Sotrovimab for COVID-19: real-time analysis of all 13 studies

Sotrovimab for COVID-19: real-time meta analysis of 7 studies

Covid Analysis (Preprint) (meta analysis)

• Meta analysis using the most serious outcome reported shows 15% [-57‑54%] improvement, without reaching statistical significance. Results are worse for Randomized Controlled Trials and similar for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment.

• 4 studies from 4 independent teams in 2 different countries show statistically significant improvements in isolation (1 for the most serious outcome).

• Efficacy is variant dependent. In Vitro studies suggest lower efficacy for omicron BA.1 [Liu, Sheward, VanBlargan] and no efficacy for omicron BA.2 [Zhou]. US EUA has been revoked. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 43% of sotrovimab studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are significantly more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

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

Covid Analysis et al., 8/12/2022, preprint, 1 author.

Real-world effectiveness of early remdesivir and sotrovimab in the highest-risk COVID-19 outpatients during the Omicron surge

Piccicacco et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkac256

Retrospective high-risk outpatients in the USA, 82 treated with remdesivir, 88 with sotrovimab, and 90 control patients, showing significantly lower combined hospitalization/ER visits with both treatments in unadjusted results. The dominant variant was omicron B.1.1.529.

risk of death, 66.4% lower, RR 0.34, p = 1.00, treatment 0 of 88 (0.0%), control 1 of 90 (1.1%), NNT 90, relative risk is not 0 because of continuity correction due to zero events, day 29.

risk of hospitalization, 34.9% lower, RR 0.65, p = 0.46, treatment 7 of 88 (8.0%), control 11 of 90 (12.2%), NNT 23, day 29.

risk of hospitalization/ER, 66.3% lower, RR 0.34, p = 0.01, treatment 7 of 88 (8.0%), control 21 of 90 (23.3%), NNT 6.5, OR converted to RR, day 29.

risk of progression, 89.8% lower, RR 0.10, p = 0.009, treatment 1 of 88 (1.1%), control 10 of 90 (11.1%), NNT 10, ER visit, day 29.

Piccicacco et al., 8/1/2022, retrospective, USA, peer-reviewed, 7 authors, study period 27 December, 2021 - 4 February, 2022, average treatment delay 4.4 days.

Change in Effectiveness of Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients During the Omicron Phase

Aggarwal et al., medRxiv, doi:10.1101/2022.06.17.22276575 (Preprint)

Retrospective 30,247 outpatients in the USA, showing no significant differences with sotrovimab with omicron BA.1.

risk of death, 38.0% lower, RR 0.62, p = 0.62, treatment 1 of 1,542 (0.1%), control 7 of 3,663 (0.2%), OR converted to RR.

risk of hospitalization, 17.5% lower, RR 0.82, p = 0.32, treatment 39 of 1,542 (2.5%), control 116 of 3,663 (3.2%), NNT 157, OR converted to RR, primary outcome.

risk of progression, 2.8% higher, RR 1.03, p = 0.83, treatment 93 of 1,542 (6.0%), control 224 of 3,663 (6.1%), NNT 1189, OR converted to RR, ED visit.

Aggarwal et al., 6/18/2022, retrospective, USA, preprint, 5 authors, study period 26 December, 2021 - 10 March, 2022.

Effectiveness of the neutralizing antibody sotrovimab among high-risk patients with mild to moderate SARS-CoV-2 in Qatar

Zaqout et al., medRxiv, doi:10.1101/2022.04.21.22274060 (Preprint)

Retrospective 345 sotrovimab treated patients in Qatar matched with 583 patients that opted not to receive treatment, showing higher progression with treatment, without statistical significance.

risk of progression, 164.7% higher, RR 2.65, p = 0.19, treatment 4 of 345 (1.2%), control 3 of 583 (0.5%), adjusted, OR converted to RR, progression to severe/critical disease or mortality.

Zaqout et al., 4/21/2022, retrospective, Qatar, preprint, 17 authors, study period 20 October, 2021 - 28 February, 2022.

FDA updates Sotrovimab emergency use authorization

FDA (News)

FDA has revoked sotrovimab's authorization in all regions due to predicted low efficacy with BA.2, and BA.2 exceeding 50% prevalence in all regions.

FDA et al., 4/5/2022, preprint, 1 author.

Real-World Evidence of the Neutralizing Monoclonal Antibody Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients

Aggarwal et al., medRxiv, doi:10.1101/2022.04.03.22273360 (Preprint)

Retrospective 522 sotrovimab patients and matched controls in the USA, showing significantly lower hospitalization and mortality with treatment.

risk of death, 88.9% lower, RR 0.11, p = 0.048, treatment 0 of 522 (0.0%), control 15 of 1,563 (1.0%), NNT 104, adjusted, OR converted to RR, propensity score matching, multivariable, day 28.

risk of hospitalization, 61.6% lower, RR 0.38, p = 0.002, treatment 11 of 522 (2.1%), control 89 of 1,563 (5.7%), NNT 28, adjusted, OR converted to RR, propensity score matching, multivariable, day 28.

