The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. HHS signed an Agreement with Gilead for 500,000 treatment courses of remdesivir on 6/29/2020. This represents 100% of July production, 90% of August production and 90% of September production. The U.S. The Department of Health and Human Services will control distribution through AmerisourceBergen and hospitals will pay no more than WAC for the drug. The government will tell AmerisourceBergen how many vials can be shipped to a state. The department of health in each state will direct the wholesaler to deliver doses to the hospitals with the highest number of inpatient COVID-19 cases. The initial supply from the Federal Stockpile of 5 million doses were exhausted at the end of June 2020. HHS will stop managing distribution of remdesivir at the end of September, when supplies are expected to stabilize.
Gilead has set AWP for remdesivir (Veklury) at $520 per vial or $3,120 for five days of treatment. This is the price for private insurance patients in the U.S. The U.S. government price for Medicaid and military hospitals is $390 per vial or $2,340 for a five-day course of treatment. This is also the price for developed countries. Pricing for remdesivir is more aligned with estimates from ICER that take into account the potential effect of dexamethasone. Gilead has entered into agreements with generic manufacturers to make the drug available at a substantially lower cost to developing countries, where healthcare resources, infrastructure and economics are lower.
The National Institute of Health recommends use of dexamethasone 6 mg daily for up to ten days in COVID-19 patients the require supplemental oxygen with or without mechanical ventilation. NIH recommends against using dexamethasone in patients that do not require supplemental oxygen. The recommendation is based on data presented from the RECOVERY trial. The WHO recommends that dexamethasone only be used in patients with severe or critical disease.
Sanofi expects to initiate a Phase I/II trial in September 2020, with potential approval in the first half of 2021. Sanofi also signed an agreement with Translate Bio for an mRNA vaccine. A Phase I trial is expected to begin by the end of 2020.
Sinopharm is initiating a Phase III trial, with an unspecified number of patients, in the United Arab Emirates.
Moderna signed an agreement with Catalent to increase capacity for filling vials and packaging doses.
ICER revised its preliminary pricing review for remdesivir on 6/24/2020. ICER has provided two pricing estimates. One is a cost recovery pricing estimate, based on a review of the cost of producing the final finished product and estimated development costs. ICER estimated a cost recovery price of $1,600 for a 10-day course of treatment. Using a threshold price of $50,000 per incremental quality-adjusted life year (and equal value of a life-year gained) and the benefits seen in the Adaptive COVID-19 Treatment Trial (ACTT), ICER estimated a cost-effective price of $4,580 to 5,080 for a 10-day course of remdesivir. ICER also estimated the effect that dexamethasone would contribute and estimated a lower cost-effectiveness price of $2,520 to $2,800 based on non-peer reviewed data from the RECOVERY trial.
In the 105 patient, Phase II, open-label, GRECCO-19 trial (NCT04326790), fewer patients treated with colchicine plus standard of care had a deterioration of 2 points on a 7-grade scale, ranging from able to resume normal activities to death, compared to only standard of care (1.8% vs 14%) in Greek patients hospitalized with COVID-19. The deterioration in the control groups was mainly due to an increased need for mechanical ventilation. Standard of care included hydroxychloroquine or chloroquine plus azithromycin in most patients with some patients also receiving lopinavir, ritonavir, tocilizumab or anticoagulation. There was no difference between groups in peak troponin levels or C-reactive protein, but colchicine did produce a reduction in dimerized plasma fragment D levels, which suggests a possible antithrombotic effect.
An article posted on an editorial server describes compassionate use of opaganib in Israel for the treatment of severe COVID-19 (NCT04435106) in five patients and compared the results to an investigator-selected matched case-control group of 18 patients. All opaganib-treated patients were discharged on room air and none required ventilation, while 33% of standard care patients required mechanical ventilation. All patients in both groups received hydroxychloroquine and most also received azithromycin.
Redhill Biopharm is initiating a 40 patient, Phase IIa U.S. trial (NCT04414618) that will evaluate opaganib in treatment of patients with severe COVID-19 pneumonia requiring hospitalization and supplemental oxygen. Redhill is also planning a European, 270 patient, Phase II/III trial.
In a 544 patient, retrospective Italian study, treatment with tocilizumab reduced the risk of mechanical ventilation or death, but had a higher incidence of new infections compared to standard of care alone after the patient sample was adjusted for sex, age, recruiting center, duration of symptoms, and Sequential Organ Failure Assessment (SOFA) score. Standard of care in Italy at the time of the study (February 21 to April 30, 2020) included treatment with oxygen, hydroxychloroquine, azithromycin, lopinavir–ritonavir or darunavir–cobicistat, and low molecular weight heparin.
Ridgeback Biotherapeutics is developing EIDD-2801, an oral nucleoside analog that inhibits the replication of RNA viruses such as influenza and coronaviruses. In May, Ridgeback licensed manufacturing and development to Merck. Pending approval of the licensing deal with Merck, Ridgeback is moving forward with development.
