Table 3a. Immune-Based Therapy Under Evaluation for the Treatment of COVID-19: Clinical Data to Date

• Convalescent plasma is not approved by the FDA. It has received an EUA from the FDA for the treatment of hospitalized patients with COVID-19.¹ Both High Titer (i.e., Ortho VITROS SARS-CoV-2 IgG tested with signal-to-cutoff ratio ≥12) and Low Titer COVID-19 Convalescent Plasma are authorized for use.^2,3 Please refer to the FDA’s Recommendations for Investigational COVID-19 Convalescent Plasma website for guidance on the transfusion of investigational convalescent plasma while blood establishments develop the necessary operating procedures to manufacture COVID-19 convalescent plasma in accordance with the Conditions of Authorization set forth in the EUA.

• Plasma donated from individuals who have recovered from COVID-19 includes antibodies to SARS-CoV-2.⁴ Thousands of U.S. patients have received convalescent plasma through clinical trials, expanded access treatment trials, and EIND applications. However, the standards and methods for screening donated plasma for SARS-CoV-2 binding and neutralizing antibodies have not been established. The variability in SARS-CoV-2 antibody levels in donor plasma may impact the product’s efficacy. Currently, there are insufficient data from well-controlled, adequately powered, randomized clinical trials to evaluate the efficacy and safety of convalescent plasma for the treatment of COVID-19.

For COVID-19:

