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Strategies to support the COVID-19 response in LMICs A virtual seminar series Therapeutics Landscape for COVID-19 Natasha Mubeen Chida, MD MSPH Associate Program Director, Infectious Disease Fellowship Program Assistant Professor, Division of Infectious Diseases Johns Hopkins University School of Medicine Objectives

• Review biological plausibility of Remdesivir for SARS-CoV-2 treatment • Review clinical data on Remdesivir • Review biological plausibility of Hydroxychloroquine for SARS-CoV-2 treatment • Review clinical data on Hydroxychloroquine • Discuss cytokine release syndrome in COVID-19 • Discuss use of anti IL-6 blockade for management of CRS • State ongoing clinical trials for Remdesivir, hydroxychloroquine, IL-6 blockade Sample of COVID-19 Therapeutic Landscape

Antivirals Immune Modulators Other Baloxavir Anakinra ACEI/ARB Chloroquine/Hydroxychloroquine Convalescent Plasma Ascorbic Acid DAS-181 Corticosteroids Azithromycin Favipiravir IVIG Epoprostenol Interferon Lenzilumab Indomethacin Lopinavir/Ritonavir Ruxolitinib Ivermectin Neuraminidase inhibitors Sarilumab Niclosamide Remdesivir Sirolimus Nitazoxanide Ribavarin Tocilizumab Statins Umifenovir Acalabrutinib SARS-CoV-2

Liu C, et al. ACS Cent Sci. doi: 10.1021/acscentsci.0c00272 (2020). Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020).

“Antivirals” Remdesivir

• 2013 Ebola outbreak • CDC/USAMRIDD/Gilead Sciences identified nucleoside lead à prodrug, RDV • Metabolized to active form, adenosine nucleoside analog • Interferes with RNA polymerase • Evades viral exoribonuclease proofreading • Decrease in RNA production • In cell/animal models efficacious in MERS-CoV, Remdesivir SARS-CoV, Marburg, Nipah, more • IV formulation

Warren TK, et al. Nature. 2016;531(7594):381-5. Sheahan TP, et al. Sci Transl Med. 2017;9(396). Remdesivir

• Clinical trials • Compassionate use: pregnant women/children • Expanded access protocol Remdesivir Clinical Trials: Examples Remdesivir Clinical Data

• Report of patients Jan- March-61 patients à 53 • 40 (75%) received the full 10-day course of Remdesivir • 34 (64%) ventilated at baseline • Median duration of ventilation prior to Remdesivir 2 days [IQR 1-8]

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). Remdesivir Clinical Data

• 18 days • 36 (68%) showed improvement in oxygen support • 57% ventilated patients extubated • Most recent follow up • 25 (47%) discharged • 7 (13%) died • 6 (18%) of those ventilated, 1(5%) not ventilated

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). Remdesivir Clinical Data

• 23% serious adverse events

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). Lopinavir/Ritonavir

• In-vitro activity against SARs-CoV, MERS-CoV • Hypothesis: inhibition of SARs/MERS protease • Benefit in retrospective studies in SARs-CoV • Some in vitro data SARS-CoV-2, but EC50 much higher than levels reached in HIV dosing • HIV protease different protease family Lopinavir/ritonavir • Optimized to fit in a specific part of the catalytic site of HIV protease, absent in coronaviruses • Some benefit in animal studies MERS-CoV • Widely used in China • Numerous retrospective studies

Li G, De Clercq E. Nat Rev Drug Discov. 2020;19(3):149-150., Yao TT, et al. J Med Virol. doi: 10.1002/jmv.2572 (2020)., Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020)., Choy KT et al. Antiviral Res. doi: 10.1016/j.antiviral.2020.104786 (2020).

