COVID-19 ilaçlarının analizi

As the COVID-19 pandemic continues, researchers and manufacturers are moving potential therapeutics into clinical trials at a dizzying pace. To date, just two therapeutics are approved to treat COVID-19: Avigan (favilavir) in China, Italy and Russia, and Veklury (remdesivir) in Japan. The search is on to find treatment candidates that lower mortality rates and lessen the severity of COVID-19 while the world waits for vaccine candidates to reach the market.
 
Potential therapies are being examined in several large international trials. The largest, SOLIDARITY, is led by the World Health Organization (WHO). More than 100 countries have joined SOLIDARITY to evaluate high-profile treatment candidates for COVID-19
 
Hydroxychloroquine/chloroquine, once considered a leading therapeutic candidate, is beginning to show evidence it could cause more harm than benefit in patients with COVID-19. The SOLIDARITY arm evaluating hydroxychloroquine/chloroquine was temporarily paused by the trial’s executive group pending a review by the Data Safety Monitoring Board, before resuming on 3 June. The governments of France, Italy and Belgium have significantly changed the way the medication can be used for COVID-19.
  
Stakeholders also are investigating therapeutic candidates originally derived for other indications, looking to repurpose approved drugs that have worked against similar coronaviruses, or are hypothesized to address SARS-CoV-2 based on the mechanism of action. Plasma and stem cells donated from patients who have recovered from COVID-19 have shown early promise as a treatment for those fighting against the virus. Organizations like the National COVID-19 Convalescent Plasma Project are coordinating initiatives to get these therapies to patients who need them.

The pandemic has created unprecedented public/private partnerships. Operation Warp Speed (OWS) is a collaboration of several US federal government departments including Health and Human Services and its subagencies, Agriculture, Energy and Veterans Affairs and the private sector. Within OWS, the US National Institutes of Health (NIH) has partnered with more than 18 biopharmaceutical companies to accelerate development of drug and vaccine candidates for COVID-19 in a collaboration dubbed Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV).
 
The European Medicines Agency (EMA) is building procedures for accelerated drug and vaccine development, promising to offer rapid reviews for scientific advice, compliance, market authorization, extensions beyond indications and market authorizations, and compassionate use for COVID-19 related initiatives.

Governments and medical societies have released guidelines on the treatment and management of patients with COVID-19. NIH’s COVID-19 treatment guidelines are led by a panel of “representatives from federal agencies, health care and academic organizations, and professional societies.”

This tracker will be updated weekly with the latest in developments for these treatment candidates. If you notice an issue with this data or wish to submit an update, please email Focus at news@raps.org.
 
Updated 5 June to include new information on favilavir, hydroxychloroquine, remdesivir, convalescent plasma, mavrilimumab and tocilizumab.
  

Frontline candidates

Drug: Remdesivir
Medication class: Antiviral
Developer: Gilead Sciences
Original use: Treatment for Ebola and Marburg virus infections
Rationale: Remdesivir, an intravenous drug that inhibits viral replication, has shown in vitro and in vivo activity against SARS-CoV-2. It was originally developed as a treatment for Ebola that ultimately proved less effective than other therapies, but has shown effectiveness in animal studies against other coronaviruses.
Regulatory actions: As studies of remdesivir have shown reduced time to clinical improvement for COVID-19 patients, countries have started allowing its use outside of trial settings. Japan is the only country so far to approve remdesivir (trade name Veklury) for COVID-19. FDA allows the use of remdesivir for COVID-19 under an emergency use authorization (EUA) based on preliminary results of NIH's ACTT trial (below). In the UK, remdesivir has received a positive scientific opinion under the Medicines and Healthcare products Regulatory Agency (MHRA) Early Access to Medicines Scheme, which will allow adults and children with COVID-19 access to the medication if they meet additional criteria. The EMA has released recommendations on how patients can receive remdesivir under compassionate use programs.
Manufacturing/Development: Gilead is ramping up production of remdesivir and improving the drug’s production pipeline, reducing the manufacturing timeline to 6-9 months from an initial 9-12 months. The company is also working with domestic and international partners to develop voluntary licensing agreements for remdesivir.
Trials: Remdesivir is being evaluated in the following high-profile trials:

• DisCoVeRy (Recruiting): A phase 3 trial in France examining remdesivir alongside lopinavir/ritonavir interferon beta-1a, hydroxychloroquine, and standard of care (NCT04315948)
• SOLIDARITY (Recruiting): Remdesivir is a treatment arm of the WHO SOLIDARITY trial.
• SIMPLE (Active, Not Recruiting): Two Phase 3 international studies from Gilead are examining moderate (NCT04292730) and severe COVID-19 cases (NCT04292899)
• ACTT (Not Recruiting): NIAID is conducting a phase 3 trial of 800 patients receiving either remdesivir or placebo (NCT04280705).
• Capital Medical University (Suspended/Terminated): Two phase 3 trials in China from Capital Medical University looking at mild/moderate (NCT04252664) and severe COVID-19 cases (NCT04257656).