• Open-Label Randomized Clinical Trial of Convalescent Plasma in 103 Hospitalized Patients With Severe or Life-Threatening COVID-19: Investigators conducted an open-label, randomized clinical trial of convalescent plasma versus SOC for patients with severe or life-threatening laboratory-confirmed COVID-19 in 7 medical centers in Wuhan, China, from February 14–April 1, 2020. The primary outcome was time to clinical improvement within 28 days, which was defined as patient discharged alive or a reduction of 2 points on a 6-point disease severity scale. Only plasma units with SARS-CoV-2 viral spike-receptor binding domain-specific IgG titer ≥1:640 were transfused. The median dose of ABO-compatible convalescent plasma was 200 mL. The time from symptom onset to randomization was 27 days in the treatment group and 30 days in the control group. Due to control of the COVID-19 outbreak in Wuhan, the trial was terminated early after 103 of the planned for 200 patients were enrolled. The convalescent plasma and control groups were well balanced by age (median age of 70 years vs. 69 years, respectively), but the control group had a higher proportion of men (65%) than the convalescent plasma group (52%). Baseline severity scores (45 patients had severe disease and 58 had life-threatening disease) and use of concomitant therapies were similar between the 2 groups. There was no significant difference between the groups in the primary outcome of time to clinical improvement within 28 days (HR 1.40; 95% CI, 0.79–2.49; P = 0.26). Among those with severe disease, 91% of the convalescent plasma recipients and 68% of the control patients improved by Day 28 (difference 23%; OR 1.34; 95% CI, 0.98–1.83; P = 0.07). Among those with life-threatening disease, 21% of the convalescent plasma recipients and 24% of the control patients improved by Day 28 (difference -3.4%; OR 0.86; 95% CI, 0.33–2.24; P = 0.75). There was no significant difference in 28-day mortality between the groups (16% vs. 24% for the treatment and control groups, respectively; OR 0.65; 95% CI, 0.29–1.46; P = 0.30). At 24, 48, and 72 hours, the rates of negative SARS-CoV-2 viral PCR were significantly higher in the convalescent plasma group than in the control group (45% vs. 15%, P = 0.003 at 24 hours; 68% vs. 33%, P = 0.001 at 48 hours; and 87% vs. 38%, P < 0.001 at 72 hours). Two transfusion-related events were reported, including 1 severe event; both events resolved with supportive care. The study’s primary limitations were its open-label design and that, on average, the convalescent plasma was transfused approximately 1 month into the disease course. In addition, the study was terminated early, and thus the sample size was insufficient to detect differences in clinical outcomes.⁵
• Open-Label, Randomized, Multicenter Clinical Trial of Convalescent Plasma in Hospitalized Patients with COVID-19 (ConCOVID Study): An open-label, randomized clinical trial of convalescent plasma versus SOC for hospitalized patients with COVID-19 was conducted in 14 hospitals in the Netherlands from April 8–July 1, 2020. Only plasma confirmed to have anti-SARS-CoV-2 neutralizing antibodies by a SARS-CoV-2 PRNT and a PRNT50 titer ≥1:80 was transfused. The primary endpoint was in-hospital mortality up to 60 days after admission. The trial was halted prematurely by the investigators and the study’s data safety monitoring board when the baseline SARS-CoV-2 neutralizing antibody titers of participant and convalescent plasma were found to be comparable, challenging the potential benefit of convalescent plasma for the study patient population. Fifty-three of 66 participants had anti-SARS-CoV-2 antibodies at baseline despite being symptomatic for a median time of only 10 days. Among 56 participants whose blood was tested using SARS-CoV-2 PRNT, 44 (79%) had neutralizing antibody levels that were comparable to those of 115 donors (median titers of 1:160 vs. 1:160, respectively, P = 0.40). When the trial was halted, 86 participants had been enrolled. No differences in mortality (P = 0.95), length of hospital stay (P = 0.68), or disease severity at Day 15 (P = 0.58) were observed between the study arms. The study was terminated early, and thus lacked sufficient power to detect differences in clinical outcomes between the study groups.⁶
• Open-Label, Randomized, Multicenter Clinical Trial of Convalescent Plasma in Hospitalized Patients with COVID-19 (PLACID Trial): Not Peer Reviewed. An open-label, randomized clinical trial of convalescent plasma versus SOC for hospitalized patients with COVID-19 was conducted in 39 tertiary care centers in India from April 22–July 14, 2020. Patients with confirmed COVID-19 and signs of severe disease with hypoxia were eligible if matched donor plasma was available at the time of enrollment. Critically ill patients (those with PaO₂/FiO₂ <200 mmHg or shock) were excluded. The primary outcome was time to disease progression through 28 days (i.e., to PaO₂/FiO₂ <100 mmHg) or all-cause mortality at 28 days. Participants in the intervention arm received 2 doses of 200 mL plasma, transfused 24 hours apart. Antibody testing to assess titers of donated plasma was not available when the trial started. Four-hundred and sixty-four participants were randomized; 235 were randomized into the convalescent plasma arm and 229 were randomized into the SOC arm. The arms were well-balanced with regard to age (median of 52 years in both arms) and days from symptom onset to enrollment (median of 8 days in both arms). There was no difference in the primary outcome (time to disease progression and 28-day mortality) across the trial arms. The composite outcome occurred in 44 patients (18.7%) in the convalescent plasma arm and 41 (17.9%) in the control arm. Thirty-four participants (14.5%) in the convalescent plasma arm and 31 patients in the control arm (13.6%) died. In each arm, 17 participants progressed to severe disease (7.2% in the convalescent plasma arm vs. 7.4% in the SOC arm). SARS-CoV-2 antibody testing was not used to select donated convalescent plasma units; therefore, many participants may have received units with low titers of SARS-CoV-2 neutralizing antibodies. Additionally, the study was not blinded.⁷
• Preliminary Safety Analysis of the First Consecutive 5,000 Patients to Receive Open-Label COVID-19 Convalescent Plasma Through a National Expanded Access Program:⁸ The Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19 program was an open-label, nonrandomized protocol primarily designed to provide patients with severe or life-threatening (critical) COVID-19 with access to convalescent plasma, which is an investigational product in the United States. Secondary objectives were to obtain safety data on the product. The protocol was sponsored by the Mayo Clinic and included a diverse range of clinical sites. Plasma donors were required to have documented COVID-19, with complete resolution of symptoms for at least 14 days prior to donation, and be either male, female without history of pregnancy, or female with history of pregnancy and negative HLA testing after the most recent pregnancy. SARS-CoV-2 antibody testing of donors was not mandated. ABO-compatible convalescent plasma was transfused preferentially, but in the absence of ABO-compatible plasma, patients could receive either Group A plasma or low anti-A titer Group O plasma, as available. The Mayo Clinic EAP was discontinued on August 28, 2020. This safety analysis describes the first 5,000 patients, enrolled between April 7–May 3, 2020. Participants were adults with a median age of 62 years; 63% were male and 81% had severe or life-threatening COVID-19. The main safety outcomes for the safety analysis were SAEs including death; SAEs were reported at 4 hours and at 7 days after transfusion, or as they occurred. SAEs were reported in 36 patients (<1%) within 4 hours of transfusion; SAEs included 15 deaths, including 4 possibly or probably related to the convalescent plasma treatment. The 21 nonfatal SAEs included 7 TACO events, 11 TRALI events, and 3 severe allergic reactions. The overall 7-day mortality rate was 14.9%. In this study, COVID-19 convalescent plasma therapy was associated with a low rate (<1%) of serious transfusion-related events. The study design, which does not include a control arm, precludes an assessment of efficacy or ADE.
• Retrospective Exploratory Analyses of Outcomes Among Tens of Thousands of Patients Receiving Open-Label COVID-19 Convalescent Plasma Through the Mayo Clinic EAP: Both the FDA and the Mayo Clinic performed retrospective, indirect evaluations of the efficacy of COVID-19 convalescent plasma by using subsets of EAP data, hypothesizing that patients who received plasma units with higher titers of neutralizing antibodies would have better clinical outcomes than those who received plasma units with lower titers of antibodies. This analytic approach was not prespecified in the Mayo Clinic EAP protocol.
• FDA Efficacy Analysis: This analysis included 4,330 patients, and donor neutralizing antibody titers were measured by the Broad Institute using a pseudovirus assay.² The analysis revealed no difference in 7-day mortality between the patients who received high-titer plasma and those who received low-titer plasma, in the patient population overall, or in the subset of patients who were intubated. However, among nonintubated patients (approximately two-thirds of those analyzed), mortality within 7 days of transfusion was 11% for those who received high-titer plasma and 14% for those who received low-titer plasma (P = 0.03).¹ In a post hoc analysis of patients aged <80 years who were not intubated and who were treated within 72 hours of COVID-19 diagnosis, 7-day mortality was lower among the patients who received high-titer plasma than among those who received low-titer plasma (6.3% vs. 11.3%, respectively; P = 0.0008).²
• Mayo Clinic Efficacy Analysis: Not Peer Reviewed. This analysis included 3,082 participants who received a single unit of plasma out of the 35,322 participants who had received plasma through the EAP by July 4, 2020. Antibody titers were measured by using the Ortho Clinical Diagnostics COVID-19 IgG assay, and outcomes in patients transfused with low- (lowest 18%), medium-, and high- (highest 17%) titer plasma were compared. After adjusting for baseline characteristics, the 30-day mortality in the low-titer group was 29% and 25% in the high-titer group. This difference did not reach statistical significance. Similar to the FDA analyses, post hoc subgroup analyses suggested a benefit of high-titer plasma in patients aged <80 years who received plasma within 3 days of COVID-19 diagnosis and who were not intubated.⁹
• Limitations of the EAP Analyses: The lack of an untreated control arm limits interpretation of the safety and efficacy data. For example, the possibility that differences in outcomes are attributable to harm from low-titer plasma rather than benefit from high-titer plasma cannot be excluded. In addition:
  • The EAP data may be subject to multiple confounders, including regional differences and temporal trends in the management of COVID-19.
  • There is no widely available and generally agreed-upon best test for measuring neutralizing antibodies, and the antibody titers in convalescent plasma from patients who have recovered from COVID-19 are highly variable.
  • The efficacy analyses rely on a subset of EAP patients who only represent a fraction of the patients who received convalescent plasma through the EAP.
  • The subgroup that demonstrated the largest estimated effect between high-titer and low-titer convalescent plasma-patients aged <80 years who were not intubated and who were transfused within 3 days of COVID-19 diagnosis was selected post hoc by combining several subset rules which favored subgroups that showed a trend toward benefit of high-titer plasma. This approach tends to overestimate the treatment effect.
  • The FDA analysis relied on 7-day mortality, which may not be clinically meaningful in the context of the prolonged disease course of COVID-19. Because participants in this observational study were not rigorously followed after they were discharged from the hospital, the 30-day mortality estimates are uncertain.
• Retrospective, Single-Center, Case-Control Study Evaluating Convalescent Plasma Plus SOC Versus SOC Without Convalescent Plasma:¹⁰ Not Peer Reviewed. This case-control study reports clinical outcomes among 39 consecutive patients who received COVID-19 convalescent plasma through the FDA’s single patient EIND program while hospitalized at Mount Sinai Hospital in New York City during the period of March 24–April 8, 2020. Recipients were transfused with 2 units of ABO-compatible convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of 1:320 dilution. The control group (n = 156) was identified retrospectively from the hospital’s EHR database. The control patients were hospitalized during the same period as the patients in the convalescent plasma group and had confirmed COVID-19 but did not receive convalescent plasma. They were matched 4:1 to the convalescent plasma recipients using propensity scores to correct for measured confounders. Convalescent plasma recipients had a mean age of 55 years and 64% were male. At the time of transfusion, 87% of the recipients required supplemental oxygen through noninvasive ventilation and 10% through invasive mechanical ventilation. By Day 14, the clinical condition had worsened in 18% of the convalescent plasma patients and 24% of the control patients (P = 0.17). As of May 1, 2020, 13% of the plasma recipients and 24% of the matched control patients had died (P = 0.04, log-rank test) and 72% of the transfused patients and 67% of the control patients had been discharged. Interpretation of the study results is limited by the lack of randomization and the potential for unmeasured patient selection bias.
• Retrospective Case-Controlled Study Evaluating Outcomes Among COVID-19 Convalescent Plasma Recipients: In this study of patients who were hospitalized between March 24 and April 8, 2020, at Mount Sinai Hospital in New York City, outcomes among 39 consecutive patients who received convalescent plasma with a SARS-CoV-2 anti-spike antibody titer of 1:320 were compared to outcomes among 156 propensity-score-matched controls. As of May 1, 2020, 13% of the plasma recipients and 24% of the matched control patients had died (P = 0.04, log-rank test), and 72% and 67% of the transfused patients and control patients, respectively, had been discharged from the hospital. Subgroup analyses suggested a benefit of convalescent plasma among patients who were not intubated, had a shorter duration of symptoms, and received therapeutic anticoagulation.¹⁰
• Retrospective Case-Controlled Study of COVID-19 Convalescent Plasma Versus SOC: This study compared convalescent plasma with SOC in patients with COVID-19 who were hospitalized between March 28 and July 6, 2020, at 8 Houston Methodist hospitals. Outcomes for the first 136 convalescent plasma recipients who reached Day 28 post-transfusion were compared with the outcomes for two sets of propensity-score matched controls at 28 days after admission. The analyses suggested a trend towards benefit of convalescent plasma, with larger differences in mortality seen primarily among subgroups of patients who were transfused early (i.e., within 72 hours of admission) with high-titer plasma (i.e., anti-spike protein receptor binding domain titer ≥1:1350).¹¹
• Other smaller, uncontrolled case series describing clinical outcomes in patients with COVID-19 have been reported and also suggest that SAEs are uncommon following COVID-19 convalescent plasma treatment.^12-17

• Not approved by the FDA

• Concentrated antibody preparations derived from pooled plasma collected from individuals who have recovered from COVID-19 can be manufactured as SARS-CoV-2 immunoglobulin, which could potentially suppress the virus and modify the inflammatory response.

• No clinical data for COVID-19, SARS, or MERS

Non-SARS-CoV-2 Specific Intravenous Immunoglobulins

• Primary immune disorders
• Thrombocytopenic purpura
• Kawasaki disease
• Motor neuropathy
• Prophylaxis of various bacterial and viral infections

• Currently, only a small proportion of the U.S. population has been infected with SARS-CoV-2. Therefore, products derived from the plasma of donors without confirmation of SARS-CoV-2 infection are not likely to contain SARS-CoV-2 antibodies. Furthermore, although IVIG contains other blood components that may have general immunomodulatory effects, it is unclear whether these theoretical immunomodulatory effects will benefit patients with COVID-19.

For COVID-19:

• Not Peer Reviewed. A retrospective, nonrandomized cohort study of IVIG for the treatment of COVID-19 was conducted across 8 treatment centers in China between December 2019 and March 2020. The study found no difference in 28-day or 60-day mortality between 174 patients who were treated with IVIG and 151 patients who were not treated with IVIG. Patients who received IVIG were hospitalized for longer (median stay of 24 days for IVIG group vs. 16 days for no IVIG group) and experienced longer duration of disease (median of 31 days for IVIG group vs. 23 days for no IVIG group). More IVIG-treated patients had severe disease at study entry (71 patients [41%] with critical status in the IVIG group vs. 32 patients [21%] in the non-IVIG group). A subgroup analysis that was limited to the critically ill patients suggested a mortality benefit at 28 days, which was no longer significant at 60 days. The results are difficult to interpret because of important limitations in the study design. In particular, patients were not randomized to receive IVIG or no IVIG, and the patients in the IVIG group were older and more likely to have coronary heart disease than those in the no IVIG group. The IVIG group also had more patients with severe COVID-19 disease at study entry. Also, patients in both groups received many concomitant therapies for COVID-19.¹⁸

Mesenchymal Stem Cells

• Not approved by the FDA

• Multipotent adult stem cells that are present in most human tissues including the umbilical cord
• It is hypothesized that MSCs could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by SARS-COV-2.
• MSCs lack the ACE2 receptor that SARS-COV-2 uses for viral entry into cells; therefore, MSCs are resistant to infection.^19,20

For COVID-19:

• A pilot study of IV MSC transplantation in China enrolled 10 patients with confirmed COVID-19 categorized according to the National Health Commission of China criteria as critical, severe, or common-type disease. Seven patients (1 with critical illness, 4 with severe illness, and 2 with common-type illness) received MSCs; 3 patients with severe illness received placebo. All 7 patients who received MSCs recovered. Among the 3 severely ill control patients, 1 died, 1 developed ARDS, and 1 remained stable with severe disease.²¹
• A small clinical trial evaluated human umbilical cord MSC (hUC-MSC) infusion in patients with severe COVID-19 who had not responded to SOC therapies after 7 to 10 days of treatment. The SOC therapies included supplemental oxygen, umifenovir/oseltamivir, antibiotics if indicated, and glucocorticosteroids. The study was intended as a randomized controlled trial; however, due to the lack of sufficient hUC-MSCs, it was not upossible to randomize the participants as originally planned. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC infusion and 29 received SOC therapies only. The study arms were well balanced with regard to demographic characteristics, laboratory test results, and disease severity. All 12 participants who received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to home, whereas 4 patients who received only SOC therapies progressed to critical illness requiring mechanical ventilation, and 3 of these patients died. These results are not statistically significant and interpretation of the study is limited by its lack of randomization and small sample size.²²

For Other Viruses:

• In an open-label study of MSCs for the treatment of H7N9 influenza in China, 17 patients received MSC treatment plus SOC, and 44 patients received SOC only. In the MSC group, 3 patients (17.6%) died; in the control group, 24 patients (54.5%) died. The 5-year follow-up was limited to 5 patients in the MSC group. No safety concerns were identified.²³

Dexamethasone

FDA-Approved Indications:

• Allergic states (e.g., severe or incapacitating asthma, dermatitis, drug HSRs)
• Dermatologic diseases (e.g., bullous dermatitis, Stevens-Johnson syndrome)
• Endocrine disorders (e.g., adrenocortical insufficiency)
• Gastrointestinal diseases (e.g., ulcerative colitis)
• Hematologic disorders (e.g., hemolytic anemia, idiopathic thrombocytopenia purpura, pure red cell aplasia)
• Neoplastic diseases (e.g., palliative treatment of leukemia, lymphoma)
• Nervous system disorders (e.g., multiple sclerosis, cerebral edema)
• Ophthalmic diseases (e.g., temporal arteritis, uveitis)
• Renal diseases (e.g., to induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome)
• Respiratory diseases (e.g., eosinophilic pneumonia)
• Rheumatic disorders (e.g., ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus)²⁴

• Long-acting potent synthetic glucocorticoid with minimal mineralocorticoid activity. Glucocorticoid activity includes anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects.²⁵
• Potent anti-inflammatory effects may mitigate or prevent the systemic inflammatory response associated with severe COVID-19.

For COVID-19:

• Please see Corticosteroids for selected clinical data from trials that evaluated dexamethasone for the treatment of COVID-19.

• IFN alfa-2b: Leukemia, melanoma, lymphoma, condylomata acuminata, Kaposi sarcoma, hepatitis B, hepatitis C
• IFN alfa-1b is not available in the United States.

• Elicits antiviral, antiproliferative, and immunomodulatory activities on numerous cell types^26-28

For COVID-19:

• Not Peer Reviewed. In a retrospective cohort study of 77 adults with moderate COVID-19 in China, those who used nebulized IFN alfa-2b with or without umifenovir (Arbidol) achieved viral clearance in the upper respiratory tract faster and had lower systemic inflammation than those who used only umifenovir. However, results are difficult to interpret because participants in the IFN alfa-2b group were substantially younger than those in the umifenovir-only group (mean age 40 years vs. 65 years) and had fewer comorbidities (15% vs. 54%) at study entry. The nebulized formulation of IFN alfa-2b is not FDA approved for use in the United States.²⁹
• Press Release. A double-blind, placebo-controlled trial conducted in the United Kingdom evaluated inhaled IFN beta-1a (once daily for up to 14 days) in nonventilated patients hospitalized with COVID-19. Compared to the patients receiving placebo (n = 50), the patients receiving inhaled IFN beta-1a (n = 48) were more likely to recover to ambulation without restrictions (HR 2.19; 95% CI, 1.03–4.69; P = 0.04), had decreased odds of developing severe disease (OR 0.21; 95% CI, 0.04–0.97; P = 0.046), and had less breathlessness. Additional detail is required to fully evaluate these findings and their implications. Note that the inhaled IFN beta-1a formulation used in this study is not commercially available in the United States.³⁰
• An open-label, randomized trial at a single center in Iran evaluated SQ IFN beta-1a (3 times weekly for 2 weeks) in patients with severe COVID-19. There was no difference in the primary outcome of time to clinical response between the IFN beta-1a group (n = 42) and the control group (n = 39), and there was no difference between the groups in overall length of hospitalization, length of ICU stay, or duration of mechanical ventilation. The reported 28-day overall mortality was lower in the IFN beta-1a group, but 4 patients in that group who died before receiving the fourth dose of IFN beta-1a were excluded from the analysis, which makes it difficult to interpret these results.³¹
• An open-label, Phase 2 clinical trial randomized 127 participants (median age 52 years) 2:1 to combination antiviral therapy or LPV/r. In the combination antiviral therapy group, the treatment regimen differed by time from symptom onset to hospital admission. Participants admitted within 7 days of symptom onset (n = 76) were randomized to triple drug therapy (IFN beta-1b 8 million international units SQ every other day for up to 7 days total, LPV/r, and ribavirin); those admitted ≥7 days after symptom onset (n = 51) were randomized to double therapy (LPV/r and ribavirin) because of concerns regarding potential inflammatory effects of IFN. All participants in the control group received LPV/r alone regardless of time from symptom onset to hospitalization. The study participants were patients in Hong Kong with confirmed SARS-CoV-2 infection who were hospitalized regardless of disease severity until they had 2 negative NP swabs. The median time to a negative SARS-CoV-2 PCR on an NP swab (the primary endpoint) was shorter for the combination group than for the control group (7 days vs. 12 days, P = 0.001). The combination group had more rapid clinical improvement as assessed by NEWS2 and SOFA score and a shorter hospital stay (9 days for combination group vs. 14.5 days for control group, P = 0.016). There was no difference in oxygen use between the groups. The antiviral and clinical effect was more pronounced in the patients hospitalized within 7 days of symptom onset, suggesting that IFN beta-1b with or without ribavirin was the critical component of the combination therapy. The study provides no information about the effect of IFN beta-1b administered ≥7 days after symptom onset.³²

• Multiple sclerosis (IFN beta-1a, IFN beta-1b)

• Elicits antiviral, antiproliferative, and immunomodulatory activities on numerous cell types (T cell, B cell, and cytokine function)^26,33
• Among IFN subtypes, IFN beta-1b shows greatest in vitro inhibition of MERS-CoV.^34,35
• In vitro activity against MERS-CoV in lung cells.³⁶

• Rheumatoid arthritis
• Cryopyrin-associated periodic syndromes, specifically neonatal-onset multisystem inflammatory disease³⁷
• IV formulation is not approved for use in the United States.