Lopinavir/ritonavir Data

• Post hoc analysis suggesting early treatment may be efficacious

Cao B, et al. N Engl J Med. doi: 10.1056/NEJMoa2001282 (2020). , Ye XT, et al. Eur Rev Med Pharmacol Sci. 2020;24(6):3390-339 Lopinavir/ritonavir Clinical Trials: Examples

Clinicaltrials.gov Chloroquine Mechanisms Against SARS-CoV-2

• Blocks viral infection by increasing endosomal pH required for virus- cell fusion • Interferes with glycosylation of SARS-CoV cellular receptors • Chloroquine interferes with entry and post-entry stages of SARS- CoV-2 infection in Vero E6 cells

Slide courtesy Michael Melia, MD

Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0. Vincent MJ et al. Virol J. 2005 Aug 22;2:69. Chloroquine Mechanisms Against SARS- CoV-2 • Vero E6 cells infected with SARS- CoV-2 at MOI 0.05 • Efficacy evaluated by quantification of viral copy numbers in cell supernatant by RT-PCR, confirmed with visualization of virus nucleoprotein expression through immunofluorescence microscopy at 48h post-infection • EC90 = 6.90 μM (clinically achievable)

Slide courtesy Michael Melia, MD Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0. CQ versus HCQ in vitro

• Cytotoxicity in VeroE6 cells measured • HCQ less potent than CQ at some MOI

Slide courtesy Michael Melia, MD

Liu J et al. Cell Discovery ( 2020) 6:16. https://doi.org/10.1038/s41421-020-0156-0 Hydroxychloroquine Clinical Data (Preprint) • Randomized, parallel-group trial • Retinal disease • Inclusion criteria: • Heart block • • Severe liver disease, including AST Age ≥18y >2x ULN • SARS-CoV-2 RT-PCR positive • Pregnant or breastfeeding • Chest CT with pneumonia • eGFR ≤30 or RRT • SaO2:SpO2 >93% or PaO2:FiO2 >300 mm Hg

• Exclusion criteria: • Severe, critical illness Slide courtesy Michael Melia, MD Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 Hydroxychloroquine Clinical Data (Preprint) • 62 patients • Outcomes • 47% men • Time to clinical recovery = afebrile • Mean age 44.7y ±15.3 and cough relief ≥72h • • All received standard therapy Chest CT d0 vs d6 • Initially planned PCR and T-cell • Oxygen recovery data not reported • Antiviral and antibacterial agents • Immunoglobulin ± corticosteroids • HCQ: 9 no fever, 9 no cough • Randomization to HCQ 200 mg • Control: 14 no fever, 16 no cough BID x5d vs standard treatment

Slide courtesy Michael Melia, MD Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 Hydroxychloroquine Clinical Data (Preprint) • Fever duration shorter with HCQ (2.2 ± 0.4d vs 3.2 ± 1.3d) • Cough duration shorter with HCQ (2.0 ± 0.2d vs 3.1 ± 1.5d) • More patients had radiographic improvement with HCQ [25/31 (81%) vs 17/31 (55%), p=0.05] • All 4 patients who progressed to severe illness were in control group • 2 patients with mild adverse reactions in HCQ group (rash, HA)

Slide courtesy Michael Melia, MD Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 Hydroxychloroquine Clinical Data

• 30 patients at a single center in China • No difference in primary endpoint • Randomized to HCQ 400 mg daily x5d + between groups conventional treatment or • 13/15 (87%) cases negative in HCQ group, conventional treatment only 14/15 (93%) in control group • Both groups received interferon • No difference in time from • Most received umifenovir or lopinavir/ hospitalization to negative NP swab, ritonavir fever resolution, radiographic findings, • Primary endpoint: negative NP swab 7d diarrhea or abnormal liver enzymes after randomization

Slide courtesy Michael Melia, MD Chen J. J Zhejiang University. 2020:[Epub ahead of print]. https://doi.org/10.3785/j.issn.1008-9292.2020.03.03. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx. Accessed 13 April 2020. HCQ + Azithromycin

• Open-label, non-randomized trial in France • Patients aged ≥12y with NP SARS-CoV-2 carriage on admission • Excluded: retinopathy, G6PD deficiency, QT interval prolonged, pregnancy • HCQ 200 mg TID x10d ± azithromycin 500 mg x1 then 250 mg QD x4d • Controls: untreated patients from another center, patients refused protocol • NP swab VL measured daily • End point: presence of virus at day 6 post-inclusion