Status: SOLIDARITY and DisCoVeRy are currently recruiting. The Capital Medical University trials have been suspended because COVID-19 has been “controlled well” in the study area, according to the trial listings. NIAID’s trial has stopped early and patients in the placebo group are being given the option to receive the study drug. Gilead Sciences’ international trials have an estimated study completion date of May 2020.
Outcomes: Remdesivir is beginning to show promise as a therapy that improves time to clinical improvement—but not improvement in mortality—for patients with COVID-19.

• ACCT: Results from 1,059 patients in the ACTT study showed remdesivir improved the time to clinical recovery from 15 days to a median of 11 days (RR, 1.32) and odds of recovery at 15 days (OR, 1.50; P < .001). Although not significant, patients in ACTT had better survival by 14 days compared with placebo (7.1% vs. 11.9%). Patients in ACTT had a median time of 9 days from symptom onset to starting treatment.
• Capital Medical University: In a multi-center, randomized, double-blinded, placebo-controlled, phase 3 trial of 237 patients, remdesivir did not significantly improve clinical symptoms (hazard ratio, 1.23; 95% CI, 0.87-1.75). Patients in this trial had a median time of 10-11 days from symptom onset to treatment; however, symptom duration of less than or equal to 10 days was associated with a non-significant faster time to clinical improvement compared with placebo.
• SIMPLE: Results from Gilead’s two SIMPLE trials show greater clinical improvement in moderate and severe COVID-19 cases, but results have not been statistically significant. Patients with moderate COVID-19 who received a 5-day course of remdesivir were 65% more likely to have clinical improvement than those who received standard of care at day 11 (P = .017), while patients receiving the 10-day course had a 31% more likely clinical improvement (P = .18). In a paper published in the New England Journal of Medicine, 64% of patients with severe COVID-19 who received a 5-day course and 54% of patients who received a 10-day course of remdesivir were more likely to have clinical improvement by day 14 compared with standard of care.

Drug: Hydroxychloroquine (Plaquenil) and chloroquine (Aralen)
Medication class: Quinoline
Manufacturers/Distributors: Sanofi (Plaquenil and Aralen); Mylan, Teva, Novartis, Bayer, Rising Pharmaceuticals, Amneal (generics)
Approved US Indications: Hydroxychloroquine is indicated to treat acute attacks of malaria due to susceptible Plasmodium strains, as well as for suppressive treatment. Chloroquine is indicated to treat uncomplicated malaria due to susceptible strains and for prophylaxis of malaria where chloroquine resistance is not found. It is also indicated to treat rheumatoid arthritis, systemic lupus erythematosus and porphyria cutanea tarda.
Rationale: Both hydroxychloroquine and chloroquine have demonstrated in vitro and in vivo activity against SARS-CoV-2. A 2005 study also showed chloroquine stopped SARS-CoV from replicating in the laboratory.
Trials: Hydroxychloroquine and/or chloroquine are being evaluated in these high-profile trials:

