.3% lower, RR 0.08, p = 0.04, treatment 0 of 53 (0.0%), control 7 of 75 (9.3%), NNT 11, relative risk is not 0 because of continuity correction due to zero events.

risk of progression, 67.8% lower, RR 0.32, p = 0.006, treatment 8 of 53 (15.1%), control 33 of 75 (44.0%), NNT 3.5, adjusted, OR converted to RR, multivariable, primary outcome.

hospitalization time, 28.9% lower, relative time 0.71, p < 0.001, treatment 53, control 75.

Komagamine et al., 19 Dec 2021, retrospective, Japan, peer-reviewed, 4 authors, average treatment delay 5.0 days.

An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies

VanBlargan et al., bioRxiv, doi:10.1101/2021.12.15.472828 (Preprint) (In Vitro)

In vitro study (Vero-TMPRSS2 and Vero-hACE2-TMPRSS2) showing complete loss of inhibitory activity for B.1.1.529 omicron with LY-CoV555, LY-CoV016, REGN10933, REGN10987, and CT-P59, ~12-fold decrease for COV2-2196/COV2-2130, and minimal change for S309.

VanBlargan et al., 17 Dec 2021, preprint, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2

Liu et al., bioRxiv, doi:10.1101/2021.12.14.472719 (Preprint) (In Vitro)

In vitro study (Vero-E6-TMPRSS2) showing 18 of 19 monoclonal antibodies were no longer effective or significantly impaired with B.1.1.529 omicron.

Liu et al., 15 Dec 2021, preprint, 23 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Association of subcutaneous or intravenous route of administration of casirivimab and imdevimab monoclonal antibodies with clinical outcomes in COVID-19

McCreary et al., medRxiv, doi:10.1101/2021.11.30.21266756 (Preprint)

Prospective study comparing subcutaneous and intravenous casirivimab/imdevimab, and comparing to a PSM matched control set, showing significantly lower mortality and hospitalization with treatment. Controls were matched with EUA-eligible risk factors only, authors were unable to determine symptom severity.

risk of death, 93.0% lower, RR 0.07, p = 0.009, treatment 1 of 652 (0.2%), control 29 of 1,304 (2.2%), NNT 48, propensity score matching.

risk of death/hospitalization, 56.0% lower, RR 0.44, p < 0.001, treatment 22 of 652 (3.4%), control 101 of 1,304 (7.7%), NNT 23, propensity score matching, primary outcome.

risk of hospitalization, 48.0% lower, RR 0.52, p = 0.005, treatment 22 of 652 (3.4%), control 85 of 1,304 (6.5%), NNT 32, propensity score matching.

risk of hospitalization/ER, 40.0% lower, RR 0.60, p = 0.003, treatment 40 of 652 (6.1%), control 133 of 1,304 (10.2%), NNT 25, propensity score matching.

SQ vs. IV death, 53.0% lower, RR 0.47, p = 0.52, treatment 1 of 969 (0.1%), control 3 of 1,216 (0.2%), NNT 697, adjusted.

SQ vs. IV death/hosp., 71.0% higher, RR 1.71, p = 0.06, treatment 27 of 969 (2.8%), control 21 of 1,216 (1.7%), adjusted.

SQ vs. IV hospitalization, 79.0% higher, RR 1.79, p = 0.046, treatment 27 of 969 (2.8%), control 20 of 1,216 (1.6%), adjusted.

SQ vs. IV ER/hosp., 15.0% lower, RR 0.85, p = 0.38, treatment 47 of 969 (4.9%), control 71 of 1,216 (5.8%), NNT 101, adjusted.

McCreary et al., 1 Dec 2021, prospective, USA, preprint, 27 authors, study period 14 July, 2021 - 26 October, 2021, average treatment delay 6.0 days.

Repeat Subcutaneous Administration of REGEN-COV® in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19

Isa et al., medRxiv, doi:10.1101/2021.11.10.21265889 (Preprint)

RCT 969 patients, 729 treated with monthly subcutaneous casirivimab/imdevimab, showing significantly lower risk of COVID-19 with treatment. There were no grade 3 injection site reactions or hypersensitivity reactions. Slightly more TEAEs were reported with treatment (54.9% vs. 48.3%), due to grade 1-2 ISRs. Serious adverse events were rare and occurred with similar percentages for treatment and control groups. There were no deaths. NCT04519437.

risk of symptomatic case, 92.6% lower, RR 0.07, p = 0.002, treatment 3 of 729 (0.4%), control 13 of 240 (5.4%), NNT 20, OR converted to RR.

risk of case, 92.7% lower, RR 0.07, p = 0.002, treatment 0 of 729 (0.0%), control 10 of 240 (4.2%), NNT 24, OR converted to RR, relative risk is not 0 because of continuity correction due to zero events, seroconversion.

Conflicts of interest: employee of the drug patent holder.

Isa et al., 16 Nov 2021, Double Blind Randomized Controlled Trial, USA, preprint, 31 authors, trial NCT04519437 (history).

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19

Somersan-Karakaya et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiac320 (date from earlier preprint)

RCT 1,336 hospitalized patients with symptom onset <=10 days on low-flow or no supplemental oxygen, showing lower mortality with treatment. Cohorts 2&3 were paused mid-trial due to increased deaths in the treatment arm and these results were not included. NCT04426695.

risk of death, 35.9% lower, RR 0.64, p = 0.02, treatment 59 of 804 (7.3%), control 45 of 393 (11.5%), NNT 24, day 28, mFAS.

risk of death, 55.6% lower, RR 0.44, p = 0.005, treatment 24 of 360 (6.7%), control 24 of 160 (15.0%), NNT 12, seronegative, day 28, mFAS.

risk of death, 21.3% lower, RR 0.79, p = 0.42, treatment 26 of 369 (7.0%), control 18 of 201 (9.0%), NNT 52, seropositive, day 28, mFAS.

risk of death/intubation, 30.9% lower, RR 0.69, p = 0.03, treatment 82 of 804 (10.2%), control 58 of 393 (14.8%), NNT 22, day 1-29, mFAS.

risk of no hospital discharge, 30.2% lower, RR 0.70, p = 0.02, treatment 90 of 804 (11.2%), control 63 of 393 (16.0%), NNT 21, day 1-29, mFAS.

Conflicts of interest: research funding from the drug patent holder, employee of the drug patent holder.

Somersan-Karakaya et al., 8 Nov 2021, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 62.0, 34 authors, study period 10 June, 2020 - 9 April, 2021, average treatment delay 6.0 days, trial NCT04426695 (history).

New phase 3 analyses show that a single dose of REGEN-COV® (casirivimab and imdevimab) provides long-term protection against COVID-19

Regeneron Press Release (News)

Long-term results for PEP RCT NCT04452318, with 841 baseline seronegative casirivimab/imdevimab patients and 842 placebo patients, showing significantly lower cases with treatment.

risk of hospitalization, 92.3% lower, RR 0.08, p = 0.03, treatment 0 of 841 (0.0%), control 6 of 842 (0.7%), NNT 140, relative risk is not 0 because of continuity correction due to zero events, 8 months.

risk of case, 81.5% lower, RR 0.19, p < 0.001, treatment 20 of 841 (2.4%), control 108 of 842 (12.8%), NNT 9.6, months 1-8.

risk of case, 81.6% lower, RR 0.18, p < 0.001, treatment 7 of 841 (0.8%), control 38 of 842 (4.5%), NNT 27, months 2-8.

risk of hospitalization/ER, 88.9% lower, RR 0.11, p = 0.06, treatment 0 of 753 (0.0%), control 4 of 752 (0.5%), NNT 188, relative risk is not 0 because of continuity correction due to zero events, day 29.

risk of symptomatic case, 81.4% lower, RR 0.19, p < 0.001, treatment 11 of 753 (1.5%), control 59 of 752 (7.8%), NNT 16, day 29.

recovery time, 62.5% lower, relative time 0.37, p < 0.001, treatment 753, control 752, short-term followup, relative time with symptoms.

time to viral-, 69.2% lower, relative time 0.31, p < 0.001, treatment 753, control 752, short-term followup, relative time with high viral load.

Regeneron et al., 8 Nov 2021, Double Blind Randomized Controlled Trial, multiple countries, preprint, 1 author, trial NCT04452318 (history).

Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for Covid-19 patients in A Real-Life Setting: A Single Institute Analysis

Kakinoki et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2022.01.067 (date from earlier preprint)

Retrospective 55 patients in Japan treated a median of 3 days from symptom onset with casirivimab/imdevimab, and 53 control patients, showing lower risk of further treatment including oxygen or antivirals.

risk of further treatment including oxygen or antivirals, 57.6% lower, RR 0.42, p = 0.049, treatment 13 of 55 (23.6%), control 22 of 53 (41.5%), NNT 5.6, adjusted, OR converted to RR, multivariable.

Kakinoki et al., 4 Nov 2021, retrospective, Japan, peer-reviewed, 16 authors, average treatment delay 3.0 days.

Antibody escape and global spread of SARS-CoV-2 lineage A.27

Kaleta et al., Research Square, doi:10.21203/rs.3.rs-995033/v1 (Preprint) (In Vitro)

Anaysis of antibody escape showing variant A.27 completely escaped neutralization with LY-COV555 and partially with REGN10987. B.1.617.2 escaped these antibodies in a similar manner, suggesting that L452R facilitates the escape. Authors note that B.1.351 and P.1 escaped LY-COV555 and REGN10933, likely facilitated by the E484K mutation, suggesting that L452R and E484K lead to escape from LY-COV555 and to partial resistance to either REGN10987 or REGN10933, respectively.

Kaleta et al., 2 Nov 2021, preprint, 33 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Monoclonal Antibody Treatment of Breakthrough COVID-19 in Fully Vaccinated Individuals with High-Risk Comorbidities

Bierle et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab570 (date from earlier preprint)

Retrospective 1,395 vaccinated COVID-19 cases, showing significantly lower hospitalization and oxygen supplementation with monoclonal antibody treatment, primarily casirivimab-imdevimab. Hospitalization was significantly associated with comorbidities.

risk of ICU admission, 88.9% lower, RR 0.11, p = 0.16, treatment 0 of 527 (0.0%), control 5 of 868 (0.6%), NNT 174, relative risk is not 0 because of continuity correction due to zero events.

risk of oxygen therapy, 85.3% lower, RR 0.15, p < 0.001, treatment 5 of 527 (0.9%), control 56 of 868 (6.5%), NNT 18, OR converted to RR.

risk of hospitalization, 75.3% lower, RR 0.25, p < 0.001, treatment 14 of 527 (2.7%), control 93 of 868 (10.7%), NNT 12, OR converted to RR.

Excluded in meta analysis: patients were treated with different medications, results specific to each medication were not reported. Conflicts of interest: research funding from the drug patent holder.

Bierle et al., 20 Oct 2021, retrospective, USA, peer-reviewed, 7 authors, average treatment delay 5.0 days.

Real-world Assessment of 2,879 COVID-19 Patients Treated with Monoclonal Antibody Therapy: A Propensity Score-Matched Cohort Study

Cooper et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab512

Retrospective 2,879 patients and matched controls in the USA, showing significantly lower mortality and hospitalization with bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab. There was significantly lower hospitalization with casirivimab/imdevimab compared to bamlanivimab or bamlanivimab/etesevimab. PSM and multivariate analysis is only provided for all treatments combined.

risk of death, 77.5% lower, RR 0.23, p = 0.18, treatment 1 of 1,148 (0.1%), control 33 of 8,534 (0.4%), NNT 334, unadjusted.

risk of ICU admission, 47.5% lower, RR 0.52, p = 0.14, treatment 6 of 1,148 (0.5%), control 85 of 8,534 (1.0%), NNT 211, unadjusted.

risk of hospitalization, 52.4% lower, RR 0.48, p < 0.001, treatment 45 of 1,148 (3.9%), control 703 of 8,534 (8.2%), NNT 23, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Cooper et al., 8 Oct 2021, retrospective, USA, peer-reviewed, 9 authors.

Real-World Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients with Early COVID-19

Webb et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab331

Retrospective 115 patients treated with casirivimab/imdevimab showing lower mortality, hospital admission, and emergency department visits with treatment. Authors falsely state that "no other COVID-19 therapies for ambulatory patients have proven effective".

risk of death, 98.3% lower, RR 0.02, p = 0.63, treatment 0 of 115 (0.0%), control 57 of 5,536 (1.0%), NNT 97, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 91.1% lower, RR 0.09, p < 0.001, treatment 1 of 115 (0.9%), control 538 of 5,536 (9.7%), NNT 11.

Webb et al., 23 Jun 2021, retrospective, USA, peer-reviewed, 14 authors.

