Therapeutics and Vaccines for COVID-19 Barry S. Zingman, MD Division of Infectious Diseases Montefiore Medical Center Albert Einstein College of Medicine
Convalescent plasma Hyperimmune plasma mAb to Spike protein TMPRSS2 inhibitor Vaccines
Courtesy of Eastman, Roth, et al, DOI: 10.1021/acscentsci.0c00489
Convalescent plasma Hyperimmune plasma mAb to Spike protein TMPRSS2 inhibitor Vaccines
The spike protein of SARS-CoV and SARS-CoV-2 is activated by the protease TMPRSS2 before it binds to the ACE2 receptor. MARKUS HOFFMANN / GERMAN PRIMATE CENTRE
Overview 1. Antivirals 2. Host Targeted/Immune Modulators 3. Symptomatic/Supportive 4. Vaccines
Antivirals
Chloroquine/Hydroxychloroquine Uncontrolled, observational studies show no benefit, possible harm in hospitalized patients (Borba; Huang, Magagnoli; Tang; Mahevas; Geleris, Columbia; Mehra) ◦ QT prolongation, arrhythmias, mortality, mortality with higher dosing and especially with azithromycin
RCT, HCQ, Post-Exposure Prevention: No benefit (Boulware) RCT, HCQ, SOLIDARITY, WHO: STOPPED 6/17/20 RCT, HCQ, PETAL network ORCHID trial: STOPPED 6/20/20 Borba et al, JAMA Netw Open. 2020;3(4):e208857; Huang et al, J Mol Cell Biol. 2020; Magagnoli et al, medRxiv. 2020. [Preprint]; Tang et al, medRxiv. 2020. [Preprint]; Mahevas et al, medRxiv. 2020. [Preprint]; Geleris et al, NEJM 2020, DOI: 10.1056/NEJMoa2012410; Boulware et al, NEJM 2020 June 3, DOI: 10.1056/NEJMoa2016638; NIH PETAL network press release June 20, 2020.
Interferon beta-1b, lopinavir–ritonavir, and ribavirin in admitted patients: open-label, randomized, phase 2 trial Hung, The Lancet DOI: 10.1016/S0140-6736(20)31042-4
** Limitations: Open label, small n, not ill or treated elsewhere, poorly controlled
Antibody Therapy: Convalescent Plasma 75 studies on clinicaltrials.gov ◦ Some encouraging uncontrolled results ◦ Joyner, J Clin Invest. https://doi.org/10.1172/JCI140200 Mayo IND, 5000 pts ◦ Well tolerated; 36 SAEs, 25 related, 2 definitely ◦ mortality (n=4); severe allergic transfusion reactions (n=3) ◦ transfusion-associated circulatory overload (TACO; n=7); transfusion-related acute lung injury (TRALI; n=11)
RCT, China (Li et al, JAMA 6/3/2020): underpowered, some positive trends esp in severe disease RCT, hospitalized respiratory disease: Montefiore/Einstein and NYU; Columbia Prophylaxis & Critical Illness: Columbia
Antibody Therapy Hyperimmune globulin Monoclonal antibodies to SARSCoV-2 spike protein (single or combo) (AstraZeneca, Lilly, Regeneron, others) ◦ ACTIV-2: outpatients; ACTG ◦ ACTIV-3: inpatients; ? PETAL network
ALTOUNIAN/SCIENCE; (IMAGES) W. SURYA, BIOCHIM. BIOPHYS. ACTA (2018); D. WRAPP, SCIENCE, (2020); E.O. SAPHIRE, SCIENCE, (2001); ORIENTATIONS OF PROTEINS IN MEMBRANES DATABASE
Remdesivir (GS-5734)
Prodrug of broad-spectrum adenosine nucleoside analog Inhibits RNA-dependent RNA polymerase activity among RNA viruses including pathogenic coronaviruses (1-5). A trial in rhesus macaques infected with SARS-CoV-2 found that remdesivir was effective in reducing clinical disease and damage to lungs (6). 1. Brown AJ, Antiviral Res. 2019; 2. Sheahan TP, Nat Commun. 2020.; 3. Agostini ML, mBio. 2018; 4. de Wit E, Proc Natl Acad Sci USA. 2013; 5. de Wit E, Proc Natl Acad Sci USA. 2020; 6. Williamson BN, bioRxIV. 2020. DOI: https://doi.org/10.1101/2020.04.15.043166
Randomized, double-blind, placebo-controlled study of remdesivir; 1:1 200 mg IV load x 1, then 100 mg IV q24H x up to 10 days total while hospitalized; or a saline solution Primary endpoint: time to recovery (score 1-3) on 8-pt ordinal score 68 sites: US, Asia, Europe, Mexico â—Ś Montefiore/Einstein and NYU/Bellevue
1063 enrolled
Kaplan–Meier Estimates of Cumulative Recoveries. Overall population Median recovery time • 11 vs 15 days (95% CI, 9 to 12) vs (95% CI, 13 to 19)
• Recovery rate ratio 1.32 (95% CI, 1.12 to 1.55; P<0.001)
(Beigel et al, NEJM May 22, 2020, DOI: 10.1056/NEJMoa2007764)
ACTT-1 Results Overall Mortality at 14 days ◦ 7.1% (remdesivir) vs 11.9% (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04) Clearest benefit in ~40% requiring low flow Oxygen ◦ Median days to recovery (7 rem vs 9 days) ◦ Recovery rate ratio (1.47, 95% CI, 1.17-1.84) for remdesivir ◦ Risk of death (2.4% rem vs 10.9%; hazard ratio 0.22, 95% CI, 0.08-0.58) (Beigel et al, NEJM May 22, 2020, DOI: 10.1056/NEJMoa2007764)
Kaplanâ&#x20AC;&#x201C;Meier Estimates of Cumulative Recoveries. 7 (mechanical ventilation or ECMO) (Severe)
(Beigel et al, NEJM May 22, 2020, DOI: 10.1056/NEJMoa2007764)
ACTT-1 Safety Very well tolerated ◦ Serious Adverse Events (Grade 3-5) ◦ 21.1% remdesivir, 27.0% placebo
◦ Less respiratory failure, lower mortality ◦ DVT ◦ 1.1% remdesivir vs 1.7% placebo
Remdesivir FDA approved Emergency Use Authorization (EUA) for Severe Disease â&#x2014;Ś Severe: SpO2 â&#x2030;¤94% on RA or requiring supplemental oxygen, mechanical ventilation, or ECMO
Gilead applying for FDA approval Need to combine it with other agents to treat all
Other Antivirals Being Studied Favipiravir Arbidol Ivermectin Famotidine EIDD-2801 Galidesivir
Host Targeted/Immune Modulators
Host Targeted/Immune Modulators: Broad Spectrum Azithromycin ◦ No convincing results ◦ Significant toxicity ◦ Not recommended outside of trials
Corticosteroids ◦ Based on mixed results during 2003 SARS, not routinely recommended except in ARDS; some reports of prolonged viral shedding ◦ Many studies of when, which, how much ◦ Best if given early? Impending respiratory failure, rising CRP?
Host Targeted/Immune Modulators: Broad Spectrum UK RECOVERY trial – Horby et al, pre-print 6-22-20 ◦ Randomized, open label, 2104 dexamethasone x 10d vs 4321 usual care ◦ Shorter hospitalization with dexa: 12 vs 13 days ◦ Progression to mechanical ventilation lower: 0.76 RR, 95% CI 0.61-0.96; p=0.21 Group
Dexamethason e
Placebo Relative Risk (95% CI, p value)
Overall
21.6%
24.6%
0.83 (0.74-0.92; p<0.001)
Mechanical ventilation
29.0%
40.7%
0.65 (0.51-0.82; p=0.0003)
Other oxygen
21.5%
25.0%
0.80 (p=0.002)
IL-6 inhibitors IL-1 inhibitors JAK/STAT inhibitors CCR5 inhibitors GM-CSF inhibitors
Baricitinib
Baricitinib
Science. 2020 Apr 17. pii: eabb8925
ACTT-2 Hyper-inflammation and cytokine release syndrome ◦ high interferon α and β and IL-6; signal through JAK–STAT pathway. [1-3].
Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, approved for rheumatoid arthritis ◦ selected for potential to inhibit signaling of multiple cytokines [4]. ◦ inhibit numb-associated kinases (NAKs), which play a role in the host epithelial cell’s ability to facilitate propagation of viruses [5].
Effects of combination therapy with remdesivir may exceed •Adapted from ACTT-2 Slide Set either component (NIH) 1. Moore, JB. Science, 2020; 2. Chen, G,. J Clin Invest, 2020; 3. Ruan, Q. Intensive Care Med, 2020; 4. Richardson, P. Lancet 2020; 5.Stebbing, J. Lancet Infect Dis 2020.
