Bamlanivimab for COVID-19: real-time analysis of all 18 studies

Bamlanivimab for COVID-19: real-time meta analysis of 11 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, ICU admission, hospitalization, and viral clearance. 10 studies from 7 independent teams (all from the same country) show statistically significant improvements in isolation (4 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 62% [37‑77%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

• Results are robust — in exclusion sensitivity analysis 6 of 11 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• Efficacy is highly variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, VanBlargan]. 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 9% of bamlanivimab studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments may be more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. 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.

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	11	79% [59‑89%]	36% [-58‑74%]	57% [33‑72%]	23,338	137
With exclusions	9	76% [50‑88%]	36% [-58‑74%]	57% [33‑72%]	13,074	121
Peer-reviewed	7	78% [54‑89%]	23% [-477‑90%]		20,819	90
RCTs	6	75% [46‑88%]	-21% [-218‑54%]	57% [33‑72%]	2,970	65
Percentage improvement with bamlanivimab treatment

Covid Analysis et al., 1/13/2022, preprint, 1 author.

Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19

Chew et al., medRxiv, doi:10.1101/2021.12.17.21268009 (Preprint)

RCT 317 outpatients in the USA showing faster viral load and inflammatory biomarker decline, but no significant differences in clinical outcomes. ACTIV-2/A5401. NCT04518410. Supplementary data is not currently available.

risk of hospitalization, 25.5% lower, RR 0.75, p = 0.60, treatment 6 of 159 (3.8%), control 8 of 158 (5.1%), NNT 78, combined.

risk of hospitalization, 52.1% lower, RR 0.48, p = 0.43, treatment 2 of 48 (4.2%), control 4 of 46 (8.7%), NNT 22, 7000mg, day 28.

risk of hospitalization, 0.9% higher, RR 1.01, p = 1.00, treatment 4 of 111 (3.6%), control 4 of 112 (3.6%), 700mg, day 28.

relative time to symptom improvement, 13.5% higher, relative time 1.14, p = 0.97, treatment 48, control 46, 7000mg.

relative time to symptom improvement, 17.1% higher, relative time 1.17, p = 0.08, treatment 111, control 112, 700mg.

viral load, 25.6% lower, relative load 0.74, p = 0.002, treatment 48, control 46, 7000mg, day 3.

viral load, 35.3% lower, relative load 0.65, p = 0.07, treatment 111, control 112, 700mg, day 3.

Chew et al., 12/21/2021, Randomized Controlled Trial, USA, North America, preprint, 23 authors, study period 19 August, 2020 - 17 November, 2020.

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.

Bamlanivimab efficacy in older and high BMI outpatients with Covid-19 selected for treatment in a lottery-based allocation process

Rubin et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab546 (Peer Reviewed)

Retrospective database analysis of 1257 PCR+ outpatients with age ≥65, BMI≥35, 191 receiving bamlanivimab via lottery. Authors note that the alpha variant was most common during the study period, and that efficacy against other variants can be much lower. Authors note confounding due to prioritization in the lottery and differential reporting in the database. The adjusted mortality result is in the abstract, with no details or mention in the paper, and we note that the change after adjustments is large: RR 0.56 -> OR 0.03.

risk of death, 97.0% lower, RR 0.03, p < 0.01, treatment 1 of 191 (0.5%), control 10 of 1,066 (0.9%), NNT 241, OR converted to RR.

risk of hospitalization, 65.3% lower, RR 0.35, p = 0.04, treatment 16 of 191 (8.4%), control 121 of 1,065 (11.4%), NNT 34, OR converted to RR, IPTW weighted logistic regression.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible. Conflicts of interest: research funding from the drug patent holder, consulting for the pharmaceutical industry.

Rubin et al., 11/3/2021, retrospective, USA, North America, peer-reviewed, 7 authors, study period 9 December, 2020 - 25 February, 2021.

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)

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., 11/2/2021, preprint, 33 authors.