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Horby et al., The Lancet, doi:10.1016/S0140-6736(22)00163-5 (date from earlier preprint)

RCT 9,785 hospitalized patients in the UK showing lower mortality with casirivimab/imdevimab, with statistical significance reached for baseline seronegative patients.

risk of death, 6.0% lower, RR 0.94, p = 0.16, treatment 943 of 4,839 (19.5%), control 1,029 of 4,946 (20.8%), NNT 76, all patients.

risk of mechanical ventilation, 1.0% higher, RR 1.01, p = 0.88, treatment 484 of 4,556 (10.6%), control 488 of 4,642 (10.5%), all patients.

risk of death, 21.0% lower, RR 0.79, p = 0.001, treatment 396 of 1,633 (24.2%), control 452 of 1,520 (29.7%), NNT 18, seronegative patients.

risk of mechanical ventilation, 13.0% lower, RR 0.87, p = 0.13, treatment 190 of 1,599 (11.9%), control 202 of 1,484 (13.6%), NNT 58, seronegative patients.

Horby et al., 16 Jun 2021, Randomized Controlled Trial, United Kingdom, peer-reviewed, 32 authors, study period 18 September, 2020 - 22 May, 2021, average treatment delay 9.0 days.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19

Weinreich et al., NEJM, doi:10.1056/NEJMoa2108163 (date from earlier preprint)

RCT 4,057 outpatients with >=1 risk factor for severe disease, showing significantly lower combined hospitalization/death, and significantly faster recovery with treatment. Median time from onset of symptoms 3 days. NCT04425629.

risk of death, 50.0% lower, RR 0.50, p = 0.45, treatment 2 of 2,091 (0.1%), control 4 of 2,089 (0.2%), NNT 1044, Table S9.

risk of death, 67.0% lower, RR 0.33, p = 0.37, treatment 1 of 1,355 (0.1%), control 3 of 1,341 (0.2%), NNT 667, 2400mg,Table S9.

risk of death, 1.6% higher, RR 1.02, p = 1.00, treatment 1 of 736 (0.1%), control 1 of 748 (0.1%), 1200mg,Table S9.

risk of death/hospitalization, 71.3% lower, RR 0.29, p < 0.001, treatment 18 of 1,355 (1.3%), control 62 of 1,341 (4.6%), NNT 30, 2400mg.

risk of death/hospitalization, 70.4% lower, RR 0.30, p = 0.002, treatment 7 of 736 (1.0%), control 24 of 748 (3.2%), NNT 44, 1200mg.

recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 1,355, control 1,341, 2400mg.

recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 736, control 748, 1200mg.

Weinreich et al., 21 May 2021, Randomized Controlled Trial, USA, peer-reviewed, 39 authors, average treatment delay 3.0 days, trial NCT04425629 (history).

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

O'Brien et al., NEJM, doi:10.1056/NEJMoa2109682 (press release 4/12/21)

Prophylaxis trial reporting lower hospitalization/ER and symptomatic cases, and faster recovery with 1,200mg subcutaneous casirivimab with imdevimab. The same trial has updated results available in [c19regn.com]. NCT04452318.

1. c19regn.com, https://c19regn.com/regeneron5.html.

risk of hospitalization/ER, 88.9% lower, RR 0.11, p = 0.06, treatment 0 of 753 (0.0%), control 4 of 752 (0.5%), NNT 188, relative risk is not 0 because of continuity correction due to zero events, day 29.

risk of symptomatic case, 81.4% lower, RR 0.19, p < 0.001, treatment 11 of 753 (1.5%), control 59 of 752 (7.8%), NNT 16, day 29.

recovery time, 62.5% lower, relative time 0.37, p < 0.001, treatment 753, control 752, relative time with symptoms.

time to viral-, 69.2% lower, relative time 0.31, p < 0.001, treatment 753, control 752, relative time with high viral load.

O'Brien et al., 12 Apr 2021, Double Blind Randomized Controlled Trial, multiple countries, peer-reviewed, 36 authors, trial NCT04452318 (history).

New phase III data shows investigational antibody cocktail casirivimab and imdevimab reduced hospitalisation or death by 70% in non-hospitalised patients with COVID-19

Regeneron Press Release (Preprint)

Press release for new phase III data showing lower hospitalization/mortality, and faster symptom resolution among the subset of patients with at least one risk factor.

Some variants may escape antibodies [cell.com].

1. cell.com, https://www.cell.com/cell/fulltext/S0092-8674(21)00367-6.

risk of death/hospitalization, 71.3% lower, RR 0.29, p < 0.001, treatment 18 of 1,355 (1.3%), control 62 of 1,341 (4.6%), NNT 30, 2,400mg IV, >=1 risk factor.

risk of death/hospitalization, 70.4% lower, RR 0.30, p = 0.003, treatment 7 of 736 (1.0%), control 24 of 748 (3.2%), NNT 44, 1,200mg IV, >=1 risk factor.

recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 1,355, control 1,341, 2,400mg IV, >=1 risk factor.

recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 736, control 748, 1,200mg IV, >=1 risk factor.

Regeneron et al., 23 Mar 2021, Randomized Controlled Trial, USA, preprint, 1 author.

Regeneron Reports Positive Interim Data with REGEN-COV™ Antibody Cocktail used as Passive Vaccine to Prevent COVID-19

Regeneron Press Release (Preprint)

Interim results of REGEN-COV prophylaxis showing 100% prevention of symptomatic infection (8/223 placebo vs. 0/186 REGEN-COV), and approximately 50% lower overall rates of infection (symptomatic and asymptomatic) (23/223 placebo vs. 10/186 REGEN-COV).

risk of symptomatic case, 93.6% lower, RR 0.06, p = 0.009, treatment 0 of 186 (0.0%), control 8 of 223 (3.6%), NNT 28, relative risk is not 0 because of continuity correction due to zero events.

risk of case, 47.9% lower, RR 0.52, p = 0.07, treatment 10 of 186 (5.4%), control 23 of 223 (10.3%), NNT 20.

Regeneron et al., 26 Jan 2021, Randomized Controlled Trial, USA, preprint, 1 author.

Regeneron's REGN-COV2 antibody cocktail reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients

Regeneron Press Release (Preprint)

Analysis of the first 275 patients in a trial of the REGN-COV2 antibody cocktail showing reductions in viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19. Greatest improvements were seen with patients that had not mounted their own effective immune response prior to treatment.

The mean time-weighted-average change from baseline nasopharyngeal viral load through Day 7 in the seronegative (no measurable antiviral antibodies) group was a 0.60 log10 copies/mL greater reduction (p=0.03) in patients treated with high dose, and a 0.51 log10 copies/mL greater reduction (p=0.06) in patients treated with low dose, compared to placebo. In the overall population, there was a 0.51 log10 copies/mL greater reduction (p=0.0049) in patients treated with high dose, and a 0.23 log10 copies/mL greater reduction (p=0.20) in patients treated with low dose, compared to placebo.

Among seronegative patients, median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, 8 days in high dose (p=0.22), and 6 days in low dose (p=0.09).

Adverse reactions were similar with treatment and placebo. There were no deaths.

recovery time, 38.0% lower, relative time 0.62, p = 0.22, treatment 92, control 91, high dose median time to recovery, group sizes estimated because they were not supplied.

recovery time, 54.0% lower, relative time 0.46, p = 0.09, treatment 92, control 91, low dose median time to recovery, group sizes estimated because they were not supplied.

Regeneron et al., 29 Sep 2020, Randomized Controlled Trial, USA, preprint, 1 author.

Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

Baum et al., Science, 21 Aug 2020, 369:6506, 1014-1018, doi:10.1126/science.abd0831 (In Vitro)

In Vitro study showing that, under pressure from individual antibodies, mutant viruses were rapidly selected that evaded the blocking function of all individual antibodies tested, including antibodies that potently bind to highly-conserved regions on the spike protein. However, escape mutants could not be efficiently generated following exposure to the REGN-COV2 cocktail since it utilizes two antibodies that can simultaneously bind to distinct regions of the RBD.

Baum et al., 21 Aug 2020, peer-reviewed, 17 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Hansen et al., Science, 21 Aug 2020, 369:6506, 1010-1014, doi:10.1126/science.abd0827

Study using humanized mice and blood samples from recovered COVID-19 patients to generate antibodies targeting multiple different regions of the critical receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The spike protein on the virus cell surface binds to the host cell and is required for infectivity. By blocking its interaction with the host cell, antibodies are able to neutralize the virus and block infection. Authors selected pairs of highly potent individual antibodies that simultaneously and non-competitively bind to the RBD. The multi-antibody approach is used to decrease the potential for the virus to escape.

Hansen et al., 21 Aug 2020, peer-reviewed, 47 authors.