• ORCHID (Recruiting): Massachusetts General Hospital and the National Heart, Lung, and Blood Institute (NHLBI) are conducting a multicenter, blinded, placebo-controlled, randomized trial evaluating hydroxychloroquine in symptomatic COVID-19 patients (NCT04332991).
• A5395 (Recruiting): NIH is conducting a Phase 2b trial of 2,000 participants with SARS-CoV-2 to receive hydroxychloroquine, azithromycin, or placebo over 7 days (NCT04358068).
• Novartis (Recruiting): The company is conducting a 444-person Phase 3 trial evaluating hydroxychloroquine alone and hydroxychloroquine with azithromycin against a placebo group (NCT04358081).
• COVID-19 PEP Study (Temporarily halted): A trial by researchers at the University of Washington collaborating with the Bill and Melinda Gates Foundation is examining whether hydroxychloroquine can serve as post-exposure prophylaxis (PEP) for COVID-19 (NCT04328961). This trial is being temporarily put on hold, a representative from MHRA told Reuters.
• HAHPS and HyAzOUT (Recruiting): Intermountain Healthcare is testing hydroxychloroquine against azithromycin in inpatients (HAHPS; NCT04329832) and outpatients (HyAzOUT; NCT04334382) with COVID-19.
• CROWN CORONA (Not Recruiting): The Washington University School of Medicine in St. Louis is conducting a trial examining various dosing combinations of chloroquine and hydroxychloroquine (NCT04333732).
• Rutgers (Recruiting): Researchers at the Rutgers Cancer Institute of New Jersey are evaluating the change in viral load among patients with COVID-19 treated with hydroxychloroquine alone compared with hydroxychloroquine with azithromycin (NCT04336332).
• COPCOV (Recruiting): Researchers are looking at the preventive potential of chloroquine for healthcare workers (NCT04303507).
• RECOVERY (Recruiting): This trial, led by researchers at the University of Oxford, is evaluating hydroxychloroquine alongside lopinavir-ritonavir, dexamethasone, azithromycin, tocilizumab, and convalescent plasma (NCT04381936).
• SOLDARITY (Temporarily halted): Chloroquine is the fifth treatment arm of WHO’s SOLIDARITY trial. This arm was temporarily paused by the trial’s executive group pending a review by the Data Safety Monitoring Board.
• DisCoVeRy (Recruiting): Hydroxychloroquine is a treatment arm in the French DisCoVeRy trial.

Efficacy: Data are beginning to indicate a potential lack of efficacy for hydroxychloroquine as a treatment for COVID-19, but most trials have a low quality of evidence, making it difficult to draw firm conclusions. At least one trial has been stopped due to adverse drug effects.

• Some evidence for use: In 368 veterans with COVID-19, hydroxychloroquine with (113 patients) and without azithromycin (97 patients) reduced the use of mechanical ventilation for patients with COVID-19 compared with a control group (158 patients). Among the 97 patients who received hydroxychloroquine alone, there was a significantly higher risk of mortality (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P = .03) compared with not receiving any intervention, but this was not significant in the hydroxychloroquine plus azithromycin group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P = .72). The results were published in the pre-print server medRxiv.
• As post-exposure prophylaxis: Hydroxychloroquine was not effective in preventing patients from developing COVID-19 after taking the drug within 4 days of a high-risk exposure, according to a New England Journal of Medicine study.
• No evidence for use: An observational study published in the New England Journal of Medicine analyzing 811 of 1,446 COVID-19 patients taking hydroxychloroquine found there was no association between use of the drug and intubation or death, although patients who received hydroxychloroquine were more likely to have severe cases of COVID-19. In a paper published in JAMA, 1,438 patients from New York State who received hydroxychloroquine with and without azithromycin did not have improved in-hospital mortality rates with either intervention compared with standard of care.
• Evidence for potential harm: An international study published in The Lancet of 96,032 patients hospitalized for COVID-19 found a higher risk of mortality and de-novo clinically significant ventricular arrhythmias in patients who received hydroxychloroquine or chloroquine with and without compared with no therapy. However, this study was retracted by The Lancet on 4 June due to questions raised about its data.
• Halted trial: Recruitment was halted in the CloroCovid-19 Study. 25% of patients receiving 600 mg of chloroquine twice daily for 10 days experienced QTc prolongation and higher mortality than in other treatment arms, which led to the study’s discontinuation, according to a paper in the pre-print server medRxiv. 

Regulatory actions: The FDA issued an EUA on 24 April allowing the use of hydroxycholorquine and chlorquine to treat adolescent and adult inpatients with COVID-19 when clinical trial participation is not possible and the potential benefit to the patient outweighs the potential risk. The FDA and EMA have repeatedly warned against using hydroxychloroquine outside of hospital and clinical trial settings.
Status: Individual trials are in various stages of recruitment (above).

Therapy: Convalescent plasma
Medication class: Immunoglobulin
Rationale: Researchers have theorized that convalescent plasma could be used as passive immunotherapy in other coronaviruses such as MERS and in SARS-CoV-2 to help neutralize the virus.
Trials: Convalescent plasma is being evaluated against placebos, other treatments, and standard of care in a number of high-profile trials.