• Competitively inhibits IL-1 binding to the IL-1 type I receptor

For COVID-19:

• A case-control study compared outcomes in 52 consecutive patients with COVID-19 treated with anakinra to outcomes in 44 historical controls. The patients in both groups were admitted to the same hospital system in Paris, France. Cases were consecutive admissions from March 24–April 6, 2020, with laboratory-confirmed SARS-CoV-2 infection or lung infiltrates on chest imaging typical of COVID-19, and either significant hypoxia (SpO₂ ≤93% with ≥6 L/min O₂) or worsening hypoxia (SpO₂ ≤93% with >3 L/min O₂ and a loss of ≥3% of O₂ saturation on room air in the previous 24 hours). Historic controls were patients fulfilling the same eligibility criteria and admitted to the hospital from March 18–March 24, 2020. SOC for both groups entailed use of HCQ, AZM, and parenteral beta-lactam antibiotics. Patients in the anakinra group received anakinra 100 mg SQ twice daily for 72 hours, followed by anakinra 100 mg daily for 7 days. Clinical characteristics were similar between the groups, except that the case patients had a lower mean BMI (25.5 kg/m² for cases vs. 29.0 kg/m² for controls), longer duration of symptoms (8.4 days for cases vs. 6.2 days for controls), and a higher frequency of HCQ use (90% for cases vs. 61% for controls) and AZM use (49% for cases vs. 34% for controls). The primary outcome of either admission to the ICU for invasive mechanical ventilation or death occurred among 13 cases (25%) and 32 controls (73%) (HR 0.22; 95% CI, 0.11–0.41). However, within the first 2 days of follow up in the control group, 6 patients (14%) had died and 19 patients (43%) had reached the composite primary outcome, which further limited intragroup comparisons and specifically analyses of time to event. CRP levels decreased by Day 4 among those receiving anakinra. Thromboembolic events occurred in 10 patients (19%) in the case group and 5 patients (11%) in the control group. The clinical implications of these findings are uncertain, due to limitations in the study design related to unmeasured confounding combined with the very high early event rate among the retrospective controls.³⁸
• A single-center case series reported on open-label use of anakinra in 9 hospitalized patients with COVID-19, presenting with 4–12 days of symptoms, requiring oxygen ≤6 L/min, and serum CRP ≥50 mg/L. Anakinra was administered SQ, 100 mg every 12 hours for 3 days followed by 100 mg daily for up to 7 more days. Two patients also received HCQ plus AZM; the other 7 patients received no specific additional treatments. Anakinra was discontinued in 1 patient who progressed to acute respiratory failure after the first dose of the drug. Good clinical outcomes were observed in the other 8 patients as assessed by oxygen flow, decline in CRP, and no progression in infiltrates on serial CT scans. Three patients had elevated liver transaminase levels. Results are difficult to interpret because of the low number of patients in the case series, the short follow-up, and the absence of a comparison group.³⁹
• A single-center, retrospective cohort study in Italy compared outcomes in 29 patients following open-label anakinra use with outcomes in 16 historical controls. All patients had COVID-19 with moderate to severe ARDS requiring noninvasive ventilation and evidence of hyperinflammation. High-dose IV anakinra 5 mg/kg twice daily was administered for a median of 9 days, followed by SQ administration (anakinra 100 mg twice daily) for 3 days to avoid inflammatory relapses. Both the anakinra and control (standard treatment) groups received HCQ and LPV/r. In the high-dose anakinra group, reductions in CRP levels were noted following anakinra initiation. The 21-day survival rate was 90% in the anakinra group and 56% in the control group (P = 0.009); however, the patients in the anakinra group were younger (median age of 62 years in anakinra group vs. 70 years in control group), and fewer patients had chronic kidney disease. High-dose anakinra was discontinued in 7 patients (24%) due to AEs (bacteremia in 4 patients, elevated liver enzymes in 3 patients); however, retrospective assessment showed that these events occurred with similar frequency in the control group. An additional group of 7 patients received low-dose SQ anakinra (100 mg twice daily); however, treatment in this group was stopped after 7 days because of lack of clinical or anti-inflammatory effects.⁴⁰

• Rheumatoid arthritis⁴¹

• Human recombinant monoclonal antibody
• IL-6 receptor antagonist⁴²

For COVID-19:

• Press Release: In a Phase 2 and 3 clinical trial (ClinicalTrials.gov Identifier NCT04315298), patients hospitalized with COVID-19 were randomized (2:2:1) to receive sarilumab 400 mg, sarilumab 200 mg, or placebo. Randomization was stratified by severity of illness (i.e., severe, critical, multisystem organ dysfunction) and use of systemic corticosteroids for COVID-19. The Phase 2 component of the trial verified that sarilumab (at either dose) reduced CRP levels. The primary outcome for Phase 3 of the trial was change on a 7-point ordinal scale, and this phase was modified to focus on the dose of sarilumab 400 mg among the patients in the critically ill group. During the conduct of the trial, there were numerous amendments that increased the sample size and modified the dosing strategies being studied, and multiple interim analyses were performed. The trial findings to date do not support a clinical benefit of sarilumab for any of the disease severity subgroups or dosing strategies studied. Additional detail (as would be included in a published manuscript) is required to fully evaluate the implications of these study findings.⁴³