Early Treatment with BamlanivimabAlone does not Prevent COVID-19 Hospitalization and Its Post-Acute Sequelae. A Real Experience in Umbria, Italy

Schiaroli et al., Mediterranean Journal of Hematology and Infectious Diseases, doi:10.4084/MJHID.2021.061 (Peer Reviewed)

Retrospective 39 patients treated with bamlanivimab in Italy, showing results far below expectations based on the BLAZE1 trial. Authors note that most patients had the alpha variant which does not have the E484K and L452R mutations known to lead to resistance.

Schiaroli et al., 10/29/2021, retrospective, Italy, Europe, peer-reviewed, 7 authors.

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 (Peer Reviewed)

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, 45.3% lower, RR 0.55, p = 1.00, treatment 1 of 473 (0.2%), control 33 of 8,534 (0.4%), NNT 571, unadjusted, bamlanivimab-etesevimab.

risk of ICU admission, 57.5% lower, RR 0.42, p = 0.33, treatment 2 of 473 (0.4%), control 85 of 8,534 (1.0%), NNT 174, unadjusted, bamlanivimab-etesevimab.

risk of hospitalization, 5.0% lower, RR 0.95, p = 0.86, treatment 37 of 473 (7.8%), control 703 of 8,534 (8.2%), NNT 241, unadjusted, bamlanivimab-etesevimab.

risk of death, 17.2% higher, RR 1.17, p = 0.59, treatment 11 of 2,427 (0.5%), control 33 of 8,534 (0.4%), unadjusted, bamlanivimab.

risk of ICU admission, 9.0% lower, RR 0.91, p = 0.81, treatment 22 of 2,427 (0.9%), control 85 of 8,534 (1.0%), NNT 1117, unadjusted, bamlanivimab.

risk of hospitalization, 28.0% lower, RR 0.72, p < 0.001, treatment 144 of 2,427 (5.9%), control 703 of 8,534 (8.2%), NNT 43, unadjusted, bamlanivimab.

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

Cooper et al., 10/8/2021, retrospective, USA, North America, peer-reviewed, 9 authors.

Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19

Ganesh et al., Journal of Clinical Investigation, doi:10.1172/JCI151697 (Peer Reviewed)

Retrospective 2,335 bamlanivimab patients and 2,335 PSM controls in the USA, showing significantly lower hospitalization with treatment.

risk of death, 74.4% lower, RR 0.26, p = 0.11, treatment 2 of 1,789 (0.1%), control 8 of 1,832 (0.4%), NNT 308, day 28.

risk of ICU admission, 48.8% lower, RR 0.51, p = 0.10, treatment 10 of 1,789 (0.6%), control 20 of 1,832 (1.1%), NNT 188, day 28.

risk of hospitalization, 37.4% lower, RR 0.63, p = 0.01, treatment 44 of 1,789 (2.5%), control 72 of 1,832 (3.9%), NNT 68, day 28.

Ganesh et al., 10/1/2021, retrospective, USA, North America, peer-reviewed, median age 63.0, 20 authors.

Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy

Choudhary et al., medRxiv, doi:10.1101/2021.09.03.21263105 (Preprint)

Analysis of ACTIV-2/A5401, showing the potential for rapid emergence of resistance during monoclonal antibody treatment, resulting in prolonged high level viral loads and clinical worsening. Treatment-emergent resistance mutations were more common after bamlanivimab 700mg (7% of 111 vs 0% of 112 participants, p=0.003). NCT04518410.

Choudhary et al., 9/15/2021, preprint, 28 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 (Peer Reviewed)

Retrospective 479 patients treated with bamlanivimab showing lower mortality, hospital admission, and emergency department visits with treatment. Authors incorrectly state that "no other COVID-19 therapies for ambulatory patients have proven effective".

risk of death, 79.7% lower, RR 0.20, p = 0.09, treatment 1 of 479 (0.2%), control 57 of 5,536 (1.0%), NNT 122.

risk of hospitalization, 52.7% lower, RR 0.47, p < 0.001, treatment 22 of 479 (4.6%), control 538 of 5,536 (9.7%), NNT 20.

risk of hospitalization/ER, 26.8% lower, RR 0.73, p < 0.001, treatment 65 of 479 (13.6%), control 1,018 of 5,536 (18.4%), NNT 21, OR converted to RR.