• NYU Langone Health and Albert Einstein (Recruiting): A Phase 2 trial of 300 participants is being conducted to determine the efficacy and safety of convalescent plasma compared with receiving sodium lactate or saline solution (NCT04364737).
• Brigham and Women’s Hospital (Recruiting): Investigators are examining how high-titer convalescent plasma from recovered COVID-19 patients performs against standard plasma in a group of 200 participants (NCT04361253).
• Cedars-Sinai Medical Center (Recruiting): In collaboration with Johns Hopkins, researchers are testing whether multiple doses of convalescent plasma could help COVID-19 patients in intensive care receiving mechanical ventilation (NCT04353206).
• Johns Hopkins (Not Recruiting): Researchers are leading three of their own trials involving convalescent plasma, evaluating its potential for prophylaxis (NCT04323800), the effects of treating children exposed to or infected with COVID-19 (Recruiting; NCT04377672), and its ability to reduce COVID-19 related complications and mortality (NCT04373460).
• Baylor Research Institute (Not Recruiting): A team is examining whether convalescent plasma fares better than receiving oxygenation in a phase 1 trial (NCT04333251).
• Stanford University (Not Recruiting): Researchers are examining the effects of convalescent plasma on reducing COVID-19 respiratory symptoms compared with standard plasma (NCT04355767).
• Stony Brook University (Invitation): Convalescent plasma is being tested against standard donor plasma in a phase 1/2 randomized trial of 500 participants, with a primary outcome of number ventilator-free days at day 28 (NCT04344535).

Outcome: A medRxiv pre-print paper analyzing safety data from 5,000 hospitalized adults indicated convalescent plasma appears safe for use. In the first peer-reviewed study of convalescent plasma, 19 of 25 patients (76%) with severe COVID-19 who received convalescent plasma saw at least 1 point of clinical improvement based on WHO’s ordinal scale measuring illness severity. A randomized clinical trial of 103 patients with severe COVID-19 published in JAMA by researchers from China showed a non-significant clinical improvement in 51.9% of patients compared with improvement in 43.1% of patients who received standard treatment (P = .26). However, the trial was halted early due to the decrease in COVID-19 patients in China during the study period, which could have contributed to the study being underpowered to detect a clinically significant result.
Regulatory actions: On 24 March, the FDA allowed the use of convalescent plasma from recovered cases of COVID-19 for patients with “serious or immediately life-threatening COVID-19 infections under an emergency investigational new drug (eIND) application. On 9 April, healthcare company Grifols announced they were partnering with BARDA to create a COVID-19 treatment based on convalescent plasma.
 
Drug: Favilavir/Avifavir
Medication class: Antiviral agent
Manufacturer/Distributor: Fujifilm Toyama Chemical (as Avigan) and Zhejiang Hisun Pharmaceutical
Approved Indication: Favilavir is approved in China and Italy to treat COVID-19. Avifavir, a generic form of Avigan, has been approved to treat COVID-19 in Russia.
Rationale: Reports from officials in China have said favilavir (formerly called fapilavir) is clinically effective against COVID-19.
Trials: There are six trials in China evaluating favilavir against other antivirals such as baloxavir and marboxil in patients with COVID-19. Fujifilm on 31 March announced a phase III clinical trial to evaluate the safety and efficacy of Avigan in Japan for patients of COVID-19. In Canada, Appili Therapeutics announced they are conducting a Phase 2 trial of favilavir with 760 participants in long-term care facilities, which includes both residents and staff. A 330-person trial of avifavir in Russia is ongoing.
Outcome: Recent data appears to show lack of efficacy of favilavir in treating COVID-19. A study published in the pre-print server medRxiv of 240 patients that evaluated favilavir against the influenza drug umifenovir (brand name Arbidol) showed neither drug was more effective at improving the clinical recovery rate of patients. Interim data from Japan suggested the favilavir was not effective in treating mild or moderate cases of COVID-19, according to independent reporting from Kyodo News.
Status: The earliest completion dates for the trials are in late April. The Russian Direct Investment Fund (RDIF) is planning to 60,000 courses of Avifavir to Russian hospitals in June.

Drug: Lopinavir-ritonavir (Kaletra)
Medication class: HIV protease inhibitor
Developer: AbbVie
Approved US Indication: Lopinavir-ritonavir is indicated in combination with other antiretrovirals to treat HIV-1 infection in adults and in pediatric patients 14 days and older.
Rationale: Lopinavir-ritonavir has been effective against SARS, showing in vitro activity against the disease in a 2004 study. Countries hard hit by COVID-19, such as Italy, have recommended the drug combination as a treatment for the novel coronavirus.
Trials: High-profile trials of lopinavir-ritonavir are evaluating the drug alone and in combination with other COVID-19 therapeutic candidates.

