Monoclonal Antibodies A Review of Pertinent Drug Information for SARS-CoV-2 Jessica Ortwine, PharmD, BCIDP Clinical Pharmacy Specialist, Parkland Health & Hospital System [email protected] @jkortwine Data as of February 25, 2021 Adaptive Immunity • Active immunity: seroconversion occurs within 1-3 weeks of COVID-19 symptom onset • Passive immunity: direct administration of monoclonal antibodies (mAb) or convalescent plasma • Benefit of mAb: target specific viral epitopes and domains, mass produced, administered in a specified quantity, no reliance on donors Zhao J, et al. Clin Infect Dis. 2020;71:2027-34. https://doi.org/10.1093/cid/ciaa344 Mechanism of Action • Monoclonal antibodies prevent and possibly treat COVID-19 via multiple effector functions • Antibody-mediated neutralization of pathogen • Antibody-dependent cellular cytotoxicity • Antibody-dependent cellular phagocytosis Lu LL, et al. Nat Rev Immunol. 2018;18:46-61. https://doi.org/10.1038/nri.2017.106 Mechanism of Action • Spike (S) protein essential for: • Viral attachment to host receptor (S1) • Virus-cell fusion (S2) • Monoclonal antibodies (mAbs) bind to receptor binding domain (RBD) of S protein • Block viral entry into host cells Jiang S, et al. Trends Immunol. 2020;41:355-9. https://doi.org/10.1016/j.it.2020.03.007 Eli Lilly – Bamlanivimab Alternate Names: LY3819253 LY-CoV555 Bamlanivimab – In vitro Activity • Greater neutralization potency than other RBD-binding, ACE2- Neutralization Potency blocking antibody finalists, despite similar binding affinities • Ability to bind to RBD in both “up” and “down” conformations may account for increased neutralization activity Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972 In vivo Animal Data Rhesus Macaque Prophylaxis Methods Antibody administered intravenously 1 day prior to viral challenge Viral Inoculum 1.1 x 105 PFU 1 mg/kg (N=4) 2.5 mg/kg (N=4) Antibody Doses 15 mg/kg (N=3) 50 mg/kg (N=3) Control (N=4) Lower respiratory tract (LRT): Nasal swab, throat swab Sample Types Upper respiratory tract (URT): BAL, lung tissue Outcomes Change in viral load (gRNA and sgRNA) Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972 In vivo Animal Data Rhesus Macaque Key Findings • Reduced viral concentrations and replication on day 1 in all BAL and most LRT samples • Viral replication undetectable in all locations by day 3 at most doses Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972 Eli Lilly – Etesevimab Alternate Names: JS016 LY3832479 LY-CoV016 Etesevimab – In vitro Activity • Two potential monoclonal antibodies initially identified from convalescing patient • Similar ability to block binding of SARS-CoV-2 RBD to ACE2 receptor • Bind to overlapping epitopes • Lower 50% neutralization dose against infected cells for CB6 Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-y In vivo Animal Data Rhesus Macaque Prophylaxis Treatment Antibody administered 1 day prior Antibody administered on day 1 and day Methods to viral challenge 3 post-viral challenge 5 Viral Inoculum 1.0 x 10 TCID50 50 mg/kg (N=3/group) Antibody Dose Placebo (N=3) Sample Type Throat swabs Change in viral load (RNA) Outcomes Pathological lung damage Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-y In vivo Animal Data Rhesus Macaque Key Findings • Low levels of virus detectable among animals receiving prophylactic doses • Treatment doses resulted in reduced viral loads by day 2 compared to placebo • Reduced infection-related lung damage in both prophylaxed and treated animals Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-y Clinical Trials NCT Number Patient Population Treatment Groups Status LY-CoV555 NCT04427501 Recruiting – some results Treatment of outpatients with mild to moderate COVID-19 illness LY-CoV555 + LY-CoV016 BLAZE-1 available Placebo LY-CoV555 NCT04497987 Prevention (and treatment) of COVID-19 illness in skilled nursing and Recruiting – press release LY-CoV555 + LY-CoV016 (treatment arm only) BLAZE-2 assisted living facility residents and staff data available Placebo LY-CoV555 NCT04634409 LY-CoV555 + LY-CoV016 Recruiting – press release Treatment of outpatients with mild to moderate COVID-19 illness BLAZE-4 LY-CoV555 + VIR-7831 data available Placebo NCT04701658 Treatment of outpatients with mild-to-moderate COVID-19 at high risk LY-CoV555 Not yet recruiting BLAZE-5 for progressing to severe illness Standard of care NCT04518410 LY-CoV555 Treatment of outpatients with mild to moderate COVID-19 