Aggarwal et al., 4/5/2022, retrospective, USA, preprint, 14 authors, study period 1 October, 2021 - 11 December, 2021.

Real-World Use of Sotrovimab for Pre-Emptive Treatment in High-Risk Hospitalized COVID-19 Patients: An Observational Cross-Sectional Study

Ong et al., Antibiotics, doi:10.3390/antibiotics11030345

Retrospective 19 sotrovimab patients and 75 controls is Singapore, showing lower progression with treatment.

risk of death, 60.5% lower, RR 0.39, p = 0.45, treatment 1 of 19 (5.3%), control 10 of 75 (13.3%), NNT 12.

risk of ICU admission, 56.1% lower, RR 0.44, p = 0.35, treatment 2 of 19 (10.5%), control 18 of 75 (24.0%), NNT 7.4.

risk of progression, 59.0% lower, HR 0.41, p = 0.047, treatment 19, control 75, Cox proportional hazards.

Ong et al., 3/5/2022, retrospective, Singapore, peer-reviewed, 10 authors, average treatment delay 2.0 days.

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., 2/16/2022, preprint, 4 authors.

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

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

Self et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(21)00751-9

RCT with 182 sotrovimab patients and 178 control patients, median 8 days from symptom onset, showing no significant differences and terminated early due to futility.

risk of death, 2.0% higher, RR 1.02, p = 0.96, treatment 14 of 182 (7.7%), control 13 of 178 (7.3%), day 90.

risk of no recovery, 10.7% lower, RR 0.89, p = 0.29, treatment 22 of 160 (13.8%), control 27 of 178 (15.2%), NNT 70, day 90, primary outcome.

risk of no recovery, 7.4% lower, RR 0.93, p = 0.69, treatment 160, control 178, pulmonary-plus ordinal outcome @day 5.

Self et al., 12/23/2021, Double Blind Randomized Controlled Trial, multiple countries, peer-reviewed, 647 authors, study period 16 December, 2020 - 1 March, 2021, average treatment delay 8.0 days, trial NCT04501978 (history) (TICO).

Resistance conferring mutations in SARS-CoV-2 delta following sotrovimab infusion

Rockett et al., medRxiv, doi:10.1101/2021.12.18.21267628 (Preprint)

Retrospective 100 sotrovimab patients in Australia, 23 PCR+ more than 10 days post-infusion (68 with status unknown), showing rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro.

Rockett et al., 12/21/2021, preprint, 26 authors.

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., 12/20/2021, preprint, 11 authors.

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

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., 12/17/2021, 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., 12/15/2021, preprint, 23 authors.

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

Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19

Gupta et al., JAMA, doi:10.1001/jama.2022.2832 (results published 12/4/21)

RCT 1,057 outpatients, 529 treated with sotrovimab, showing significantly lower hospitalization >24h or mortality with treatment.

risk of death, 80.0% lower, RR 0.20, p = 0.50, treatment 0 of 528 (0.0%), control 2 of 529 (0.4%), NNT 264, relative risk is not 0 because of continuity correction due to zero events, day 29.

risk of mechanical ventilation, 88.9% lower, RR 0.11, p = 0.12, treatment 0 of 528 (0.0%), control 4 of 529 (0.8%), NNT 132, relative risk is not 0 because of continuity correction due to zero events, day 29.

risk of progression, 75.0% lower, RR 0.25, p < 0.001, treatment 7 of 528 (1.3%), control 28 of 529 (5.3%), NNT 25, day 29.

risk of hospitalization >24hrs or death, 79.0% lower, RR 0.21, p < 0.001, treatment 6 of 528 (1.1%), control 30 of 529 (5.7%), NNT 22, day 29, ITT, primary outcome.

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

Gupta et al., 12/4/2021, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 68 authors, average treatment delay 2.6 days, trial NCT04545060 (history) (COMET-ICE).

Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab

Gupta et al., NEJM, doi:10.1056/NEJMoa2107934 (news release 5/26/2021) (Preprint)

Interim results from the COMET-ICE trial showing significantly lower hospitalization with treatment. NCT04545060.

risk of death, 66.6% lower, RR 0.33, p = 1.00, treatment 0 of 291 (0.0%), control 1 of 292 (0.3%), NNT 292, relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 80.0% lower, RR 0.20, p = 0.50, treatment 0 of 291 (0.0%), control 2 of 292 (0.7%), NNT 146, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 90.9% lower, RR 0.09, p = 0.06, treatment 0 of 291 (0.0%), control 5 of 292 (1.7%), NNT 58, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 80.9% lower, RR 0.19, p < 0.001, treatment 4 of 291 (1.4%), control 21 of 292 (7.2%), NNT 17.

risk of hospitalization, 85.7% lower, RR 0.14, p < 0.001, treatment 3 of 291 (1.0%), control 21 of 292 (7.2%), NNT 16, >24hrs, primary outcome.

Gupta et al., 5/26/2021, Double Blind Randomized Controlled Trial, USA, preprint, 22 authors, trial NCT04545060 (history).

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption