May 2020
MRx PIPELINE Bonus COVID-19 Edition
TABLE OF CONTENTS Welcome Introduction Overview Drug Pipeline Vaccine Pipeline Early Phase Development Glossary
EDITORIAL STAFF Maryam Tabatabai, PharmD Senior Director, Drug Information Carole Kerzic, RPh Drug Information Pharmacist Special thanks to Robert Greer, RPh, BCOP, Senior Director, Clinical Strategy and Programs for his contributions.
magellanrx.com/pipeline Disclaimer: The content in this article is not a substitute for professional medical advice. For questions regarding any medical condition or if you need medical advice, please contact your healthcare provider.
Welcome to the MRx PIPELINE+ There has never been a time in history when a pandemic met a rapid flow and exchange of observations and data. We have learned so much, so quickly about COVID-19, but in some cases have done so without the usual rigor of the scientific method and peer review. At Magellan Rx, we understand that with the vast amount of information surrounding COVID-19 it can be challenging to know where to find factual and timely information. To help organize the material out there, we developed a bonus edition of the MRx pipeline that exclusively covers COVID-19 drugs and vaccines currently in development. While new COVID-19 cases begin a slow downward trajectory in many regions of the world and some areas of the United States, other areas are experiencing an upward swing. As shelter in place restrictions begin to ease across the country, there is an even greater sense of urgency for safe and effective vaccines and therapies to combat COVID-19. We all want to see an end to the personal and societal impacts of the pandemic. As new clinical data emerges, the critical need for validated evidence to inform clinical decisions is further underscored. Moreover, safety must be a central consideration in treatment selection. Drawing on our rich experience in reviewing pipeline therapies, our team has created MRx Pipeline+. MRx Pipeline+ profiles the history and development of select drug and vaccine candidates for COVID-19. Given the rapid pace of change in COVID-19, the content in our publication will change as new information emerges and new candidates enter the market. We understand that this is a challenging time. We intend for this report to centralize and clarify the flurry of activity and information surrounding COVID-19. Our team is passionate about sharing drug information highlights and making this data accessible to everyone. Stay well, and best wishes.
Caroline Carney, MD, MSc, FAPM, CPHQ Chief Medical Officer Magellan Rx Management
INTRODUCTION WHAT TO KNOW: OVER
5.9 MILLION GLOBAL CASES CONFIRMED
OVER
357,000
DEATHS
THERE ARE
NO FDA APPROVED
US CONFIRMED CASES EXCEED
US DEATHS EXCEED
1.7 MILLION 100,000
COVID-19 VACCINES
DID YOU KNOW?
THE AVERAGE TIME TO DEVELOP AND APPROVE A VACCINE IS
10 TO 15 YEARS
WHAT'S INSIDE: Insights on the 200+ drugs & vaccines being evaluated for COVID-19 DID YOU KNOW? 90 of those are in human trials.
A deep dive into the three drugs authorized for emergency use.
DID YOU KNOW? One of the drugs was originally studied for Ebola virus infection.
An overview of the 10 vaccine candidates currently in human clinical trials DID YOU KNOW? 100+ vaccines are in preclinical evaluation.
The Coronavirus Treatment Acceleration Program (CTAP), respond to study applicants within record time of 24 hours DID YOU KNOW? Typically, the FDA has 60 days to response to new drug applications letting the applicant know if the agency will review the drug.
4 | magellanrx.com
OVERVIEW Disease Background Our understanding of this contagious virus continues to evolve. To add perspective to the different therapeutic modalities being researched for COVID-19, a basic understanding is needed. COVID-19 is caused by the novel severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2). SARS-CoV-2 belongs to the family of coronaviruses, named for the crown-like spikes on the virus surface. Coronaviruses can cause the common cold as well as serious respiratory illnesses such as SARS (caused by the SARS-CoV-1 virus) and Middle East respiratory syndrome (MERS). Transmission of SARS-CoV-2 is primarily through person-to-person contact via respiratory droplets, particularly when in close proximity, but it is also possible to acquire the virus through contact with contaminated surfaces. The incubation period ranges from 2 to 14 days, although most cases occur 4 to 5 days after exposure. Clinical presentation ranges from asymptomatic infection or mild illness (about 80% of cases) to fatal illness. Symptoms include fever, fatigue, shortness of breath, cough, loss of smell/taste, and myalgias. Risk factors identified for severe complications include advanced age and underlying chronic conditions (e.g., cardiovascular, pulmonary, diabetes). Severe cases of COVID-19 can be associated with multi-organ (e.g., lungs, kidneys, heart, brain) dysfunction. Patients can rapidly progress from having shortness of breath to respiratory failure. One of the major complications of severe disease is pneumonia with acute respiratory distress syndrome (ARDS). ARDS can be accompanied by cytokine release syndrome (CRS) – referred to as “cytokine storm” – where inflammatory markers are unleashed, leading to severe inflammation, as well as low oxygen levels, low blood pressure, and fever. Ultimately in ARDS, there is inflammation and accumulation of fluid in the lungs making it difficult or impossible to breathe. This is the leading cause of COVID-19 death in hospitalized patients. Recently, the CDC issued an alert regarding a rare and potentially life-threatening condition linked with COVID-19. Multisystem inflammatory syndrome in children (MIS-C) is associated with fever, abnormal levels of inflammatory markers, severe illness with hospitalization, and multi-organ involvements, as well as Kawasaki disease-like symptoms (e.g., rash, fever, inflammation, lymph nodes). Limited information is available on MIS-C and its connection to COVID-19.
Accelerated Framework To hasten research and development for COVID-19 treatments, the FDA created an emergency program called Coronavirus Treatment Acceleration Program (CTAP). As of May 11, 2020, the agency reported 144 active clinical trials of therapeutic agents and a surge of another 457 development programs are in planning stages. The FDA’s CTAP responds to study applicants in record time with ultra-rapid protocol reviews completed within 24 hours of submission and around-the-clock reviews of single patient expanded access requests, often completed within 3 hours. The FDA is also engaged in a public-private partnership with the NIH and other US and international stakeholders. The NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership expedites the development of COVID-19 vaccines and therapies through a collaborative framework of prioritizing vaccine and drug candidates and related efforts to respond to the current and future pandemics. Remdesivir, hydroxychloroquine, and chloroquine have each received emergency use authorizations (EUAs) for use in select hospitalized patients with COVID-19. An EUA is intended to provide temporary availability of an unapproved medical product or unapproved use of an FDA-approved agent during a public health emergency. This authority allows the agency to bolster our nation’s public health protections against chemical, biological, radiological, and nuclear (CBRN) threats by facilitating access and use of medical counter measures (MCMs) needed during public health emergencies. An EUA is not equal to FDA approval. The WHO along with other stakeholders launched the Solidarity Trial in an effort to rapidly identify the impact of 4 late-stage treatment options on COVID-19 disease progression and mortality. With this study, WHO anticipates to reduce the time to design and conduct clinical trials for COVID-19 by 80%. Over 400 hospitals in 35 countries have signed on to participate in the study, which will randomize hospitalized COVID-19 patients (n~3,500) to receive local standard of care alone or with the addition of remdesivir, lopinavir/ritonavir, hydroxychloroquine, or interferon beta-1a. Interim trial analyses are conducted by the independent Global Data and Safety Monitoring Committee. Notably, the hydroxychloroquine arm is temporarily on hold while the panel reviews safety data of the product. | 5
Drug Pipeline SPOTLIGHT Extraordinary measures have been introduced during the COVID-19 outbreak to speed drug development. Studies are underway for medications to either directly combat the virus (e.g., antivirals) or to treat respiratory or other complications (e.g., immune modulators). Agents being evaluated to treat the illness include emerging new molecular entities, as well as approved drugs that are already available to treat other conditions and are now being repurposed for COVID-19. Repurposed drugs include select HIV-1 antiretrovirals that are thought to interfere with virus replication and may show in vitro activity against coronaviruses, as well as immunomodulating biologics, such as interleukin (IL) inhibitors (e.g., sarilumab, tocilizumab, anakinra, canakinumab) and Janus kinase (JAK) inhibitors (e.g., baricitinib, ruxolitinib), which may reign in an overactive immune response to the virus. Over 200 drugs are being evaluated for COVID-19. Most are in early stages of study, with approximately 90 advanced to human trials. Below highlights notable drugs in late stage development.
Remdesivir Gilead has broadened its research for its investigational IV direct-acting antiviral remdesivir. Originally studied for Ebola virus infection, the broad spectrum agent also demonstrates activity against RNA viruses, including coronaviruses (e.g., SARS, MERS, and SARS-CoV-2). Remdesivir targets viral replication by inhibiting RNA-dependent RNA polymerase (RdRP). Although there have been initial mixed results for the treatment of COVID-19, remdesivir appears to be the furthest in the developmental stage. A phase 3 study conducted in China failed to show a clinical response with remdesivir. In addition, confounding factors (e.g., uncontrolled study) of other trials prevent interpretation of results. In contrast, published preliminary data from the NIH-sponsored NIAID Adaptive COVID-19 Treatment Trial (ACTT) report a significant response with the drug. This randomized, double-blind, placebo-controlled study treated 1,063 hospitalized patients with COVID-19 and pulmonary involvement with up to 10 days of remdesivir. It demonstrated a 31% median faster time to either hospital discharge or discontinuation of supplemental oxygen with remdesivir compared to placebo (11 versus 15 days, respectively; p<0.001). Further, the study suggests a trend toward lower mortality rate, albeit not statistically significant, with remdesivir compared to placebo (7.1% versus 11.9%, respectively) by day 14. Based on this trend, the NIAID made the decision to give remdesivir to patients assigned to the placebo group, a choice that is not supported by some medical experts since it limits the studyâ&#x20AC;&#x2122;s ability to demonstrate effect on mortality. However, the data does suggest that remdesivir's beneficial impact on mortality was significant among patients who required supplemental oxygen at baseline, but not in those who needed more intensive support. The most common adverse events reported with remdesivir include: anemia, pyrexia, elevated liver function tests, and acute kidney injury. A lower rate of serious adverse events occurred with remdesivir than with placebo (21.1% versus 27%, respectively), including respiratory failure (5.2% versus 8%, respectively). On May 8, 2020, the NIAID announced that the double-blind ACTT-2 trial is underway to evaluate the impact on the time to recovery when the oral immune modulator baricitinib (OlumiantÂŽ; Eli Lilly) is added to remdesivir. The study is expected to enroll over 1,000 hospitalized COVID-19 patients with pulmonary involvement. Case reports have described potential benefit of baricitinib used in critically ill patients who recovered from COVID-19. Baricitinib may provide anti-inflammatory properties by blocking cytokine signaling in the body that plays a role in causing inflammatory responses. Baricitinib is currently FDA-approved to treat RA. The US FDA concluded that it is reasonable to believe that the known and potential benefits of remdesivir outweigh the known and potential risks of the drug for the treatment of patients hospitalized with severe COVID-19. On May 1, 2020, the agency granted an EUA for remdesivir for its use in select hospitalized patients with COVID-19 during the COVID-19 outbreak. The distribution of remdesivir will be controlled by the US government based on the scope of the authorization. The manufacturer, Gilead, is donating the first 1.5 million doses, which based on a 10-day regimen, will cover about 140,000 treatment courses. Based on a 10-day regimen, Gilead plans to produce at least 500,000 treatment courses by October 2020, 1 million treatment courses by December 2020, and if needed significantly more doses in 2021. The optimal duration of remdesivir treatment is unknown. Two Gilead-sponsored phase 3, open-label trials (SIMPLE) are evaluating 5- and 10-day courses of remdesivir in hospitalized patients with moderate and severe COVID-19. In patients with severe illness, topline data demonstrated similar improvement in clinical status between the treatment groups (odds ratio, 0.75 [95% CI, 0.51 to 1.12]) at day 14. Initial data in patients with moderate illness are expected at the end of May 2020. 6 | magellanrx.com
Hydroxychloroquine (HCQ) and Chloroquine (CQ) HCQ and CQ are old drugs FDA-approved for the treatment of malaria. Their immunomodulatory properties provide benefit for use in individuals with lupus erythematosus and RA for which HCQ is also indicated. Moreover, HCQ and CQ and have shown in vitro activity against SARS-CoV-2. Various oral doses of HCQ and CQ are being studied for treatment or prevention of COVID-19. Benefit for prophylaxis in healthcare workers has not been established to date. HCQ and CQ are also being studied in combination with the macrolide antibiotic azithromycin, which may prevent secondary bacterial infections and may lend immunomodulatory properties in pulmonary inflammatory disorders. Limited data, retrospective analysis, and anecdotal reports provide mixed results for treatment of COVID-19 ranging from no benefit, negative results, to possible clinical benefit (e.g., decreased viral load, decreased duration of illness) in small studies. A small randomized study conducted in Brazil in hospitalized patients with severe COVID-19 evaluated CQ given as low-dose (450 mg twice daily for 1 day then 450 mg once daily for 2 to 5 days) or high-dose (600 mg twice daily for 10 days) regimens in addition to azithromycin and ceftriaxone. The high-dose arm was stopped early due to reports of cardiotoxicity with QT interval prolongation and higher death rates compared to the low-dose arm. A retrospective analysis by the VA reported no evidence of decreased risk of mechanical ventilation when HCQ Âą azithromycin was given to men ages 59 to 75 years hospitalized for COVID-19. An observational study demonstrated no effect on risk of intubation or death in 1,376 hospitalized COVID-19 patients who were started on HCQ (600 mg twice daily on day 1, followed by 400 mg daily for a median of 5 days) within 24 to 48 hours of presentation. Conversely, a study in China, reported a shorter time to clinical recovery and a higher rate of improved pneumonia (80.6% versus 54.8% in the control group) when hospitalized patients (n=62) with COVID-19 were treated with HCQ 400 mg per day for 5 days. In a single-arm study conducted in France, HCQ 600 mg per day for 10 days resulted in a decreased viral load and duration of viral detection in COVID-19 patients (n=20) who were asymptomatic or had upper and/or lower respiratory tract infection; additional benefit was seen when azithromycin was also used. Another study in France showed no change in the rate of ICU admission or death when hospitalized COVID-19 patients (n=181) were treated with HCQ 600 mg per day. Ongoing trials in the US include the phase 3 ORCHID trial evaluating oral HCQ daily for 5 days (200 mg twice on day 1, followed by 200 mg once daily thereafter) added to standard care in over 500 hospitalized patients with COVID-19; published results are expected in July 2021. A placebo-controlled study by Novartis began on May 1, 2020 to evaluate HCQ Âą azithromycin for the treatment of COVID-19; results are expected later in 2020. Additionally, an NIAID-sponsored AIDS Clinical Trials Group (ACTG) phase 2b, randomized, double-blind, placebo-controlled study (called A5395) began enrolling mild to moderate symptomatic (e.g., fever, cough, dyspnea) adults in the US with confirmed SARS-CoV-2 infection in May 2020. Approximately 2,000 patients will be randomized to HCQ and azithromycin or matching placebos. Patients will take the medications at home, have follow-up visits via telephone, and record their symptoms and major events such as hospitalization for 20 days; additional telephone visits will be conducted at 3 and 6 months post treatment. Adults with comorbid conditions (e.g., CVD, diabetes), those over 65 years of age as well as HIV-positive or pregnant/breast feeding individuals will be eligible for the study. HCQ and CQ are associated with cardiotoxicity, including QT prolongation; azithromycin also carries risk of cardiac arrhythmias. The FDA issued a safety alert reporting adverse cardiac effects with HCQ and CQ and cautioned against their use outside a clinical trial or hospital setting. Based on limited data and safety concerns, the NIH COVID-19 treatment guidelines caution against use of these agents for COVID-19 outside the setting of a hospital or clinical trial. Similarly, the Infectious Diseases Society of America (IDSA) and the American College of Physicians (ACP) only support use of HCQ and CQ, alone or in combination with azithromycin, in hospitalized COVID-19 patients as part of a clinical trial. On March 28, 2020 the US FDA issued an EUA for HCQ and CQ donated to the Strategic National Stockpile (SNS) to be distributed for select hospitalized adolescent and adult patients with COVID-19, when a clinical trial is not available or participation is not feasible. Millions of doses of HCQ and CQ have been donated to the SNS.
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DRUG PIPELINE
Drugs in late stage development Antivirals (products with antiviral properties) Most agents listed below are being studied in hospitalized patients with COVID-19 infection. Chloroquine, hydroxychloroquine, nitaxozanide, and emtricitabine/tenofovir disoproxil fumarate (TDF) are also being evaluated for pre- and/or post-exposure prophylaxis in healthcare workers or individuals at risk for severe complications. Repurposed Medications (agents already approved for indications other than COVID-19) DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
HIV-1 Antiretrovirals darunavir/cobicistat (Prezcobix®) Janssen
protease inhibitor/ CYP3A inhibitor
HIV-1 treatment
oral
emtricitabine/TDF (Truvada®) Gilead
nucleoside analog reverse transcriptase
HIV-1 treatment and prophylaxis
oral
lopinavir/ritonavir (LPV/r; Kaletra®) Abbvie
protease inhibitor
HIV-1 treatment
oral
randomized, open-label trial reported no treatment benefit of LPV/r compared to standard care in patients with severe COVID-19; a randomized, open-label trial demonstrated superiority of LPV/r + ribavirin + interferon compared to LPV/r alone.
Influenza agents baloxavir (Xofluza ) Genentech
RNA polymerase
influenza treatment
oral
oseltamivir (Tamiflu®) Genentech
neuraminidase inhibitor
influenza treatment and prevention
oral
generics available
®
Topical Antiseptics chlorhexidine
topical anti-infective
skin antiseptic
oral/nasal rinse
studied to reduce oro- and nasoparyngeal viral load
povidone/iodine
topical anti-infective
skin antiseptic
oral/nasal rinse
studied to reduce oro- and nasoparyngeal viral load
oral
antiviral activity includes coronaviruses; anti-inflammatory activity; cardiotoxic effects; studied with or without azithromycin; EUA in select hospitalized patients
Other Therapeutic Classes chloroquine phosphate (NIH)
antimalarial
malaria, extraintestinal amebiasis
hydroxychloroquine (NIH)
antimalarial
malaria, systemic lupus erythematosus and RA
oral
antiviral activity includes coronaviruses; anti-inflammatory activity; cardiotoxic effects; studied with or without azithromycin; EUA in select hospitalized patients
ivermectin
anthelmintic
parasitic worm infections
oral
in vitro activity against SARS-CoV-2 demonstrates broad spectrum antiviral activity; potential for high barrier to resistance; postexposure prevention of infection in healthcare workers and elderly residents of long-term care facilities
nitazoxanide (Alinia®) Lupin
antiprotazoal
diarrhea caused by Giardia lamblia or Cryptosporidium parvum
oral
ribavirin (Virazole®) Bausch Health
synthetic nucleoside with antiviral activity
respiratory syncytial virus
inhaled
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DRUG PIPELINE continued Emerging Medications DRUG NAME MANUFACTURER
THERAPEUTIC TARGET
DOSAGE FORM
clevudine Gilead
pyrimidine nucleoside analog
oral
danoprevir Roche
protease inhibitor
oral
studied with ritonavir for COVID-19; available outside the US for hepatitis C virus infection
DAS181 Ansun
broad spectrum antiviral fusion protein
inhaled
prevents viral entry
favipiravir (Avigan®) Fujifilm
viral RNA polymerase inhibitor
IV
available outside the US for influenza
inosine pranobex (Isoprinosine®)
induces a type 1 T helper celltype response in mitogen- or antigen-activated cells
oral
immunomodulatory antiviral available outside the US
interferon alfa-2b
interferon
nebulize
available in the US for SC administration for chronic hepatitis C infection
leronlimab CytoDyn
chemokine receptor 5 (CCR5)
SC
viral-entry inhibitor into T cells
meplazumab
anti-CD147 antibody
IV
could block the infection of SARS-CoV-2
merimepodib Biosig
inosine monophosphate dehydrogenase (IMPDH) inhibitor
oral
broad-spectrum antiviral
pegylated interferon lambda Eiger
interferon
SC
remdesivir Gilead
RNA polymerase inhibitor
IV
also investigated for Ebola infection; compassionate use and EUA access; ACTT2 trial is evaluating remdesivir with baricitinib
umifenovir (Arbidol®) Pharmstandard
blocks viral fusion by inhibiting hemagglutinin fusion
oral
broad-spectrum antiviral; available outside the US for influenza and other respiratory viruses
COMMENTS
Immune Modulators Immune modulators may mediate inflammatory response to treat acute respiratory ARDS and CRS that are associated with COVID-19 infection. According to the pathological findings of pulmonary edema and hyaline membrane formation, timely and appropriate use of immune modulators together with ventilator support should be considered for the severe patients to prevent ARDS development. Repurposed Medications (agents already approved for indications other than COVID-19) DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
Interferons emapalumab-lzsg (Gamifant™) Novimmune
interferon beta-1a & -1b
interferon gamma blocking antibody
interferon beta
hemophagocytic lymphohistiocytosis
multiple sclerosis
IV
SC
early studies demonstrated interferon beta was 5 to 10 times more effective than other human interferons against SARS-CoV
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DRUG PIPELINE continued DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
Interleukin receptor inhibitors anakinra (Kineret ) Biovitrum
IL-1R inhibitor
RA, cryopyrin-associated periodic syndromes
SC
canakinumab (Ilaris®) Novartis
IL-1 beta inhibitor
periodic fever syndromes, systemic JIA
SC
®
has potential to interrupt cytokine-mediated pulmonary injury precipitated by COVID-19
sarilumab (Kevzara®) Sanofi
IL-6R inhibitor
RA
SC
siltuximab (Sylvant®) EUSA
IL-6R inhibitor
Castleman’s disease
IV
tocilizumab (Actemra®) Genentech
IL-6R inhibitor
CRS, RA, giant cell arteritis, polyarticular and systemic JIA
IV, SC
also studied in combination with pembrolizumab (Keytruda®) ACTT2 trial is evaluating baricitinib in combination with remdesivir
Janus Kinase Inhibitors baricitinib (Olumiant®) Eli Lilly
Janus kinase inhibitor
RA
oral
ruxolitinib (Jakafi®) Incyte
Janus kinase inhibitor
myelofibrosis, polycythemia vera, steroid-refractory acute GVHD
oral
bevacizumab (Avastin®) Genentech
vascular endothelial growth factor (VEGF) inhibitor
various solid tumor types
IV
colchicine
alkaloid
gout, familial Mediterranean fever (Colcrys® only)
oral
corticosteroids (dexamethasone, hydrocortisone, methylprednisolone)
glucocorticoids
ARDS, asthma exacerbation, other immune or inflammatory conditions
IM, IV, oral
duvelisib (Copiktra®) Verastem
phosphatidylinositol-3-kinase (PI3K) kinase inhibitor
leukemia, lymphoma
oral
etopside
DNA synthesis inhibitor
neoplastic diseases
IV
fingolimod (Gilenya ) Novartis
sphingosine 1-phosphate receptor
multiple sclerosis
oral
ibrutinib (Imbruvica®) Abbvie/Janssen
Bruton's tyrosine kinase inhibitor
leukemia, lymphoma, GVHD
oral
imatinib (Gleevec®) Novartis
tyrosine kinase inhibitor
leukemia, mastocytosis, gastrointestinal stromal tumor
oral
immune globulin
Other Therapeutic Classes
®
immune enhancer
primary immune deficiency
IV
nivolumab (Opdivo®) Bristol-Myers Squibb
programmed death-1 (PD-1)
various solid tumor types, Hodgkin lymphoma
IV
sargramostim (Leukine®) Partner
recombinant GM-CSF
neutrophil recovery
IV, SC
selinexor (Xpovio™) Karyopharm
nuclear export/cellular protein XPO1
multiple myeloma
oral
sirolimus
mTOR inhibitor
organ rejection, lymphangioleiomyomatosis
oral
tacrolimus
calcineurin-inhibitor
organ rejection prevention
IV, oral
unknown
multiple myeloma, erythema nodosum leprosum
oral
thalidomide (Thalomid®) Bristol Myers Squibb
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may mediate activation of interleukin-1β
studied for prevention of CRS
plasma-derived
immunomodulator, antiinflammatory
DRUG PIPELINE continued Emerging Medications DRUG NAME MANUFACTURER
THERAPEUTIC TARGET
DOSAGE FORM
avdoralimab Innate
anti-C5aR antibody
IV
aviptadil Relief Therapeutics/NeuroRx
synthetic human vasoactive intestinal polypeptide (VIP)
inhaled
CD24Fc OncoImmune
CD24-directed fusion protein
IV
clazakizumab Vitaeris/CSL
IL-6R inhibitor
IV
CM4620 CalciMedica
calcium release-activated calcium (CRAC) channels inhibitor; tumor necrosis factor (TNF) inhibitor; IL-2 inhibitor
IV
dociparstat* Chimerix
C-X-C motif chemokine 12 (CXCL12) and chemokine receptor 4 (CXCR4) inhibitor
IV
gimsilumab Roivant
GM-CSF-directed monoclonal antibody
SC
lenzilumab Humanigen/Gilead
GM-CSF-directed monoclonal antibody
IV
LY3127804 Eli Lilly
angiopoietin 2 monoclonal antibody
IV
metenkefalin/tridecactide (Enkorten®)†
opioid peptide/alpha-melano-stimulating hormone (α-MSH)
injection
olokizumab R-Pharm
IL-6R inhibitor
IV
RPH-104 TRPharm
IL-1R inhibitor
SC
tradipitant Vanda
neurokinin-1 (NK1) receptor antagonist
oral
* heparin derivative with anti-inflammatory properties † Available outside the US
Miscellaneous Therapeutic Classes Repurposed Medications (agents already approved for indications other than COVID-19) DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
Anticoagulants There is evidence that severe cases of COVID-19 may be associated with a hypercoagulable state alteplase (Activase®) Genentech
tissue plasminogen activator (tPA)
myocardial infarction, pulmonary embolism, ischemic stroke
IV, nebulized
aspirin
antiplatelet, analgesic, antiinflammatory, antipyretic
minor aches, fever, minor inflammation, CVD
oral
dipyridamole
platelet inhibitor
post-operative thromboembolic complication prevention
IV, oral
enoxaparin
low molecular weight heparin
DVT, PE, MI
SC
nebulized route of administration is not approved in the US
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DRUG PIPELINE continued DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
Cardiovascular agents Patients with conditions such hypertension and cardiovascular disease are at increased risk for COVID-19 complications amiodarone
angiotensin-converting enzyme (ACE) inhibitors
ventricular fibrillation/ tachycardia
antiarrhythmic
renin-angiotensin system (RAS) inhibitors
hypertension, CVD
IV, oral
potential to interfere with coronavirus entry
oral
potential to inhibit or increase SARS-CoV-2 entry into lung tissue; multiple medical organizations advise against stopping or starting ACE inhibitors to prevent or treat COVID-19 potential to inhibit or increase SARS-CoV-2 entry into lung tissue; multiple medical organizations advise against stopping or starting ARBs to prevent or treat COVID-19
angiotensin Receptor Blockers (ARBs) (losartan, telmisartan, valsartan)
renin-angiotensin system (RAS) inhibitors
hypertension, CVD
oral
sildenafil
phosphodiesterase type 5 inhibitor (PDE5)
pulmonary arterial hypertension
oral
verapamil
calcium channel blocker
hypertension
oral
Nutritional Supplements Select nutritional supplements may support to body’s defenses against viral infections ascorbic acid (vitamin C) – high dose
antioxidant
nutritional supplement
IV, oral
support host defenses
cholecalciferol (vitamin D)
vitamin
nutritional supplement
oral
potential to balance reninangiotensin system (RAS) and reducing lung damage
zinc
trace element
nutritional supplement
oral
impairs replication of some RNA viruses including SARS-CoV in vitro
Other Therapeutic Classes acetylcysteine
azithromycin
intracellular antioxidant
macrolide antibiotic
acetaminophen overdose
bacterial infections of the respiratory tract, skin, and genitourinary tract
IV, oral
reduces of liver injury
IV, oral
demonstrates in vitro activity against some viruses; studied in combination with HCQ for COVID-19─may result in faster decrease in viral load versus HCQ alone; NIH recommends against use in combination with HCQ outside of clinical trials, due to the risk of cardiotoxicity
dapagliflozin (Farxiga®)
SLGT2 inhibitor
diabetes
oral
may have protective effects against CV and renal effects of COVID-19; however, there could be increased risk of diabetic ketoacidosis
famotidine – high dose
histamine 2 (H2) receptor antagonist
gastroesophageal reflux, duodenal ulcer, and hypersecretory conditions
IV
studied in combination with HCQ; may block an enzyme needed for viral replication
fluvoxamine
selective serotonin reuptake inhibitor (SSRI)
depression
IV
studied in combination with HCQ; may block an enzyme needed for viral replication
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DRUG PIPELINE continued DRUG NAME MANUFACTURER
THERAPEUTIC CLASS
FDA-APPROVED INDICATION
DOSAGE FORM
COMMENTS
Other Therapeutic Classes continued Ibuprofen, indomethacin, naproxen
NSAIDs
mild to moderate pain; inflammation; pyrexia
oral
isotretinoin
retinoid
acne
oral
pyridostigmine bromide
cholinesterase inhibitor
myasthenia gravis
oral
tranexamic acid
antifibrinolytic
heavy menstrual bleeding
oral
may have anti-inflammatory effect may reduce the infectivity and virulence of the virus; studied in inpatient and outpatient settings
Emerging Medications DRUG NAME MANUFACTURER
THERAPEUTIC TARGET
DOSAGE FORM
vafidemstat Oryzon Genomics
dual lyseine-specific demethylase-1 (LSD1)/ monoamine oxidase B (MAO-B) inhibitor
oral
vazegepant* Biohaven
calcitonin gene-related peptide (CGRP) inhibitor
intranasal
*May blunt the severe inflammatory response at the alveolar level
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Vaccine Pipeline SPOTLIGHT Development and Timeline Researchers around the world are working tirelessly in the race against time to discover a vaccine against SARS-CoV-2. Vaccines follow an approval process similar to drugs. The development of vaccines adhere to a set of standards (Figure 1) of testing to ensure they are safe, generate the desired immune response, and prevent healthy people from getting sick if exposed to the virus. During the pandemic, many stages are conducted in parallel fashion to speed up the process, which can ordinarily take 10 to 15 years. The Ebola vaccine, newly-minted in December 2019, took about 6 years to get licensure, whereas an HIV/AIDS vaccine has still not come to market after about 40 years. Extraordinary measures have been introduced during the COVID-19 outbreak to speed vaccine development. Each stage of vaccine study can take months to years and many do not progress. There are different estimations of when a possible vaccine will be available. “Operation Warp Speed,” a White House initiative to accelerate COVID-19 development, anticipates a few hundred million vaccine doses could be ready by the end of 2020. Dr. Anthony Fauci, Director of NIAID, estimates that it could take 12 to 18 months before a COVID-19 vaccine comes to market. Figure 1. Standard Development Timeline 10-15 yrs
10-15 yrs
PHASE I
EXPLORATORY
PRE-CLINICAL
PHASE II
PHASE III
CLINICAL DEVELOPMENT
REGULATORY MANUFACTURING REVIEW & APPROVAL
QUALITY CONTROL
VACCINE
Manufacturing Once a vaccine is approved, a massive manufacturing scale-up will be needed for mass commercial access. In anticipation, a number of companies are ramping up parallel manufacturing to substantially boost their manufacturing capacity “at-risk” without knowing if their vaccine candidate will be successful. The US government plans to stockpile promising COVID-19 vaccines to have supply ready for distribution should any receive a regulatory green light. During initial rollout on an emergency use basis, access may need to be prioritized for high risk patients, healthcare workers, and vulnerable individuals. In the US, over 390,000 patients have recovered from COVID-19. While it is unclear how long immunity to SARS-CoV-2 lasts in patients who have been infected, herd immunity may play a role in protecting those who are unable to receive the vaccine.
Platforms Based on our research of the World Health Organization (WHO) and the clinicaltrials.gov registry, there are over 100 vaccines in development but only 10 vaccines have entered human trials. Of the 10 vaccine candidates, multiple vaccine platform technologies being studied include RNA, DNA, non-replicating adenovirus vectors, inactivated viruses, and protein subunits. Each vaccine construct targets the virus through different paths to confer immunity against this RNA virus. RNA- and DNA-based platforms utilize synthetic processes to make the vaccine. They can be made more quickly because they do not require culture or fermentation. Currently, there are no RNA vaccines approved. Inactivated viruses help the body develop antibodies to the pathogen without the risk of getting infected. Vectors for non-replicating adenovirus (a version of the common cold) are genetically engineered with a replication-defective mutant virus. Protein subunits only show the body part of the virus and use an adjuvant to make antibodies against the virus. The end goal for vaccines, regardless of the construct, is to prompt the body to safely mount an immune response to ward off the virus.
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Players Moderna’s mRNA-1273 vaccine, given as 2 doses about 1 month apart, is funded by the NIAID and the Biomedical Advance Research and Development Authority (BARDA). It is the first coronavirus vaccine to receive Fast Track designation from the FDA, paving the way to facilitate development and a more expedited FDA review for this unmet need. In May 2020, Moderna announced positive interim immunogenicity data from its phase 1 trial showing the vaccine elicited a response with antibody levels similar to or greater than reported in patients who recovered. In the study, adults (n=15 per cohort) were given a single dose of 250 μg or 2 doses of 25 μg or 100 μg. In all 3 study groups, seroconversion was detected by day 15 (after a single dose). At day 43, levels of binding antibodies – which indicate if a person is infected with the virus ─ met (25 μg dose; n=15) or exceeded (100 μg dose; n=10) levels reported in convalescent serum. To date, neutralizing antibody data are available for the initial 8 participants, which revealed neutralizing antibodies in both the 25 μg and 100 μg groups. Regarding vaccine safety, 3 individuals in the 250 μg group experienced grade 3 systemic symptoms after the second dose; no grade 4 adverse events were reported in any group. While the data on Moderna’s vaccine are encouraging, these early results are interim and only available in a very small number of patients; broader scale studies are needed. The manufacturer has received the green light to advance to phase 2 studies. Moderna is expected to begin phase 3 trials in July 2020 and, if successful, to file for licensure with the FDA. Data on the single-dose University of Oxford (UK)/AstraZeneca vaccine candidate are expected around July 2020. Pfizer’s vaccine candidate, a venture between the US and Germany’s BioNTech, hopes to start larger scale studies in September 2020. A number of vaccine developers, including UK’s Oxford/AstraZeneca and US/Germany/China Pfizer/BioNTech/Fosun, have announced plans to have initial supply of their vaccines available in the fall/winter 2020 timeframe, if their candidates are successful. A non-injectable formulation, intradermal (Inovio; US), is also among vaccine contenders. A non-randomized, open-label, single-center, phase 1 trial conducted in Wuhan, China demonstrated safety and immunogenicity of the Ad5 vectored COVID-19 vaccine developed by CanSino Biologics and the Beijing Institute of Biotechnology (China). In the study, healthy SAR-CoV-2-negative adults received a single IM dose of the vaccine at 1 of 3 dose levels (low, middle, high; n=36 in each group). A rapid immune response was evident, with peak T-cell response reported at day 14 after vaccination. At day 28 post vaccination, at least a 4-fold increase in rapid binding antibodies was seen in 97%, 94%, 100% of participants in the low-, middle-, and high-dose groups, respectively. Also at day 28, at least a 4-fold increase in neutralizing antibodies to the live virus was reported in 50%, 50%, and 75% of participants in the low-, middle-, and high-dose groups, respectively. At baseline, 56%, 53%, and 44% of participants in each group, respectively, had high levels of pre-existing Ad5 neutralizing antibodies (>1:200), which appeared to compromise seroconversion of neutralizing antibodies post vaccination. In addition, participants ages 45 to 60 years appeared to have lower neutralizing antibody seroconversion compared to younger participants. The most common adverse reactions were fever, fatigue, headache, and muscle pain with no significant difference in the incidence of adverse reactions across the groups. Most adverse events reported were mild or moderate in severity.
Notables Of growing interest are monoclonal antibodies. These neutralizing antibodies work by mimicking an immune response to the virus with the desired effect of preventing a mutation and avoiding an antibody-enhanced disease. Monoclonal antibodies can be synthesized in mass quantities. Recently, Sorrento Therapeutics reported that its antibody candidate (STI-1499) fully inhibits COVID-19 in vitro. While of interest, these results are preclinical, require further testing, and must be studied in randomized clinical trials. Sorrento plans to submit its full results in a peerreviewed publication and pursue COVI-SHIELD™ (cocktail of 3 antibodies including STI-1499) and develop a standalone STI-1499 (COVI-GUARD™). A number of agents being studies for COVID-19 are beyond the scope of this report. Notably, convalescent plasma, a century-old way for passively transferring immunity through plasma-containing antibodies collected from recovered patients to sick patients, is being evaluated.