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949 HCQ + Azithromycin

• 36* patients • Mean age 45.1 ± 22y • 42% (15/36) men • 4.0 ± 2.6d between symptom onset & inclusion • Clinical characteristics • 8 patients with LRTI symptoms (all had evidence of pneumonia by CT scan) • 22 patients with URTI symptoms (rhinitis, pharyngitis, fever, myalgia) • 6 asymptomatic patients

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949 HCQ + Azithromycin

• At day 6 post-inclusion: • 70% HCQ-treated patients (vs 12.5% controls) tested NP RT-PCR negative • 100% HCQ + azithromycin- treated patients (vs 57% patients treated with HCQ monotherapy) tested NP RT- PCR negative

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949 HCQ + Azithromycin

• One patient treated with HCQ + azithromycin tested RT-PCR negative at day 6 and then positive at day 8 • Patients treated with HCQ + azithromycin had lower viral RNA loads at treatment initiation than HCQ and control groups • Sites other than the primary site did not perform daily PCR testing • 38% of data for control group imputed (vs 5% for treatment group) • 6 treated patients omitted from analysis owing to ICU transfer (3), death (1), hospital discharge (1), nausea (1)

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949. Kim AHJ, Sparks JA et al. Ann Intern Med. Doi:10.7326/M20-1223 HCQ + Azithromycin

• 11 consecutive patients • 7 men, 4 women • Mean age 59y (range 20-77) • 8 with significant comorbidities • HCQ 600 mg daily x10d + azithro 500 mg x1 then 250 mg QD x4d • At treatment initiation, 10/11 had fever and were receiving oxygen • Within 5d, one patient died, two transferred to ICU • One course discontinued after 4d (QT 405 → 460-470) • NP RT-PCR positive in 8/10 patients at 5-6d after treatment initiation

Slide courtesy Michael Melia, MD Molina JM et al. Medecine et Maladies Infectieuses (2020), doi: https://doi.org/10.1016/j.medmal.2020.03.006 HCQ + Azithromycin

• Case series of 80 patients at one institution • All patients treated with HCQ 200 mg TID + azithromycin 500 mg x1 then 250 mg QD for ≥3d & followed for ≥6d included • Excluded: QTc >500 ms, ECG suggesting channelopathy • HCQ 200 mg TID x10d ± azithromycin 500 mg x1 then 250 mg QD x4d • Ceftriaxone added for pneumonia and NEWS score ≥5 • NP swab VL measured ~daily by RT-PCR • Primary end points: • Clinical outcome, including O2 therapy or ICU transfer after ≥3d treatment • Contagiousness as assessed by PCR and culture • Length of inpatient stay

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf HCQ + Azithromycin

• 80 patients • Clinical characteristics • Median age 52.5y (IQR 42-62) • 54% LRTI symptoms • 52.5% (42/80) men • 41% URTI symptoms • 57.5% at least one chronic • 5% asymptomatic condition • 15% had fever • 4.9 ± 3.6d between symptom onset • 92% low NEWS score (0-4) & treatment initiation

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf HCQ + Azithromycin

• 15% (12/80) received O2 • 81% (65/80) discharged • 17% (14/80) still hospitalized • 4% (3/80) transferred to ICU • 1% (1/80) died • Mean time from initiation to hospital discharge 4.1d • Mean LOS 4.6d

Slide courtesy Michael Melia, MD Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf HCQ Clinical Trials: Examples

Name/Sponsor Pertinent Characteristics Estimated completion

ACTG 5396 Hospitalized Pending

ACTG 5395 Outpatients Pending

Multiple Prophylaxis trials HCWs or household contacts Ongoing

SOLIDARITY/WHO 8. Hospitalized March 2020-2022

DISCOVERY/INSERM 9. Hospitalized March 2020-2023 On the Horizon

• Remdesivir has biological plausibility and in vitro data to support its candidacy as a SARS-CoV-2 therapeutic agent • Clinical trial data forthcoming • Lopinavir/ritonavir has minimal supportive in vitro data in SARS-CoV-2 • Current clinical data does not support its candidacy as a SARS-CoV-2 therapeutic agent • Clinical trial data forthcoming • In patients with non-severe disease, and as part of multi-component therapy, HCQ may: • Be associated with shorter durations of fever and cough • Be associated with radiographic improvement • Inadequate data to comment on impact of HCQ on viral RNA shedding