Webb et al., 6/23/2021, retrospective, USA, North America, peer-reviewed, 14 authors.

Emergence of SARS-CoV-2 Spike Escape Mutation Q493r After Bamlanivimab/Etesevimab Treatment for COVID-19

Focosi et al., Research Square, doi:10.21203/rs.3.rs-524959/v1 (Preprint)

Case study showing that a mutation resistant to both bamlanivimab and etesevimab can arise in vivo. Authors note that accelerated evolution can occur under selective pressure from therapeutic interventions with neutralizing antibodies, and that bamlanivimab was withdrawn as a monotherapy because of failure against E484K-positive SARS-CoV-2 variants.

Focosi et al., 5/18/2021, preprint, 7 authors.

Impact of monoclonal antibody treatment on hospitalization and mortality among non-hospitalized adults with SARS-CoV-2 infection

Bariola et al., medRxiv, doi:10.1101/2021.03.25.21254322 (Preprint)

Retrospective 234 patients receiving bamlanivimab and 234 matched controls, showing lower hospitalization and mortality with treatment. Greater benefit was seen with administration within 4 days of their positive COVID-19 test.

risk of death, 66.8% lower, RR 0.33, p = 0.05, treatment 4 of 234 (1.7%), control 12 of 234 (5.1%), NNT 29, OR converted to RR.

risk of death/hospitalization, 64.3% lower, RR 0.36, p < 0.001, treatment 16 of 234 (6.8%), control 45 of 234 (19.2%), NNT 8.1, OR converted to RR.

risk of hospitalization, 60.7% lower, RR 0.39, p = 0.001, treatment 15 of 234 (6.4%), control 39 of 234 (16.7%), NNT 9.8, OR converted to RR.

Bariola et al., 3/30/2021, retrospective, USA, North America, preprint, 22 authors.

Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19

Lilly, Press Release (Preprint)

Results from the BLAZE-1 study of combined bamlanivimab/etesevimab, showing significantly lower mortality and combined mortality/hospitalization with treatment.

risk of death, 92.3% lower, RR 0.08, p = 0.01, treatment 0 of 511 (0.0%), control 4 of 258 (1.6%), NNT 64, relative risk is not 0 because of continuity correction due to zero events.

risk of death/hospitalization, 86.5% lower, RR 0.13, p < 0.001, treatment 4 of 511 (0.8%), control 15 of 258 (5.8%), NNT 20.

Lilly et al., 3/10/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 1 author.

Lilly's neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents

Lilly, Press Release (Preprint)

Press release on the BLAZE-2 trial at nursing homes showing significantly lower symptomatic COVID-19 with treatment.

risk of symptomatic case, 57.0% lower, RR 0.43, p < 0.001, treatment 483, control 482, group sizes estimated because they were not supplied.

risk of symptomatic case, 80.0% lower, RR 0.20, p < 0.001, treatment 150, control 149, nursing home residents, group sizes estimated because they were not supplied.

Lilly et al., 1/21/2021, Randomized Controlled Trial, USA, North America, preprint, 1 author.

Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19

Gottlieb et al., JAMA, doi:10.1001/jama.2021.0202 (Peer Reviewed)

RCT for LY-CoV555 monotherapy and LY-CoV555/LY-CoV016 combination therapy with 592 patients showing lower hospitalization/ER visits with treatment.