• Multicentric Castleman disease

• Recombinant human-mouse chimeric monoclonal antibody
• IL-6 antagonist⁴⁴

For COVID-19:

• Not Peer Reviewed. In a single-center observational study of 21 patients with COVID-19 who developed pneumonia and ARDS and received treatment with IV siltuximab, some patients experienced decreased CRP levels (16 of 21 patients) and improved clinical condition (7 of 21 patients) following siltuximab treatment. Other patients experienced no clinically relevant change in condition (9 of 21 patients) or worsening condition (5 of 21 patients). Among the 5 patients with worsening condition, there was 1 death and 1 cerebrovascular event (median follow-up of 8 days).⁴⁵

• Cytokine release syndrome (induced by CAR T-cell therapy)
• Rheumatoid arthritis
• Giant cell arteritis
• Polyarticular juvenile idiopathic arthritis
• Systemic juvenile idiopathic arthritis⁴⁶

• Recombinant humanized monoclonal antibody
• IL-6 receptor antagonist

For COVID-19:

• Press Release: The industry-sponsored Phase 3 COVACTA trial (ClinicalTrials.gov Identifier NCT04320615) randomized 450 adults hospitalized with severe COVID-19-related pneumonia to receive tocilizumab or placebo. The trial failed to meet its primary endpoint or several key secondary endpoints. The primary outcome was improved clinical status, which was measured using a 7-point ordinal scale to assess clinical status based on the need for intensive care and/or ventilator use and the requirement for supplemental oxygen over a 4-week period. Key secondary outcomes included 4-week mortality. Differences in the primary outcome between the tocilizumab and placebo groups were not statistically significant (OR 1.19; 95% CI, 0.81–1.76; P = 0.36). At Week 4, mortality rates did not differ between the tocilizumab and placebo groups (19.7% vs. 19.4%; difference of 0.3%; 95% CI, -7.6% to 8.2%; P = 0.94). The difference in median number of ventilator-free days between the tocilizumab and placebo groups did not reach statistical significance (22 days for tocilizumab group vs. 16.5 days for placebo group; difference of 5.5 days; 95% CI, -2.8 to 13.0 days; P = 0.32). Infection rates at Week 4 were 38.3% in the tocilizumab group and 40.6% in the placebo group; serious infection rates were 21.0% and 25.9% in the tocilizumab and placebo groups, respectively.⁴⁷
• Press Release. Early results were reported for the CORIMUNO-TOCI trial (ClinicalTrials.gov Identifier NCT04331808), an open-label, randomized trial of hospitalized patients with COVID-19 (n = 129) at 7 sites in France. The patients, who had moderate or severe disease at study entry, were randomized to receive tocilizumab plus SOC (n = 65) or SOC alone (n = 64). The dosing strategy was tocilizumab 8 mg/kg on Day 1; if there was no response (i.e., no decrease of oxygen requirement), a second infusion was repeated on Day 3. In this preliminary report, the proportion of participants who died or needed ventilation (noninvasive or mechanical) was lower in the tocilizumab group than in the SOC alone group. Detailed results of the trial have not been reported.
• Sixty-three adults hospitalized with COVID-19 were enrolled in a prospective open-label study of tocilizumab for severe COVID-19. All patients received off-label ARV PIs. Patients received either tocilizumab 8 mg/kg IV or tocilizumab 324 mg SQ; within 24 hours, a second dose of tocilizumab was administered to 52 of the 63 patients. Following tocilizumab administration, fevers resolved in all but 1 patient, and CRP, ferritin, and D-dimer levels declined. The mean PaO₂/FiO₂ ratio increased between admission (152 +/-53 mm Hg) and Day 7 (284 +/-116 mm Hg). No moderate or severe AEs attributable to tocilizumab were reported. Overall mortality rate was 11% (7 deaths among the 63 patients). No details were provided regarding the rate of secondary infections after tocilizumab use. The authors report an association between earlier use of tocilizumab and reduced mortality, but provide no details regarding a comparison group or specify an a priori comparison, which limits interpretation of this result.⁴⁸
• An uncontrolled, retrospective cohort study of 21 hospitalized COVID-19 patients who received tocilizumab reported improvement in oxygenation and systemic inflammation. At study entry, among the 21 patients (mean age 56 years; range 25 to 88 years), 17 had severe disease and 4 had critical disease. All patients were febrile, had abnormal chest CT findings, and required oxygen supplementation (2 required mechanical ventilation). Mean CRP level was 75 mg/L, mean IL-6 expression level was 153 pg/mL, mean D-dimer level was 0.80 𝜇g/mL, and mean lymphocyte percentage was 15.5%. Eighteen patients were given tocilizumab IV infusion once, and within 12 hours, 3 patients received a second infusion for indication of fever. Following tocilizumab administration, fevers normalized, lymphocyte percentages improved, and CRP levels declined. By Day 5, oxygen requirements were reduced in 15 of 20 participants (75%). There were no serious AEs attributed to tocilizumab, and no concurrent bacterial, fungal, or viral infections were observed during the treatment. The interpretability of this retrospective case series is limited due to its small sample size and lack of control group.⁴⁹
• Additional data supporting the use of tocilizumab for COVID-19 include a small retrospective cohort study, a case series, and a case-control study.^50-52