Gilead is evaluating remdesivir administered as an inhalation in a Phase I study in healthy volunteers and hopes to initiate a COVID-19 patient trial in August 2020, with this formulation.
NIH discontinued the ORCHID study in June 2020. The Orchid trial was evaluating hydroxychloroquine as a treatment for hospitalized patients with COVID-19. The discontinuation was recommended by the data and safety monitoring board after an interim analysis of data from 470 patients indicated that while hydroxychloroquine was safe, it was unlikely to demonstrate a beneficial effect.
You can get an early look at the dexamethasone data from the RECOVERY trial in a draft of the paper that is available on an editorial server.
Regeneron scientists published an article describing the development of resistance to antibodies for the spike protein that potently neutralizes SARS-CoV-2. During in vitro testing mutations rapidly appeared in the presence of individual antibodies or combinations of antibodies with overlapping binding regions for the spike protein, causing the antibodies to lose activity. However, when antibody combinations with non-competing binding sites were used, resistance to the combination did not develop.
Grifols began to manufacture hyperimmune immunoglobulin for COVID-19 in the U.S. in June. Grifols is working with the FDA and NIH to use initial supplies to validate a manufacturing process, preclinical testing, and then move to clinical testing. Grifols is also working on setting up collection and manufacturing in Europe.
Lilly will evaluate baricitinib (Olumiant) as a treatment for cytokine storm in mild, moderate, and severe COVID-19 patients in a 400 patient, Phase III, COV-BARRIER trial (NCT04421027). The primary endpoint of the trial will be the number of patients on a ventilator or who die at 28-days. Baricitinib in combination with remdesivir is also being evaluated in an NIAID, 1,000 patient, Phase III ACTT 2 trial (NCT04401579).
The 11,500 patient RECOVERY trial has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, and convalescent plasma. An analysis of 6,425 patients enrolled in the dexamethasone arm found that 10-days treatment with dexamethasone 6 mg (2,104 patients) reduced mortality by 35% in patients on ventilators and 20% in non-ventilator patients that required oxygen compared to supportive care only (4,321). No mortality benefit was found in patients that did not require oxygen. The WHO recommended that dexamethasone only be used in patients with severe or critical disease.
Humanigen is testing lenzilumab, an anti-human GM-CSF monoclonal antibody, as a treatment for severe COVID-19 pneumonia. An unpublished, unedited article described 12 patients with severe COVID-19 pneumonia treated under an FDA emergency IND with lenzilumab. Treatment with lenzilumab resulted in at least a 2-point improvement in an 8-point scale (death to discharged) in 11/12 of patients. Humanigen is evaluating lenzilumab as a treatment for immune-mediated cytokine release syndrome in patients with severe COVID-19 pneumonia in a 238 patient, Phase III trial (NCT04351152).
PTC299, a dihydroorotate dehydrogenase (DHODH) inhibitor that is being developed by PTC Therapeutics as a treatment for acute myeloid leukemia. PTC299 has been shown in vitro to inhibit replication of the SARS-CoV-2 virus and modulate the immune response by attenuating the stress-induced inflammatory cytokine storm.
The WHO removed hydoxychloroquine and chloroquine as treatments in the multi-national SOLIDARITY COVID-19 trial on June 17, 2020.
Mavrilimumab is a granulocyte macrophage colony stimulating factor antagonist, being developed by MedImmune for the treatment of rheumatoid arthritis. Mavrilimumab is being evaluated as treatment for COVID-19 pneumonia due to its anti-inflammatory actions. In a 28-day, 39 patient trial, all patients treated with mavrilimumab (n=13) plus hydroxychloroquine, azithromycin and lopinavir–ritonavir improved by two or more points (7-point scale of death to discharge) compared to 65% treated with hydroxychloroquine, azithromycin and lopinavir–ritonavir without mavrilimumab (n=26) in non-ventilated patients with COVID-19 pneumonia and systemic hyperinflammation.
Gilead is evaluating the safety, tolerability, pharmacokinetics, and efficacy of remdesivir in a single-arm Phase II/III trial (NCT04431453) in 50 pediatric patients with moderate-to-severe COVID-19, including newborns through adolescents.
Italian researchers announced that in a 123 patient trial, treatment with tocilizumab did not reduce admission to intensive care (28.3% vs. 27.0%) or 30-day mortality (3.3% vs. 3.2%) compared to placebo in patients with early-stage COVID-19 pneumonia.
Lilly is co-developing two monoclonal antibody products with partners. Lilly estimates it could have an emergency use authorization for one of the products as soon this fall.
Hydroxychloroquine and Chloroquine
In 28-day, 150 patient, Chinese trial, the addition of hydroxychloroquine to standard of care treatment did not result in negative conversion of PCR viral tests compared to standard of care in patients hospitalized with mild to moderate COVID-19. Initiation of hydroxychloroquine was delayed with an average 16-days between symptom onset and drug administration. Standard of care included antivirals in half of patients. So, given the delayed initiation of the drug and high use of antivirals, it is difficult to use the information provided in this study.
In a 21-day, 173 patient French retrospective analysis, hydroxychloroquine given within 48 hours of hospital admission did not reduce ICU admission or death compared to standard of care (76% vs 75%). The analysts used propensity scores to control for potential confounding variables. The study was performed in hospitalized French patients with a moderate COVID-19 requiring oxygen. No patients in the study received antivirals or anti-inflammatory treatments, including NSAIDs, steroids or biologics such as tocilizumab.
Researchers at Oxford announced results from the hydroxychloroquine arm of the RECOVERY trial. The 11,000 patient RECOVERY trial has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab and convalescent plasma. An interim analysis of 4,674 patients enrolled in the hydroxychloroquine arm found no decrease in mortality at 28-days compared to supportive care (25.7% vs 23.5%). Due to the lack of benefit, the researchers discontinued enrollment in the hydroxychloroquine arm of the trial.
Hydroxychloroquine and Chloroquine
A retrospective analysis of 96,032 patients from the proprietary Surgisphere multinational database of information from electronic health records, supply chain databases, and financial records compared patients that received chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide to patients who received none of these treatments. The analysis found no benefit for chloroquine or hydroxychloroquine with or without a macrolide and the data suggested an increase in morbidity due to a higher incidence of arrhythmias. Due to the analysis of this trial, the WHO put a hold on the hydroxychloroquine arm of the trial for a safety review. The analysis was published in the journal Lancet. The Lancet editors issued an open letter to the authors of the analysis questioning the data integrity, highlighting flaws in the data aggregation and inadequate adjustment of confounders. They also pointed out the consequences of using a widely reported article on treatment decisions, clinical trials and public health policy. Information from the same database was used in an analysis of the safety of antihypertensive use in COVID-19 patients and published in the New England Journal of Medicine. The editors of NEJM published a similar letter of concern. After examining the concerns about the Lancet study, the WHO restarted the hydroxychloroquine arm of the study. Both NEJM and Lancet have asked to review the Surgisphere database and methods used to extract, store and retrieve data. In a response, Surgisphere has agreed to an independent academic audit to validate where the data comes from, the database, and the statistical analysis required for the two studies. Both the study published in Lancet and in NEJM have been retracted, because all authors of each article were not granted access to the full data set for either study.
In a 14-day, 821 patient trial, prophylactic use of hydroxychloroquine did not reduce the incidence of infection compared to placebo (11.8% vs 14.3%) in healthy patients exposed to a known or suspected COVID-19 patient. An NEJM editorial points out inconsistent proof of exposure and confirmation of the development of infection. The prophylaxis regimen was initialed three days or later after exposure, which could have also decreased efficacy.
In a 28-day, 103 patient Chinese trial, treatment with convalescent plasma did not lead to a statistical difference in clinical improvement (discharge or reduction in severity) compared to placebo (51.9% vs 43.1%) in patients with severe or critical COVID-19 infection. An editorial in JAMA pointed out that patients with severe COVID-19 demonstrated clinical improvement (91.3% vs 68.2%) but not patients with critical infection (20.7% vs 24.1%).
Anti-inflammatories and cytokine storm prevention
CTI Biopharma is evaluating pacritinib for the treatment of severe COVID-19 in the 28-day, 358 patient, Phase III PRE-VENT trial.
Operation Warp Speed, a U.S. program designed to rapidly accelerate the development and availability of a vaccine for COVID-19, has chosen five vaccines they consider having the best chance to succeed. The vaccines chosen are being developed by Moderna (currently in Phase II), AstraZeneca (currently Phase II), Pfizer (currently in two Phase I/II trials) and vaccines in pre-clinical development from Johnson & Johnson and Merck.
The FDA has created a resource page of COVID-19 information for health care professionals. The page will be continuously updated and include information on emergency use authorizations, personal protective equipment, and medical products, including investigational drugs and fraudulent devices.
Gilead announced that in the first 585 patients enrolled in an 11-day, Phase III trial (NCT04292730), patients treated with a 5-day course of remdesivir were 65% more likely to have at least a 1-point improvement on a seven-point scale that runs from death to not hospitalized in hospitalized patients with moderate COVID-19. A 10-day course of remdesivir did not differ from placebo in the treatment of moderate COVID-19 patients.
Lilly initiated a Phase I trial to evaluate a single dose of LY-CoV555 as a treatment for hospitalized COVID-19 patients at the beginning of June. Results are expected by the end of June and positive results will lead to a Phase II trial. LY-CoV555 is a neutralizing IgG1 monoclonal antibody targeting the spike protein of SARS-CoV-2. AbCellera and NIAID identified the antibody from a COVID-19 patient and Lilly developed a way to produce the antibody.
Moderna initiated a 600 patient, Phase II trial in late May. Patients will be given two doses 28-days apart of mRNA-1273 vaccine low dose (50 micrograms), high dose (100 micrograms) or placebo. Half of the patients enrolled in the trial will be older than 55. The Phase III trial is expected to begin in July 2020. Moderna hopes to file a BLA for mRNA-1273 in early 2021.