illness Recruiting ACTIV-2 Placebo NCT04501978 LY-CoV555 Treatment of hospitalized patients with COVID-19 illness Halted – results available ACTIV-3 Placebo Source: https://clinicaltrials.gov Ambulatory Treatment BLAZE-1 Study Design Treatment Groups Outcomes • Phase 2, double-blind RCT • Part A: LY-CoV555 • Primary: • Non-hospitalized adults monotherapy • Change from baseline viral • 7000 mg IV x 1 load at day 11 (± 4 days) • ≥ 1 mild/moderate COVID- • 2800 mg IV x 1 from positive results 19 symptom • 700 mg IV x 1 • Secondary: • 1st positive SARS-CoV-2 • Placebo • Safety test ≤ 72 hours from start • Part B & C: LY-CoV555 + • Symptom burden of infusion LY-CoV016 combination • COVID-19 related hospitalization, ED visit, or • High risk for complications • 2800 mg/2800 mg IV x 1 (Part C only) death at day 29 • Placebo • Viral clearance Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 Gottlieb RL, et al. JAMA. 2021. [Epub ahead of print]. https://doi.org/10.1001/jama.2021.0202 Ambulatory Treatment LY- CoV555 Monotherapy Characteristic Ly-CoV555 (N=309) Placebo (N=143) Ly-CoV555 dosing: Age (years), median (range) 45 (18-86) 46 (18-77) ≥ 65, n (%) 33 (10.7) 20 (14.0) • 700 mg (N=101) Body-mass index (kg/m2), median 29.4 29.1 • 2800 mg (N=107) ≥ 30 to < 40, n/total (%) 112/304 (36.8) 56/139 (40.3) • 7000 mg (N=101) ≥ 40, no/total (%) 24/304 (7.9) 9/139 (6.5) Risk factors for severe COVID-19, n(%) 215 (69.6) 95 (66.4) Disease status, n(%) Risk factors for severe disease: Mild 232 (75.1) 113 (79.0) • Age ≥ 65 years Moderate 77 (24.9) 30 (21.0) • BMI ≥ 35 kg/m2 Days since symptom onset, median 4.0 4.0 • Prespecified coexisting illness Viral load (cycle threshold), mean 23.9 23.8 Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 Ambulatory Treatment LY- CoV555 Monotherapy Primary Outcome: Mean change from baseline in viral load at day 11 Treatment Group Viral Load Change, mean Difference (95% CI) Placebo -3.47 LY-CoV555, 700 mg -3.67 -0.20 (-0.66 to 0.25) LY-CoV555, 2800 mg -4.00 -0.53 (-0.98 to -0.08) LY-CoV555, 7000 mg -3.38 0.09 (-0.37 to 0.55) Pooled LY-CoV555 doses -3.70 -0.22 (-0.60 to 0.15) Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 Ambulatory Treatment LY- CoV555 Monotherapy Secondary Outcome: Mean change from baseline in viral load at days 3 and 7 Day 3 Day 5 Treatment Group Viral Load Change, Difference Viral Load Change, Difference mean (95% CI) mean (95% CI) Placebo -0.85 -2.56 LY-CoV555, 700 mg -1.27 -0.42 (-0.89 to 0.06) -2.82 -0.25 (-0.73 to 0.23) LY-CoV555, 2800 mg -1.50 -0.64 (-1.11 to -0.17) -3.01 -0.45 (-0.92 to 0.03) LY-CoV555, 7000 mg -1.27 -0.42 (-0.90 to 0.06) -2.85 -0.28 (-0.77 to 0.20) Pooled LY-CoV555 doses -1.35 -0.49 (-0.87 to -0.11) -2.90 -0.33 (-0.72 to 0.06) Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 Ambulatory Treatment LY- CoV555 Monotherapy Secondary Outcomes: Hospitalizations, ED visits and Death • No deaths in any treatment group Treatment Group Hospitalization/ER Visits at Day 29* • Nearly all events were hospitalizations Placebo 9/143 (6.3) • 2 ED visits in placebo group • Post hoc analysis of high-risk patients LY-CoV555, 700 mg 1/101 (1.0) • LY-CoV555: 4/96 (4%) hospitalizations LY-CoV555, 2800 mg 2/107 (1.9) • Placebo: 7/48 (15%) hospitalizations LY-CoV555, 7000 mg 2/101 (2.0) Pooled LY-CoV555 doses 5/309 (1.6) *Placebo: 7 hospitalizations, 2 ER visits; LY-CoV555 all doses: 5 hospitalizations Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 Emergency Use Authorization for bamlanivimab 700mg IV. Center for Drug Evaluation and Research (CDER) Review. Available at: https://www.fda.gov/media/144118/download Ambulatory Treatment LY- CoV555 Monotherapy Secondary Outcomes: Symptom Score • Median time to symptom improvement • Pooled treatment: 6 days • Placebo: 8 days Chen P, et al. N Engl J Med. 2021;384(3):229-37. https://doi.org/10.1056/NEJMoa2029849 US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab. Available at: https://www.fda.gov/media/143603/download Ambulatory Treatment LY- CoV555 Monotherapy Secondary Outcomes: Safety LY-CoV555 (N=309) Placebo 700 mg 2800 mg 7000 mg Pooled Doses (N=143) (N=101) (N=107) (N=101) (N=309) Serious adverse events, n(%) 0 0 0 0 1 (0.7) Adverse events Any 24 (23.8) 23 (21.5) 22 (21.8) 69 (22.3) 35 (24.5) Mild 16 (15.8) 18 (16.8) 10 (9.9) 44 (14.2) 18 (12.6) Moderate 7 (6.9) 3 (2.8) 8 (7.9) 18 (5.8) 16 (11.2) Severe 0 2 (1.9) 3 (3.0) 5 (1.6) 1 (0.7) Infusion-related reactions -- -- -- 7 (2.3) 2 (1.4) Chen P, et al.