For viral load at day 11, a statistically significant reduction was found with combination therapy but not monotherapy.

risk of hospitalization/ER, 70.6% lower, RR 0.29, p = 0.046, treatment 4 of 101 (4.0%), control 7 of 52 (13.5%), NNT 11, LY-CoV555 all dosages.

risk of hospitalization/ER, 79.9% lower, RR 0.20, p = 0.13, treatment 1 of 37 (2.7%), control 7 of 52 (13.5%), NNT 9.3, LY-CoV555 700mg.

risk of hospitalization/ER, 75.2% lower, RR 0.25, p = 0.25, treatment 1 of 30 (3.3%), control 7 of 52 (13.5%), NNT 9.9, LY-CoV555 2800mg.

risk of hospitalization/ER, 56.3% lower, RR 0.44, p = 0.31, treatment 2 of 34 (5.9%), control 7 of 52 (13.5%), NNT 13, LY-CoV555 7000mg.

risk of hospitalization/ER, 91.8% lower, RR 0.08, p = 0.04, treatment 0 of 31 (0.0%), control 7 of 52 (13.5%), NNT 7.4, relative risk is not 0 because of continuity correction due to zero events, LY-CoV555/LY-CoV016.

Gottlieb et al., 1/21/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 27 authors.

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

ACTIV-3/TICO LY-CoV555 study group, NEJM, doi:0.1056/NEJMoa2033130 (Peer Reviewed)

Late stage RCT of LY-CoV555 added to remdesivir, showing non-statistically significant higher mortality with the addition of LY-CoV555.

risk of death, 100% higher, RR 2.00, p = 0.22, treatment 9 of 163 (5.5%), control 5 of 151 (3.3%), adjusted, proportional hazards regression.

ACTIV-3/TICO et al., 12/22/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 1 author, average treatment delay 7.0 days.

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

Chen et al., NEJM, doi:10.1056/NEJMoa2029849 (Peer Reviewed)

Interim analysis of the BLAZE-1 phase 2 trial of outpatients showing lower hospitalization or ER visits (1.6% versus 6.3%), and improvements in symptoms and viral load compared to placebo. NCT04427501.

risk of hospitalization, 74.3% lower, RR 0.26, p = 0.02, treatment 5 of 309 (1.6%), control 9 of 143 (6.3%), NNT 21.

Chen et al., 10/28/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 12 authors.

Lilly Statement Regarding NIH’s ACTIV-3 Clinical Trial

Lilly, Press Release (News)

ACTIV-3 intermin analysis shows LY-CoV555 is unlikely to help hospitalized patients. ACTIV-2, BLAZE-1 and BLAZE-2 trials remain ongoing.

Lilly et al., 10/26/2020, preprint, 1 author.

SARS-CoV-2 neutralizing antibody program update

Lilly, Press Release (Preprint)

Interim results from the BLAZE-1 outpatient RCT showing improvements in viral load, symptoms and hospitalization.

Combination therapy significantly reduced viral load at day 11 (p=0.011). A greater effect is seen at day 7 (p<0.001). The proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0 percent) versus placebo (20.8 percent), corresponding to a nominal p value of p<0.0001 without multiplicity adjustment. No emergent putative resistance variants have been observed thus far in patients treated with combination therapy.

The rate of COVID-related hospitalization and ER visits was lower for patients treated with combination therapy (0.9 percent) versus placebo (5.8 percent), a relative risk reduction of 84.5 percent (p=0.049). This was also similar to observations for LY-CoV555 monotherapy.

Combination therapy has been generally well tolerated with no drug-related serious adverse events. In LY-CoV555 monotherapy studies there have been isolated drug-related infusion reactions or hypersensitivity that were generally mild (two reported as serious infusion reactions, all patients recovered).

NCT04427501

risk of hospitalization or ER visit, 84.5% lower, RR 0.15, p = 0.049, treatment 112, control 156.

Lilly et al., 10/7/2020, Randomized Controlled Trial, USA, North America, preprint, 1 author.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Povidone-Iod..	(meta)
Conv. Plasma	(meta)	Probiotics	(meta)
Curcumin	(meta)	Proxalutamide	(meta)
Ensovibep	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption