Pfizer and BioNTech initiated a Pfizer funded, 30,000 patient, Phase II/III trial for vaccine candidate BNT162b2 (one of four in development) on July 27. BNT162b2 will be administered as two 30 mcg immunizations. The vaccine elicited neutralizing antibodies in older adults (65-85 years of age) greater than the level seen in a panel of 38 recovered COVID-19 patients.
Moderna and NIAID initiated an NIAID funded, 30,000 patient, Phase III trial (NCT04470427) for COVID-19 vaccine candidate mRNA-1273 on July 27. The vaccine will be administered as two 100 mcg immunizations given 28 days apart.
AstraZeneca is evaluating its COVID-19 vaccine, AZD1222, in a 2,000 patient, Phase I/II trial in South Africa (NCT04444674) and in a 10,260 Phase II/III trial in the U.K (NCT04400838).
Johnson & Johnson initiated a 1,000 patient, Phase I/IIa trial (NCT04436276) on July 22 in the U.S. and Belgium with initial results expected in September.
COVID-19 Vaccine Pricing: Pfizer plans to price the two dose COVID-19 vaccine regimen at a minimum of $19.50 per dose or $39 for the two dose course of immunizations for the additional 500 million doses the U.S. can purchase under an Agreement. The price will be the same for other developed countries that make the same volume commitment. AstraZeneca and Johnson & Johnson have agreed to sell their vaccines near cost and may be charging as low as $3 per dose. Moderna may price the two dose COVID-19 vaccine regimen at $50 to $60. However, given the pricing from other companies, they will likely charge a lower price.
Roche announced that in the BARDA sponsored 28-day, 450 patient, Phase III COVACTA trial (NCT04320615), treatment with tocilizumab did not improve clinical status ventilator-free days or mortality compared to placebo in hospitalized patients with severe COVID-19-associated pneumonia. Patients treated with tocilizumab were discharged sooner than those in the placebo group (20 vs 28 days).
NIAID is comparing lenzilumab plus remdesivir to remdesivir monotherapy on the need for mechanical ventilation in hospitalized patients with COVID-19, in the 28-day, 200 patient, BIG EFFECT trial (NCT04351152).
New Dedicated COVID-19 Antibody Page
Check out the status of COVID-19 monoclonal antibodies under development from AstraZeneza, Lilly, Regeneron and Vir on our new Blood-Derived Products Under Evaluation or the Treatment of COVID-19 web page.
HHS and the BARDA awarded Pfizer and BioNTech $1.95 billion for the first 100 million doses of their experimental COVID-19 vaccine as part of operation Warp Speed. The U.S. government also has an option for an additional 500 million doses.
Novavax signed an agreement with Fujufilm Diosynth Biotechnologies to manufacture the Novavax COVID-19 vaccine NVX-CoV2373. Novavax expects to announce the results of its Phase I trial in early August and begin the Phase II trial in mid-August. A 30,000 patient Phase III trial is expected to begin in the fall.
Glenmark Pharmaceuticals announced that in a 150 patient, open-label, Indian Phase III trial, treatment with favipiravir added to supportive care resulted in 28.6% faster viral clearance and a 40% faster attainment of clinical cure compared to supportive care alone in patients with mild to moderate COVID-19. Patients were initiated on favipiravir within 48-hours of a positive test. Glenmark did not specify whether other antivirals were included in standard supportive care in India.
In a 15-day, 423 patient, Phase III, Brazilian trial, hydroxychloroquine alone or with azithromycin did not improve clinical status (7-point scale from hospitalized and no symptoms to death) compared to placebo in hospitalized patients with COVID-19. Hydroxychloroquine alone or with azithromycin was associated with a prolongation of the QT interval and an increase in liver-enzymes.
Researchers at Montefiore Medical Center retrospectively reviewed the medical records of 1,806 hospitalized COVID-19 patients and found that glucocorticoids administered within 48 hours of admission was not associated with a decrease in mortality or mechanical ventilation. However, patients with a CRP of 20 mg/dL or greater had a reduced risk of mortality and mechanical ventilation, while use in patients with a CRP < 10 mg/dL was associated with an increased risk of mortality or mechanical ventilation.
In a 14-day, 423 patient, Phase III trial conducted by the University of Minnesota, hydroxychloroquine did not substantially reduce symptom severity (scale no symptoms to severe symptoms) in outpatients with early to mild COVID-19.
A final version of the preliminary report of the dexamethasone arm of the 11,500 patient RECOVERY trial (NCT04381936) was published in the New England Journal of Medicine. The results included 2,104 patients that received dexamethasone (6 mg for 10 days) compared to 4,321 patients that received supportive care only. Overall 28-day mortality was 22.9% with dexamethasone compared to 25.7% with placebo. The mortality rate for patients on ventilators was 29.3% with dexamethasone compared to 41.4% with supportive care only. Dexamethasone also had a lower mortality rate in patients requiring oxygen, but not on a ventilator (23.3% vs. 26.2%) but did not reduce mortality in patients not receiving respiratory support at enrollment (17.8% vs. 14.0%).
In a 28-day, 81 patient, Israeli trial, adding subcutaneous interferon beta 1a to hydroxychloroquine plus lopinavir/ritonavir or atazanavir/ritonavir did not decrease the time to clinical response, but did increase discharge rate on day 14 and decreased 28-day mortality, compared to not adding interferon in patients with severe COVID-19.
Synairgen announced that in a 101 patient trial, treatment with nebulized interferon beta 1a (SNG001) reduced the risk of developing severe COVID-19 and increased the likelihood of recovering in patients hospitalized with COVID-19.
Subcutaneous interferon beta 1a is currently being evaluated as a treatment for COVID-19 in the UK’s RECOVERY trial and the WHO-led SOLIDARITY study.
In a 56-day, 1,077 patient, Phase I/II, British trial (NCT04324606), neutralizing antibody levels after a single dose of AstraZeneca’s and the University of Oxford’s AZD1222 vaccine, peaked at 28-days and remained elevated through day 56 with 90% of participants developing antibodies. A booster dose was given four weeks later to 10 patients and resulted in higher antibody levels. Many patients developed systemic reactions (e.g., chills, fever) compared to meningococcal conjugate vaccine, but the reactions were reduced with acetaminophen. AstraZeneca is working with contract research organization IQVIA to accelerate enrollment and completion of a Phase III trial for AZD1222 as part of Operation Warp Speed.
In a 45 patient, Phase I, NIAID trial (NCT04283461), the antibody level increased with higher doses of Moderna’s mRNA-1273 (25, 100 and 250 mcg). Antibody titers further increased with a booster dose at 1-month. All doses produced serum-neutralizing activity that were similar to the levels seen in recovered patients. The incidence of adverse effects was higher after the second vaccination, especially with the 250 mcg dose.
In a 508 patient, dose-ranging, Phase II, Chinese trial (NCT04341389), a single dose of CanSino’s COVID-19 vaccine resulted in seroconversion in more than 96% of participants; 85% produced neutralizing antibodies and 90% had T-cell response. As was seen in the Phase I trial, participants that were 55 or older and those with adenovirus immunity had lower humoral responses, but this did affect T-cell responses. The most frequent systemic reactions were fatigue, fever and headache.
In a 60 patient, open-label, dose-ranging, Phase I/II, German trial (NCT04380701), participants were given two doses of Pfizer’s and BioNTech’s BNT162, separated by three weeks. The vaccine elicited a dose-dependent antibody response with the 50 mcg dose resulting in neutralizing antibody levels that were three times those in recovered COVID-19 patients. The article also describes the T-cell responses in 36 patients with both CD4 cells (34 patients) and CD8 cells (29 patients).
J&J began development work on a single dose vaccine, Ad26.COV2-S in March 2020. A 1,000 patient, Phase I/IIa trial (NCT04436276) is expected to begin on July 22 in the U.S. and Belgium with initial results available in September. Additional trials include a Phase I study in Japan and a Phase II study in the Netherlands, Spain, and Germany. A successful Phase I/IIa trial would lead to a 30,000 patient, NIAID Phase III trial in September.
Sinopharm initiated a 15,000 patient, Phase III trial in the United Arab Emirates on 7/16/2020.
The NIH has updated its guidelines for the treatment of patients with COVID-19. The updates include recommendations for the use of remdesivir when supplies are limited and use of dexamethasone. The update also includes new clinical evidence regarding lopinavir/ritonavir, hydroxychloroquine/azithromycin, convalescent plasma, kinase inhibitors and immunomodulators.
French researchers prospectively monitored the heart rhythms of 41 hospitalized COVID-19 patients being treated with lopinavir and ritonavir and found that 22% (nine patients) experienced bradycardia at least 48 hours after initiating the drugs.
Fujita Health University researchers announced that in an 89 patient trial, treatment with favipiravir did not improve COVID-19 symptoms compared to placebo in patients with early-stage COVID-19.
In an observational trial, University of Michigan researchers examined outcomes in 154 mechanically ventilated patients with severe COVID-19 that received tocilizumab to those not receiving tocilizumab. Around a quarter of patients in each group received hydroxychloroquine and/or a corticosteroid and 3% received remdesivir. Patients that received tocilizumab were younger (55 vs. 60), less likely to have chronic pulmonary disease (10% vs. 28%), and lower D-dimer values (2.4 vs. 6.5 mg/dL). During a 47-day follow-up, tocilizumab patients had a higher rate of superinfections (54% vs. 26%), but a lower 28-day mortality rate (18% vs. 36%).
Moderna completed enrollment in a 600 patient, Phase II trial (NCT04405076) in early July. Patients were given a low dose (50 micrograms), high dose (100 micrograms) or placebo. Half of the patients enrolled in the trial are older than 55. Moderna plans to initiate a 30,000 patient, NIAID sponsored, Phase III trial on July 27, 2020 using the 100 mcg vaccine dose.
The FDA granted Fast Track status to two vaccines in the BioNTech and Pfizer COVID-19 BNT162 program. A Pfizer funded 30,000 patient, Phase III trial is expected to begin in late July or early August.
NIAID has established the COVID-19 Prevention Trials Network (COVPN), as part of Operation Warp Speed. The Network is designed to accelerate the development of vaccines and monoclonal antibodies for the prevention of COVID-19. COVPN is composed of four clinical trial networks, three that had focused on HIV/AIDS and a fourth targeting the development of vaccines and treatments for infectious diseases.
Hydroxychloroquine and Chloroquine
Oxford University is evaluating hydroxychloroquine and chloroquine as prophylaxis of COVID-19 in health care professionals at risk for infection in the 40,000 patient, COPCOV trial (NCT04303507). The UK Medicines Healthcare Regulatory Agency (MHRA) halted enrollment in the COPCOV study on 5/26/2020. After review, MHRA allowed the study to continue on 6/26/2020.
In a 2,541 patient, retrospective study, hydroxychloroquine reduced the hazard ratio for death by 66% and the combination of hydroxychloroquine plus azithromycin reduced the hazard ratio by 71% compared to neither treatment in hospitalized patients with COVID-19. A high number of patients received corticosteroids and a small number received tocilizumab. More patients that received hydroxychloroquine also received a corticosteroid compared to not receiving the drug (78.9% vs 35.7%). The same was true with tocilizumab but use of the drug was small (2.7% vs 1.2%). When controlling for confounders using Cox regression modeling and propensity scores, hydroxychloroquine monotherapy and hydroxychloroquine combined with azithromycin were associated with higher survival among patients with COVID-19.
Researchers at Oxford announced results from the lopinavir-ritonavir 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 1,596 patients enrolled in the lopinavir-ritonavir arm found no decrease in mortality at 28-days compared to 3,376 patients that received only supportive care (22.1% vs 21.3%). Since only 4% of patients were on ventilators, there was not a large enough patient population to determine if the combination had an effect in patients that are mechanically ventilated. Due to the lack of benefit, the researchers discontinued enrollment in the lopinavir-ritonavir arm of the trial. The WHO discontinued the lopinavir/ritonavir arm of the Solidarity Trial 7/4/2020.
Sanofi and Regeneron discontinued a Phase III trial when an interim analysis of 194 patients revealed that treatment with sarilumab did not improve the percentage of patients who achieved at least a 1-point change from baseline on a 7-point scale (death to hospital discharge) compared to placebo in COVID-19 patients requiring mechanical ventilation. As of early July 2020, a Sanofi study evaluating sarilumab in the treatment of severe and critical COVID-19 remained active after an interim analysis.
In early July 2020, Regeneron and NIAID initiated a 2,000 patient, Phase III trial (NCT04452318) to evaluate REGN-COV2 in the prevention of COVID-19 in uninfected people that have had a close exposure to a COVID-19 patient.
The U.S. Department of Health and Human Services and Department of Defense awarded Regeneron $450 million for a for large-scale U.S. manufacturing demonstration project to produce REGN-COV2. The goal of the project is to produce 70,000 to 300,000 treatment doses, which would also correspond to 420,000 to 1,300,000
prevention doses, which would be ready to ship by fall. If clinical trials are successful and REGN-COV2 receives Emergency Use Authorization or full approval, the doses could be shipped immediately at no cost, since the government has paid for the doses.
Novavax has received $1.6 billion grant from the Departments of Defense and Health and Human Services as part of Operation Warp Speed. The grant will cover the manufacture of 100 million doses of its COVID-19 vaccine, NVX-CoV2373, and a Phase III trial. Dose manufacturing and clinical testing will occur in parallel. Novavax expects to begin a 30,000 patient, Phase III trial in the fall.
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