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 An unpublished, unedited article described 12 patients with severe COVID-19 pneumonia treated under an FDA emergency IND with lenzilumab.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.