• Tongji Hospital (Recruiting): A Phase 4 randomized controlled trial of lopinavir-ritonavir is evaluating the drug against arbidol hydrochloride and oseltamivir (NCT04255017).
• A study in South Korea is pitting lopinavir-ritonavir against hydroxychloroquine in patients with mild cases of COVID-19 (NCT04307693),
• Lopinavir-ritonavir alone and in combination with interferon-beta are two arms of the WHO SOLIDARITY trial.
• The UK-based RECOVERY trial is also evaluating lopinavir-ritonavir in one of its treatment arms.

Outcomes: Findings are beginning to indicate that lopinavir-ritonavir may not result in clinical improvement from COVID-19.

• Evidence for use: A study published in The Lancet of 127 patients randomized 2:1 to receive a combination of interferon beta-1b, lopinavir–ritonavir and ribavirin, or lopinavir–ritonavir alone and found the combination therapy was more effective than treating with lopinavir–ritonavir on its own.
• Evidence showing no benefit: A randomized, controlled trial published in the New England Journal of Medicine showed no therapeutic benefit for lopinavir-ritonavir in patients with cases of severe COVID-19. After publication of this trial, some researchers have noted clinicians have stopped using the therapy. A journal pre-proof study by researchers from Guangzhou Medical University in China published in the journal Med found no difference in COVID-19 outcomes between 34 patients who received lopinavir-ritonavir, 35 patients who received arbidol and 17 patients who took no antiviral medication. “Our findings suggest that we need to cautiously consider before using these drugs,” the researchers said in a press release.

Status: The trial from researchers in South Korea is expected to be completed in May. The Tongji Hospital study is expected to be completed by July. Trial completion dates of the studies based in China vary, with the earliest completion dates listed in late April. SOLIDARITY is currently recruiting.
 

Novel candidates

Drug: EIDD-2801
Medication class: Oral broad-spectrum antiviral
Developer: Drug Innovation Ventures at Emory (DRIVE), Ridgeback Biotherapeutics, Merck
Rationale: The antiviral has shown effectiveness against infections such as influenza, chikungunya, Ebola and equine encephalitis. It has a similar mechanism of action to remdesivir and prevents replication of the virus. In animal models, EIDD-2801 inhibited the replication of SARS-CoV-2 and MERS, according to a recent paper.
Regulatory actions: On 8 April, the FDA authorized use of EIDD-2801 for COVID-19 under an investigative new drug (IND) application. On 13 April, MHRA cleared EIDD-2801 for human testing. 
Status: Emory is launching a clinical trial evaluating EIDD-2801 in humans. The trial is expected to begin in late May. On 26 May, Merck announced it had entered into an agreement with Ridgeback Biotherapeutics to co-develop EIDD-2801 and related molecules.

Drug: Mavrilimumab
Medication Class: Monoclonal antibody
Developer: Kiniksa Pharmaceuticals
Rationale: The potential treatment is designed to antagonize GM-CSF signaling by binding to the alpha subunit of the GM-CSF receptor (GM-CSFRα). Kiniksa’s lead indication for mavrilimumab is giant cell arteritis. 
Trial: Italian physicians have run a single-active-arm, single-center pilot study.
Study Design: The Italian investigators are evaluating mavrilimumab in a prospective, single-center investigator-initiated study based on the initial results from the treatment protocol. The primary objective is prevention of respiratory failure.
Outcome: Six patients were treated with mavrilimumab as of 31 March, according to Kiniksa. All experienced early resolution of fever and improved oxygenation within one to three days. None had required mechanical ventilation as of that time. On 11 May, Kiniksa released new details about the Italian trial, which showed mavrilimumab increases time and level of clinical improvement in COVID-19 patients, with 11 of 13 patients (85%) experiencing improvement compared with 11 of 26 patients (42%) in a control group.
Status: A consortium of US academic sites is initiating parallel prospective, interventional studies with mavrilimumab in patients with severe COVID-19 pneumonia and hyperinflammation. Kiniksa said it is engaging with FDA regarding the path forward for potential Phase 2/3 clinical development of mavrilimumab in COVID-19 pneumonia. The company announced that it would present positive trial results on mavrilimumab at the EULAR 2020 e-Congress.