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma⁵³

• Second-generation oral BTK inhibitor
• Inhibits BTK signaling of the B-cell antigen receptor and cytokine receptor pathways
• Potential modulation of signaling that promotes inflammation and cytokine storm⁵⁴

• Data regarding acalabrutinib are limited to a retrospective case series in 19 patients with severe COVID-19. However, data interpretation to discern any clinical benefit is limited by the study’s small sample size and lack of a control group.⁵⁵

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Marginal zone lymphoma
• Waldenström macroglobulinemia
• Chronic graft-versus-host disease in stem cell transplant recipients⁵⁶

• First-generation oral BTK inhibitor
• Inhibits BTK signaling of the B-cell antigen receptor and cytokine receptor pathways
• Potential modulation of signaling that promotes inflammation and cytokine storm⁵⁷

For COVID-19:

• Data regarding ibrutinib are limited to an uncontrolled, retrospective case series of 6 patients with COVID-19 who were receiving ibrutinib for a condition other than COVID-19. However, evaluation of the data for any clinical benefit is limited by the study’s small sample size and lack of control group.⁵⁷

• Mantle cell lymphoma⁵⁸

• Second-generation oral BTK inhibitor
• Inhibits BTK signaling of the B-cell antigen receptor and cytokine receptor pathways
• Potential modulation of signaling that promotes inflammation and cytokine storm⁵⁴

• No clinical data for COVID-19, SARS, or MERS

• Rheumatoid arthritis⁵⁹

• JAK inhibitor selective for JAK1, JAK2, and TYK2, relative to JAK3
• Theoretical direct antiviral activity through inhibition of kinases (AAK1 and cyclin G-associated kinase) that regulate viral endocytosis in pulmonary AT2 epithelial cells, which may prevent SARS-CoV-2 entry into and infection of susceptible cells.
• Dose-dependent inhibition of IL-6 induced STAT3 phosphorylation⁶⁰

For COVID-19:

• Not Peer Reviewed. A small, nonrandomized study of 12 patients with moderate COVID-19 pneumonia compared therapy with baricitinib and LPV/r with SOC alone (i.e., combination LPV/r and HCQ).⁶¹ Baricitinib and LPV/r therapy demonstrated a statistically significant time to improvement in clinical and respiratory symptoms and reduction in measured CRP.⁶¹

• Myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease⁶²

• JAK inhibitor selective for JAK1 and JAK2
• Theoretical antiviral properties through inhibition of AAK1 which may prevent viral entry into and infection of pulmonary AT2 alveolar epithelial cells^63,64
• Inhibition of IL-6 via JAK1/JAK2 pathway inhibition

For COVID-19:

• A small, prospective, single-blind, randomized, controlled Phase 2 trial in patients with COVID-19 in China compared ruxolitinib 5 mg PO twice daily (n = 20) to placebo (vitamin C 100 mg; n = 21), both given in combination with SOC therapy. The median age of the patients was 63 years. There were no significant demographic differences between the 2 arms. Treatment with ruxolitinib was associated with a nonsignificant reduction in median time to clinical improvement (12 days for ruxolitinib vs. 15 days for placebo; P = 0.15), defined as a 2-point improvement on a 7-category ordinal scale or hospital discharge. There was no difference between the groups in the median time to discharge (17 days for ruxolitinib vs. 16 days for placebo; P = 0.94). More patients in the ruxolitinib group than in the placebo group had radiographic improvement on CT scans of the chest at Day 14 (90% for ruxolitinib vs. 61.9% for placebo; P = 0.05), and a shorter time to recovery from initial lymphopenia when present (5 days for ruxolitinib vs. 8 days for placebo; P = 0.03). The use of ruxolitinib was not associated with an increased risk of AEs or mortality (no deaths in the ruxolitinib group vs. 3 deaths [14% of patients] in the control group). Despite the theoretical antiviral properties of JAK inhibitors, there was no significant difference in time to viral clearance among patients who had detectable viral loads at randomization to ruxolitinib (n = 8) or placebo (n = 9). Limitations of this study include the small sample size, the exclusion of patients who required mechanical ventilation at study entry, and the concomitant use of antivirals and steroids by 70% of patients.⁶⁵
• A small, retrospective, single-arm study in Germany reported no safety concerns in 14 patients with severe COVID-19 who received a brief course of ruxolitinib therapy (median 9 days).⁶⁶

• Rheumatoid arthritis
• Psoriatic arthritis
• Ulcerative colitis⁶⁷

• JAK inhibitor selective for JAK1 and JAK3 with modest activity against JAK2
• Blocks signaling from gamma-chain cytokines (IL-2, IL-4) and gp130 proteins (IL-6, IL-11, IFNs)
• Shown to decrease levels of IL-6 in rheumatoid arthritis⁶⁸

• No clinical data for COVID-19, SARS, or MERS