Symptomatic/Supportive
Venous and Arterial Thromboembolic Diseases Approaches to anticoagulation; in situ thrombosis ◦ Prophylactic or therapeutic ◦ Timing and duration ◦ Unfractionated heparin, LMWH, Factor Xa inhibitors, thrombolytics ◦ Combination therapy
Vaccines
Public/Private Partnerships Operation Warp Speed ◦ US departments (DHHS, Agriculture, Energy, Veterans Affairs) and private sector ◦ NIH/Industry collaborative: ACTIV BARDA o
HHS Office of the Asst Secretary for Preparedness and Response
Convalescent plasma Hyperimmune plasma mAb to Spike protein TMPRSS2 inhibitor Vaccines
The spike protein of SARS-CoV and SARS-CoV-2 is activated by the protease TMPRSS2 before it binds to the ACE2 receptor. MARKUS HOFFMANN / GERMAN PRIMATE CENTRE
Potential COVID Vaccines Mechanisms of Delivery 1) Inactivated or Live Attenuated4) Adenovirus-based 5) Nucleic acid-based ◦ Antibody and cellular immunity ◦ Easily infect many cell types, ◦ Mimics infection or immunization ◦ Risks: mutated pathogen, disease in genetic manipulation simple, with live organisms immunocompromised, reversion stable without mutations, easily ◦ T helper and B cell responses 2) Live attenuated subunit-based made to high titers ◦ Safer production, quickest to ◦ Types of immunity vary ◦ Adenovirus vector has gene produce, no culture or ◦ Not highly potent segment from the virus of fermentation ◦ Relatively fast to produce interest inserted ◦ None FDA approved to date ◦ 3) Live attenuated peptide-based Advantages of live attenuated ◦ DNA or mRNA but with stronger immune ◦ Antibody and cellular immunity ◦ 2 Types of mRNA vaccines response ◦ Risks: mutated pathogen, disease in immunocompromised, reversion ◦ Less robust CD8+ response for intracellular pathogens Zhang et al, Front. Immunol., 27 March 2019 | https://doi.org/10.3389/fimmu.2019.00594
◦ Conventional ◦ Self-amplifying
Major Vaccine Candidates Moderna • US-based Moderna Therapeutics • Vaccine candidate mRNA-1273 • Trials in progress
Novavax • Vaccine candidate: NVX-CoV2373 • Trials starting
Inovio • DNA-based • Vaccine candidate: INO-4800 • Completed phase 1
Pfizer and BNTECH • Pfizer: US; BNTECH: German • Vaccine candidate: mRNA-based BNT162 • Trials in progress
Johnson & Johnson
Sinovac Biotech • • • •
Beijing-based Vaccine candidate: PiCoVacc Commenced phase 1 trial First dosing of vaccine for the volunteers has been completed
• Adenovirus-based: Ad26.COV2-S • Plan US trials September 2020 University of
CanSino Biologics • • • •
Chinese vaccine maker Adenovirus Type 5 Vector Vaccine candidate: Ad5-nCoV Trials in progress
COVID-19 vaccine current status: Here are the 10 top contenders for coronavirus vaccines adapted from https://bit.ly/2Y6TMSY
Oxford/AstraZeneca • Adenovirus-based: AZD1222 • Trials in progress
Vaccine Candidates with Major Support by US for Phase 3 Trials Moderna • US-based Moderna Therapeutics • Vaccine candidate mRNA-1273 • Trials in progress • Phase 3 July
University of Oxford & AstraZeneca
Pfizer and BNTECH
• Vaccine candidate: adenovirus-based AZD1222 • UK Phase 3 begun • US Phase 3 August
• Pfizer: US; BNTECH: German • Vaccine candidate mRNA-based BNT162 • Trials in progress • Phase 3 September
Johnson & Johnson/Sanofi • Adenovirus-based: Ad26.COV2-S • US Phase 3 September COVID-19 vaccine current status: Here are the 10 top contenders for coronavirus vaccines adapted from https://bit.ly/2Y6TMSY
Vaccine Unknowns Timeline to successful first vaccine results Timeline to rollout of first successful vaccine Availability worldwide of successful vaccine(s) Degree of protection Duration of protection Schedule of administration, boosters, etc Side effects Acceptance/Uptake Costs