Drug: CD24Fc
Medication class: Recombinant fusion protein
Developer: OncoImmune
Original proposed indication: CD24Fc was recently part of a Phase 2 trial and is currently being evaluated in a Phase 3 trial for the prophylactic treatment of graft-versus-host disease (GVHD) in leukemia patients receiving hematopoietic stem cell transplantation.
Rationale: The recombinant fusion protein targets a novel immune pathway checkpoint and modulates immune response through binding to Danger-Associated Molecular Patterns (DAMPS) and sialic acid-binding immunoglobulin-type lectins (Siglecs). The developers of CD24Fc believe it can be an effective non-antiviral biological modifier in COVID-19 because of it also showed reduction of multiple inflammatory cytokines in animal models.
Trials: OncoImmune is preparing a randomized, placebo-controlled, double-blind, multicenter, Phase 3 trial of COVID-19 patients with absolute lymphocyte counts ≤ 800/mm³ in peripheral blood (NCT04317040).
Status:  On 8 April, OncoImmune announced it had received authorization from the FDA to begin a 230-person trial.
 
Drug: Lenzilumab
Medication class: Anti-human GM-CSF monoclonal antibody
Developer: Humanigen
Original proposed indication: Lenzilumab has been shown to have a protective effect against cytokine release syndrome (CRS) associated with CAR-T therapy. It’s believed that lenzilumab can aid cytokine-mediated immunopathology of lung injury and ARDS. On 2 April, FDA authorized use of lenzilumab in COVID-19 patients under an eIND application.
Trials: Humanigen is planning a multicenter, Phase 3, randomized, double-blinded, controlled, clinical trial with lenzilumab for the prevention of ARDS in patients with pneumonia associated with COVID-19.
Status: On 15 April, Humanigen announced it had received FDA clearance to begin a Phase 3 trial of patients with COVID-19. Humanigen said it had dosed its first patient in the Phase 3 trial on 7 May.
 
Drug: Leronlimab
Medication class: Humanized IgG4 monoclonal antibody
Developer: CytoDyn (as PRO 140)
Original proposed indication: Leronlimab has received FDA fast track designation for use with carboplatin to treat CCR5-positive metastatic triple-negative breast cancer and in combination with highly active antiretroviral therapy (HAART) in HIV.
Rationale: Leronlimab is a CCR5 antagonist that blocks the CCR5 co-receptor on the surface of immune cells like CD4 cells. It is believed that leronlimab can enhance the immune response in patients experiencing CRS from respiratory distress caused by COVID-19.
Trials: CytoDyn is planning two clinical trials evaluating leronlimab in patients with mild to moderate and severe cases of COVID-19. In the trial of severe COVID-19 cases, announced on 1 April, CytoDyn aims to enroll 342 patients and administer leronlimab or placebo for 2 weeks with a primary endpoint of 14-day mortality. Another trial in collaboration with the Mexican National Institutes of Health is also planned.
Outcome: FDA authorized use of leronlimab in COVID-19 patients under an eIND. Patients treated under the eIND have a lower level of cytokine storm and lower levels of IL-6 and TNF-alpha. A pre-print of results from the trial evaluating severely or critically ill COVID-19 patients showed leronlimab was effective at reducing IL-6 expression and in reversing immunosuppression, which led to a lower plasma viral load.
Status: A Phase 2b trial has enrolled 15 patients with mild-to-moderate COVID-19 and one patient with severe disease has been treated in a Phase 2b/3 trial, CytoDyn announced 15 April. On 30 April, CytoDyn’s CEO noted that 49 patients treated with leronlimab under eIND were responding “extremely well” and expects publication of their first results shortly.
 
Drug: Gimsilumab
Medication class: Human monoclonal antibody
Developer: Roivant Sciences
Rationale: Gimsilumab targets the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF), which researchers have seen elevated in the blood of patients with COVID-19 and may be associated with acute respiratory distress syndrome in these patients.
Trials: Roivant has announced their randomized, double-blinded, placebo-controlled BREATHE trial (NCT04351243) will evaluate the efficacy of intravenous gimsilumab in 270 patients with COVID-19 with ARDS or lung injury.
Status: On 15 April, Roivant announced the first patient in the trial had been treated. On 13 May, Roivant said they would allow participants in the BREATHE trial to use convalescent plasma or antiviral agents like remdesivir in addition to receiving gimsilumab or placebo.
 
Drug: Otilimab
Medication class: Monoclonal antibody
Developer: MorphoSys (licensed by GSK)
Rationale: Otilimab is an anti-GM-CSF antibody developed and currently being evaluated for rheumatoid arthritis. GSK has identified the drug as a potential candidate for COVID-19 treatment in patients who experience CRS.
Trials: GSK is sponsoring the randomized Phase 2 OSCAR trial of 800 participants with COVID-19 who will receive standard of care plus either a single IV infusion of otilimab or placebo (NCT04376684).
Status: The trial is currently recruiting, and is expected to begin by the end of May, according to GSK.
 
Therapeutic: INOpulse
Medication class: Nitric oxide
Developer: Bellerophon Therapeutics, Inc.
Rationale: Inhaled nitric oxide has been explored as a treatment for COVID-19 patients due to its success in improving arterial oxygenation in patients with ARDS due to SARS-CoV. Results from patients treated with INOpulse under an emergency expanded access program have proved promising, the company said.
Regulatory Actions: FDA allowed INOpulse for compassionate use in COVID-19 patients on 20 March.
Trials: Bellerophon is performing a Phase 3 randomized, placebo-controlled trial to evaluate the safety and efficacy of INOpulse in up to 500 COVID-19 patients where supplemental oxygen is needed prior to a patient requiring mechanical ventilation support. The primary endpoints are respiratory failure and mortality of patients in both groups.
Status: The FDA approved an IND for the therapy on 11 May, greenlighting a Phase 3 trial.
 

Therapeutics approved for other indications

Drug: Ivermectin
Medication class: Antihelmintic
Discoverer: Kitasato Institute; Merck
Approved US Indications: Intestinal strongyloidiasis and onchocerciasis (tablets), lice and rosacea (topical)
Rationale: Ivermectin has been proven effective in vitro of inhibiting SARS-CoV-2 within 48 hours of treatment with a 5,000-fold reduction in the virus, according to a paper published in Antiviral Research.
Trials: Japan plans to test ivermectin against COVID-19 in a clinical trial, according to Prime Minister Shinzo Abe reported in Pharma Japan.
Status: No other details have been released at this time.

Drug: Tocilizumab
Medication class: Interleukin-6 (IL-6) receptor antagonist
Developer: Roche (as Actemra)
Approved US Indications: Tocilizumab is indicated for to treat moderately to severely active rheumatoid arthritis in adults where one or more DMARDs have provided adequate response; to treat giant cell arteritis in adults; to treat active polyarticular juvenile idiopathic arthritis (JIA) in patients age 2 years or older; to treat systemic JIA in patients age 2 years and older; and to treat CRS in patients age 2 years or older who have severe or life-threatening CRS induced by chimeric antigen receptor T-cell (CAR-T) treatment.
Rationale: Research from China has shown tocilizumab may be an effective treatment for patients with severe cases of COVID-19.
Trials: Roche is launching a randomized, controlled Phase 3 trial (COVACTA) to evaluate tocilizumab’s effectiveness in severe COVID-19 cases (NCT04320615). The Hôpitaux de Paris is also evaluating 228 participants with COVID-19 associated pneumonia in a randomized parallel-assignment trial where patients receive tocilizumab 8mg/kg D1 or standard of care (NCT04331808).
Outcomes: Evidence is beginning to point to tocilizumab having a beneficial outcome for COVID-19 patients in some, but not all, scenarios.
 

• Evidence for benefit: Preliminary results from CORIMUNO-19 of 129 patients randomized to tocilizumab or placebo showed the drug “improves significantly clinical outcomes” of pneumonia associated with COVID-19, according to a press release. In a paper published in the pre-print server medRxiv, tocilizumab was associated with a 45% reduction in mortality and improved clinical outcome compared with patients who did not receive the therapy.
• Evidence showing no benefit: In Italy, 65 patients in the COVID-BioB Study who received tocilizumab instead of standard of care had improved clinical outcomes (69% vs. 61%; P = .61) and reduced mortality (15% vs. 33%; P = .15), but neither result was statistically significant. Results posted in medRxiv by researchers at the University of North Carolina, Chapel Hill, of 11 patients with severe COVID-19 requiring ventilation showed tocilizumab reduced C-reactive protein levels but did not result in significant improvement in temperature and oxygen requirements. The researchers cautioned against using tocilizumab in severe cases of COVID-19 based on the results.

Status: COVACTA is active, but not currently recruiting.