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VACCINE PIPELINE Vaccines The COVID-19 vaccine landscape is fluid and evolving rapidly. Until further updates, please refer to the WHO for the latest list of vaccine candidates. NAME
DEVELOPER COUNTRY
FORMULATION/ REGIMEN
STUDY PHASE*
inactivated virus + aluminum
N/A 2 doses; day 0 and day 14 or 28
Phase 1/2
VACCINE TYPE Vaccine Platform: Inactivated Virus
Inactivated SARS-CoV-2 vaccine
Sinovac
Inactivated SARS-CoV-2 vaccine
Sinopharm/Beijing Institute of Biological Products
inactivated virus
N/A
Phase 1/2
Inactivated SARS-CoV-2 vaccine
Sinopharm/Wuhan Institute of Biological Products
inactivated virus
N/A
Phase 1/2
Inactivated SARS-CoV-2 vaccine
Institute of Medical Biology, Chinese Academy of Medical Sciences
inactivated virus
N/A
Phase 1
lipid nanoparticle (LNP)encapsulated mRNA
IM 2 doses; days 0 and 28
Phase 1/2
DNA plasmid with electorporation
intradermal 2 doses; day 0 and week 4; each followed by electroporation
Phase 1
3 LNP-mRNAs
IM studied as 1 and 2 dose regimens
Phase 1/2
Vaccine Platform: Nucleic Acid mRNA-1273
INO-4800
BNT162†
Moderna/NIAID
Inovio
Pfizer/BioNTech/ Fosun
Vaccine Platform: Protein Subunit NVX-CoV2373
recombinant spike protein nanoparticle with or without Matrix-M™ adjuvant
Novavax
IM 2 doses; days 0 and 21
Phase 1
Vaccine Platform: Viral Vector Ad5-nCoV AZD1222 (formerly ChAdOx1 nCoV-19)
CanSino/Beijing Institute of Biotechnology University of Oxford/ AstraZeneca
adenovirus type 5 vector/nonreplicating
IM 1 dose
Phase 1/2
non-replicating
IM 1 dose
Phase 2/3
* Timing of initiation of study phases may very among vaccine candidates. † Pfizer is studying 4 variants of the BNT162 vaccine.
• Immunitor (Canada) has developed the V-SARS therapeutic vaccine. The product, which may work by stimulating the immune system, is in phase 1/2 trials in patients with confirmed COVID-19. • The Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated strain of Mycobacterium bovis FDA-approved for the prevention of tuberculosis. Intradermal injections of the product are being studied for prophylaxis against COVID-19 in healthcare workers. Development of a safe and effective vaccine typically takes 10 to 15 years. The insidious nature of COVID-19 has led to the investigation of a large number of vaccines against SARS-CoV-2. Vaccine candidates against SARS-CoV-2 may move from preclinical studies to clinical trials in humans (phase 1, 2, 3) at a relatively fast pace. Further, there could be parallel partnerships among different countries and multiple studies evaluating a single vaccine. As a result, vaccine candidates may be in different stages of investigation. Due to the fluid nature of this arena, all vaccine candidates and/or study phases may not be reflected in this report.
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Early Phase DEVELOPMENT Medications in early phase development Antivirals Emerging Medications • • • • • •
apabetalone (Resverlogix) astrodrimer (Italfarmaco) bemcetinib (Bergenbio) camostat mesylate (Ono) EIDD-2801 (Ridgeback) emetine (Acer)
• • • • • •
FW-1022 (Firstwave) galidesivir (Biocryst) ifenprodil (Algernon) nafamostat (Ensysce) reproxalap (Aldeyra) zotatifin (Effector)
Immune Modulators Repurposed Medications • acalabrutinib (Calquence®; AstraZeneca) • apremilast (Otezla®; Amgen)
• eculizumab (Soliris®; Alexion) • leflunomide (Arava®; Sanofi)
Emerging Medications • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2019-nCoV mAbs (Regeneron) astaxanthin (Cardax) AT-100 (Airway) AVM0703 (dexamethasone sodium phosphate)(AVM) bemcentinib (Bergenbio) brensocatib (Insmed) brilacidin (Innovation) bucillamine (Revive) Coronavirus Antibody Program (Vir/Biogen) Coronavirus Antibody Program (Vir/NIAID) Coronavirus Antibody Program (WuXi/Vir) Coronavirus mAbs (Harbour/Mount Sinai) Coronavirus Plasma-Derived Products Program (Emergent) COVI-GUARD (Sorrento) COVI-SHIELD (STI-1499; Sorrento) COVID-19 Antibody Program (Amgen/Adaptive) COVID-19 Antibody Program (Atreca/BeiGene/IGM) COVID-19 Antibody Program (Brii Biosciences) COVID-19 Antibody Program (Chugai/A*STAR) COVID-19 Antibody Program (Eli Lilly/AbCellera) COVID-19 Antibody Program (Mitsubishi Tanabe) COVID-19 Antibody Program (VIB) COVID-19 Antibody Program (VUMC/Twist) COVID-19 Revive (Revive) CYNK-001 (Celularity) dactolisib (Restorbio/Novartis) DeltaRex-G (Aveni Foundation) fadraciclib (Cyclacel) fenretinide (Scitech) FT516 (Fate)
• • • • • • • • • • • • • • • • • • • • • • • • • • • • •
ibudilast (Medicinova) idronoxil (Noxopharm) JS016 (Eli Lilly) KP1237 (Kleo) mAb Program (Evotec/Ology) mAb Program (Vanderbilt/Ology) mavrilimumab (Kiniksa/AstraZeneca/CSL) methotrexate mosedipimod (Enzychem) NAb Program (Junshi/IMCAS) natural killer cells (various manufacturers) pacritinib (CTI) PolyTope mAb Therapy (ImmunoPrecise Antibodies) pritumumab (Nascent) REGN-COV2 (Regeneron) rintatolimod (AIM Immunotech/Merck) seliciclib (Cyclacel) silmitasertib (Senhwa) sodium (meta)arsenite (Komipharm) ST266 (Noveome) STI-4920 (Sorrento) TJM2 (I-Mab) trabedersen (Mateon) True Human Antibody Program (XBiotech) TZLS-501 (Tiziana Life) upamostat (Redhill) vidofludimus (Immunis) VIR-7831 (Vir) VIR-7832 (Vir)
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Miscellaneous Medications Repurposed Medications • chlorpromazine • crofelemer (Mytesi®; Bausch Health) • deferoxamine (Desferal®; Novartis)
• lucinactant (Surfaxin®; Windtree) • oxypurinol • progesterone (in males only)
Emerging Medications • B38-CAP (Kafrelsheikh University) • bromhexine (WanBangDe) • luminespib (Ligand)
• sodium bicarbonate 8.4% (inhaled) • TD-0903 (Theravance) • trans sodium crocetinate (Diffusion)
Vaccines in early phase development The below list of early phase vaccine products is not all inclusive. Timing of clinical development may vary among vaccine candidates. • aAPC Vaccine (Shenzhen Geno-Immune Medical Institute; China) • AdCOVID (Altimmune; US) • bacTRL-spike (Symvivo; Canada) • Chimigen COVID-19 Vaccine (Akshaya; Canada) • CoroFlu (Flugen/Bharat Biotech/Univ. of Wisconson; US) • Coronavirus Antibody Vaccine (Sorrento/SmartPharm; US) • Coronavirus mRNA Vaccine (GreenLight; US) • Coronavirus Vaccine (Akers/Premas; US) • Coronavirus Vaccine (Axon; Austria) • Coronavirus Vaccine (Clover/Dynavax; China) • Coronavirus Vaccine (CureVac; Germany) • Coronavirus Vaccine (eTheRNA/Epivax/Reprocell; Belgium) • Coronavirus Vaccine (Generex; US) • Coronavirus Vaccine (GeoVax/BravoVax; US) • Coronavirus Vaccine (GlaxoSmithKline/CEPI; United Kingdom) • Coronavirus Vaccine (Greffex; US) • Coronavirus Vaccine (Janssen; US) • Coronavirus Vaccine (Lineage; US) • Coronavirus Vaccine (NanoViricides; US) • Coronavirus Vaccine (Sanofi/GlaxoSmithKline; France) • Coronavirus Vaccine (Vaxart/Emergent; US) • Coronavirus Vaccine Program (Baylor College of Medicine; US) • Coronavirus Vaccine Program (Merck; US) • Coronavirus VLP Vaccine (Mitsubishi Tanabe; Japan) • CORVax12 (Oncosec; US) • CoVaccine HT (Soligenix/Boston Scientific; US) • COVID-19 prophylactic vaccine (OSE Immunotherapeutics; France) • COVID-19 Vaccine (CEPI/Institute Pasteur; France) • COVID-19 Vaccine Program (Dynavax; US) • COVID-19 Vaccine (Dynavax/Sinovac; US) • COVID-19 Vaccine (ReiThera/Leukocare/Univercells; Italy) • COVID-19 Vaccine (SK Bioscience; South Korea) • COVID-19 Vaccine (Themis; Austria) • COVID-19 Vaccine (VIDO-InterVac/ZYUS; Canada)
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• DNA plasmid vaccine (AnGes/FunPep/Osaka University; Japan) • DNA plasmid vaccine (Zydus Cadila; India) • DNA vaccine (Bionet Asia; Thailand) • DNA vaccine (Takis/Applied DNA/Evvivax; Italy) • DNA vaccine (University of Waterloo; Canada) • DNA vaccine with electroporation (Cobra/Karolinska Institute; Sweden) • DPX-COVID-19 (IMV; Canada) • EPV-CoV19 (Epivax; US) • Epitope COVID-19 Vaccine (Neovii; Switzerland) • Fusogenix DNA vaccine (Entos; Canada) • GP-96 Coronavirus Vaccine (Heat Biologics; US) • IBIO-200 (Ibio/CC-Pharming; US) • Inactivated vaccine (Institute of Medical Biology; China) • Inactivated vaccine (Osaka University/Biken/Nibiohn; Japan) • LEAPS-COVID-19 (CEL-SCI; US) • LUNAR-COV19 (Arcturus; US) • LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute; • China) • mRNA Coronavirus Vaccine (BIOCAD; Russia) • Pan-Coronavirus Vaccine (VBI/National Research Council of US/Canada) • PiCoVacc (Sinovac; China) • RUTI vaccine (Archivel; Spain) • SARS-CoV-2 Vaccine (ERC-Worldwide; Belgium) • STI-6991 (Sorrento; US) • TerraCoV2 (Noachis Terra; US) • TNX-1800 (Tonix/University of Alberta; US/Canada) • TNX-1810 (Tonix/University of Alberta; US/Canada) • TNX-1820 (Tonix/University of Alberta; US/Canada) • TNX-1830 (Tonix/University of Alberta; US/Canada) • Tropis® Needle-free vaccine (Immunomic/EpiVax/PharmaJet; US) • VaxCelerate Program (HaloVax/Hoth/Voltron; US) • Versamune Vaccine Program (PDS; US) • VLA2001 (Valneva/Dynavax; United Kingdom) • VSV Vector Coronavirus Vaccine (Sumagen; South Korea)
GLOSSARY ACE Angiotensin Converting Enzyme
PE Pulmonary Embolism
AIDS Acquired Immunodeficiency Syndrome
RA Rheumatoid Arthritis
ARDS Acute Respiratory Distress Syndrome
SARS Severe Acute Respiratory Syndrome
BARDA Biomedical Advance Research and Development Authority
SC Subcutaneous
COVID-19 Coronavirus Disease 2019 CRS Cytokine Release Syndrome CV Cardiovascular CVD Cardiovascular Disease DVT Deep Vein Thrombosis
SGLT2 Sodium-GLucose coTransporter-2 US United States VA Veterans Health Administration WHO World Health Organization XPO1 Exportin-1
EUA Emergency Use Authorization FDA Food and Drug Administration GM-CSF granulocyte-macrophage colony stimulating factor GVHD Graft-Versus-Host Disease HIV-1 Human Immunodeficiency Virus-1 ICU Intensive Care Unit IL-1 Interleukin-1 IL-6R Interleukin-6 Receptor IV Intravenous JIA Juvenile Idiopathic Arthritis MERS Middle East Respiratory Syndrome MI Myocardial Infarction mRNA messenger Ribonucleic Acid mTOR mammalian Target of Rapamycin N/A Not Available NIH National Institutes of Health NIAID National Institute of Allergy and Infectious Diseases NSAID Non-Steroidal Anti-Inflammatory Drug
2020 Magellan Rx Management, LLC. All rights reserved. MRX1119.1_0520
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