Anti IL-6 Agents COVID-19 Cytokine Release Syndrome

• Similar to CRS seen in CART-T Therapy • Driven by IL-6 • Anti IL-6 blockade: Tocilizumab utilized • Like in CAR-T therapy, appears to be characterized by • Fever • Blood pressure abnormalities • Progressive respiratory decline • Elevation of certain inflammatory laboratories • ARDS ≠ Cytokine Release Syndrome

Mehta P, et al. Lancet. 2020;395(10229):1033-1034. CRS

Moore BJB, June CH. Science. doi: 10.1126/science.abb8925 (2020).

COVID-19 Clinical Course

Zhou F, et al. Lancet. 2020395(10229):1054-1062. Observational Cohorts: Published

• Retrospective observational study of 15 patients admitted to a hospital in China • Classified into moderately ill (13%), seriously ill (40%), critically ill (47%) • Median age 73 [IQR 62-80] • Heterogeneous dosing, timing • Half received methylprednisolone

Luo P, et al. J Med Virol. doi: 10.1002/jmv.25801 (2020). Observational Cohorts: Published

• 3 patients died (20%) • When in clinical course did patients receive tocilizumab? • Were they ARDS or developing signs of CRS?

Luo P, et al. J Med Virol. doi: 10.1002/jmv.25801 (2020). Observational Cohorts: Preprint

• Retrospective observational study of 21 patients with proven COVID-19 admitted to 2 hospitals in China • Defined as • Severe: RR ≥ 30 breaths/min, SpO2 ≤ 93% on ambient air, PaO2/FiO2 ≤ 300 mmHg • Critical: Mechanical ventilation, shock, organ failure requiring ICU admission • Patients received standard of care + tocilizumab • Standard of care = lopinavir/ ritonavir, methylprednisolone, oxygen

Xu X, et al. http://www.chinaxiv.org/abs/202003.00026 (Accessed 4/19/2020). Observational Cohorts: Preprint

• 19% discharged at time of paper submission • Based on this data National Health Commission of China included tocilizumab in COVID-19 therapy recommendations • When in clinical course did patients receive tocilizumab? • Were they ARDS or developing signs of CRS?

Xu X, et al. http://www.chinaxiv.org/abs/202003.00026 (Accessed 4/19/2020). Observational Cohorts: Preprint

• 21 patients with COVID-19 and ARDS in Italy • Using noninvasive ventilation • Part of Siltuximab compassionate use program • Median age 64 years [IQR 48-75]; 18 (85.7%) men • Median IL-6 139.5 pg/mL, CRP 23.4 mg/dL • Comorbidities • Hypertension: 9 (42.3%) • Diabetes 5: (23.8%) • Cardiovascular disease 4 (19.1%) • Median 3 days hospitalization prior to siltuximab

Gritti G, et al. https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf. Accessed 4/20/20 Observational Cohorts: Preprint

Gritti G, et al. https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf. Accessed 4/20/20 Themes Of Current Clinical Data

• Outcome related to tocilizumab or natural history • Heterogeneity in patients • Variability in clinical course • Variability in administration • Dosing • Timing of administration • Concomitant use of other agents/anti-inflammatories • Heterogeneous outcomes Anti IL-6 Clinical Trials: Examples

>7 more trials between China, Europe Anti IL-6 Key Points

• Some patients with COVID-19 may develop a syndrome similar to the cytokine release syndrome seen in CAR-T therapy • Characterized by specific clinical findings and inflammatory laboratories • There is a paucity of reliable published data • Clinical trial data forthcoming • Anecdote: early administration appears more effective than late in the course of illness Convalescent Plasma

• In the US, IND • Clinical trials, Convalescent Plasma expanded access, emergency individual use Chen Z. medRxiv preprint doi: https://doi.org/ 10.1101/2020.03.22.20040758 • Current data: Case reports/series • Limitations: Plasma • Study launching at JHH Objectives