Drug: Sarilumab
Medication class: IL-6 receptor antagonist
Developer: Sanofi and Regeneron (as Kevzara)
Approved US Indication: Sarilumab in indicated to treat moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to one or more DMARDs.
Rationale: Sarilumab is being evaluated for its potential benefit in reducing the inflammatory response in the lungs among patients with COVID-19 who develop acute respiratory distress syndrome.
Trials: A Phase 2/3 trial of 400 patients sponsored by Sanofi and Regeneron is currently underway in the United States. A second, Phase 2/3 trial is being conducted in Italy, Spain, Germany, France, Canada and Russia.
Outcome: Preliminary data from an Italian paper in the pre-print server medRxiv indicates sarilumab may be a promising treatment for COVID-19, but concomitant administration of other treatments does not make it clear whether it was sarilumab that provided the benefit. Sarilumab was given to 53 patients in the study, but 50 patients (94.3%) received hydroxychloroquine, 45 patients (74.9%) had received a prophylactic dose of heparin, 37 patients (69.8%) received darunavir/ritonavir, 29 patients (54.7%) received azythromicin, and 13 patients (24.5%) received lopinavir/ritonavir. The authors said 83% of patients had clinical improvement after administration.
Status: Both trials are currently recruiting. On 30 March, Regeneron and Sanofi announced that the first patient in their trial outside the US had been treated. Results from the Phase 2 portion of the Regeneron trial released by the company on 27 April showed sarilumab was not effective in treating severe COVID-19 cases or critical cases requiring a ventilator. After a review by the Independent Data Monitoring Committee, Regeneron plans to continue the trial with critical cases only and discontinuing the lower-dose treatment arm (200 mg) in favor of the higher-dose arm (400 mg).

Drug: Canakinumab
Medication class: Human monoclonal antibody
Developer: Novartis (as Ilaris)
Approved Indications: Treatment of cryopyrin-associated periodic syndromes (FDA, European Medicines Agency); tumor necrosis factor receptor associated periodic syndrome, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, familial mediterranean fever (FDA)
Rationale: Canakinumab is a monoclonal antibody that targets interleukin (IL)-1β. Two studies published in The Lancet of COVID-19 showed patients had elevated levels of IL-1β and other cytokines during cytokine storm syndrome.
Trials: Novartis is conducting the Phase 3 CAN-COVID trial to evaluate whether canakinumab can treat cytokine storm syndrome in patients with COVID-19. The company plans to enroll 450 patients from France, Germany, Italy, Spain, UK and the US.
Status: Novartis expects results from the trial by “mid-summer,” according to a company press release.
 
Drug: Ravulizumab
Medication class: Human monoclonal antibody
Developer: Alexion (as Ultomiris)
Approved Indications: Paroxysmal nocturnal hemoglobinuria (FDA)
Rationale: Ravulizumab is C5 complement inhibitor originally engineered from eculizumab to have a longer-lasting half-life and longer intervals between dosing for treatment of paroxysmal nocturnal hemoglobinuria. Preclinical data of animal models published in the open-access journal mBio suggested the treatment lowers cytokine and chemokine levels in viral pneumonia. Alexion said patients with COVID-19 accessing eculizumab through compassionate use programs also have shown some clinical benefit.
Trials: Alexion is conducting a Phase 3 global study of 270 patients with COVID-19 hospitalized with severe pneumonia randomized to receive weight-based loading dose of ravulizumab followed by a weight-based dose on day 5 and day 10, and a 900-mg dose on day 15.
Regulatory Actions: The FDA has approved an IND for ravulizumab to treat patients with severe COVID-19, according to a company press release.
Status: The trial is slated to begin in May 2020.
 
Drug: Acalabrutinib
Medication class: Kinase inhibitor
Developer: AstraZeneca (as Calquence)
Approved indication: Mantle cell lymphoma (MCL) for patients who have received at least one prior therapy and chronic lymphocytic leukemia (CLL) in the US.
Rationale: Acalabrutinib inhibits the enzyme Bruton’s tyrosine kinase (BTK). The BTK pathway has been implicated in TNF-alpha, IL-6, IL-10, and MCP-1 production and early data from the CALAVI trial has shown that acalabrutinib is effective in reducing respiratory distress caused by COVID-19.
Trials: AstraZeneca is testing whether 428 participants in the CALAVI trial with COVID-19 and respiratory distress respond to standard of care with and without acalabrutinib (NCT04346199).
Status: The trial is not currently recruiting, and no other information has been released at this time.
 
Drug: Dapagliflozin
Medication class: Oral sodium-glucose co-transporter 2 (SGLT2) inhibitor
Developer: Bristol-Myers Squibb (as Farxiga)
Approved Indication: Type 2 diabetes; heart failure with reduced ejection fraction
Rationale: Dapagliflozin is primarily used to treat type 2 diabetes by promoting glucosuria. In the DECLARE CV trial, the drug was associated with a lower rate of heart failure resulting in hospitalization and cardiovascular death. Other trials have shown dapagliflozin also has kidney-protective effects.
Trials: AstraZeneca is evaluating dapagliflozin in a Phase 3 trial of 900 participants with COVID-19 and comorbid conditions such as hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and/or stage 3-4 chronic kidney disease (NCT04350593).