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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 Baloxavir Immune Modulators Anakinra Other ACEI/ARB Chloroquine/Hydroxychloroquine DAS-181 Convalescent Plasma Corticosteroids IVIG Ascorbic Acid Azithromycin Epoprostenol Indomethacin Ivermectin Niclosamide Nitazoxanide Statins Favipiravir <ul style="display: flex;"><li style="flex:1">Interferon </li><li style="flex:1">Lenzilumab </li></ul><ul style="display: flex;"><li style="flex:1">Ruxolitinib </li><li style="flex:1">Lopinavir/Ritonavir </li></ul>Neuraminidase inhibitors Remdesivir Sarilumab Sirolimus <ul style="display: flex;"><li style="flex:1">Ribavarin </li><li style="flex:1">Tocilizumab </li></ul><ul style="display: flex;"><li style="flex:1">Acalabrutinib </li><li style="flex:1">Umifenovir </li></ul>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, SARS-CoV, Marburg, Nipah, more •ꢀ IV formulation Remdesivir 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 <ul style="display: flex;"><li style="flex:1">Remdesivir Clinical Trials: Examples </li><li style="flex:1">Remdesivir Clinical Data </li></ul>•ꢀ 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 viruscell 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; <a href="/goto?url=https://doi.org/10.1038/s41422-020-0282-0" target="_blank">https://doi.org/10.1038/s41422-020-0282-0</a>. 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 <a href="/goto?url=https://doi.org/10.1038/s41422-020-0282-0" target="_blank">Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0. </a>CQ versus HCQ in vitro •ꢀ Cytotoxicity in VeroE6 cells measured •ꢀ HCQ less potent than CQ at some MOI Slide courtesy Michael Melia, MD <a href="/goto?url=https://doi.org/10.1038/s41421-020-0156-0" target="_blank">Liu J et al. Cell Discovery ( 2020) 6:16. https://doi.org/10.1038/s41421-020-0156-0 </a>Hydroxychloroquine Clinical Data (Preprint) •ꢀ Retinal disease •ꢀ Heart block •ꢀ Randomized, parallel-group trial •ꢀ Inclusion criteria: •ꢀ Severe liver disease, including AST •ꢀ Age ≥18y >2x ULN •ꢀ SARS-CoV-2 RT-PCR positive •ꢀ Chest CT with pneumonia •ꢀ Pregnant or breastfeeding •ꢀ eGFR ≤30 or RRT •ꢀ SaO2:SpO2 >93% or PaO2:FiO2 >300 mm Hg •ꢀ Exclusion criteria: •ꢀ Severe, critical illness Slide courtesy Michael Melia, MD <a href="/goto?url=https://doi.org/10.1101/2020.03.22.20040758" target="_blank">Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 </a>Hydroxychloroquine Clinical Data (Preprint) <ul style="display: flex;"><li style="flex:1">•ꢀ 62 patients </li><li style="flex:1">•ꢀ Outcomes </li></ul><ul style="display: flex;"><li style="flex:1">•ꢀ 47% men </li><li style="flex:1">•ꢀ Time to clinical recovery = afebrile </li></ul>and cough relief ≥72h •ꢀ Chest CT d0 vs d6 •ꢀ Mean age 44.7y ±15.3 •ꢀ All received standard therapy •ꢀ Oxygen •ꢀ Initially planned PCR and T-cell recovery data not reported •ꢀ Antiviral and antibacterial agents •ꢀ Immunoglobulin ± corticosteroids •ꢀ HCQ: 9 no fever, 9 no cough •ꢀ Control: 14 no fever, 16 no cough •ꢀ Randomization to HCQ 200 mg BID x5d vs standard treatment Slide courtesy Michael Melia, MD <a href="/goto?url=https://doi.org/10.1101/2020.03.22.20040758" target="_blank">Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 </a>

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