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5 October: CR Trump Special
What did they give him?
Trump is still receiving remdesivir, famotidine and dexamethasone. All relevant data on these compounds can be found in our COVID Reference book (for dexa, which was added on Saturday to his therapy, see also the WHO statement below). However, the most interesting treatment he has received is 8 g IV of REGN-CoV-2, a pair of two new monoclonal antibodies, named REGN10987 and REGN10933. Here we summarize the data published to date, based on key publications.
Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science. 2020 Aug 21;369(6506):1010-1014. PubMed: https://pubmed.gov/32540901 . Full-text: https://doi.org/10.1126/science.abd0827
Researchers from Regeneron have generated a large panel of antibodies against the spike protein from humanized mice and from three recovered patients. From this panel, approximately 40 antibodies with distinct sequences and potent neutralization activities were chosen for additional characterization, including antibody pairs that do not compete for binding to the receptor binding domain (RBD). REGN10987 and REGN10933 represent such a pair of antibodies: REGN10933 binds at the top of the RBD, extensively overlapping the binding site for ACE2. On the other hand, the epitope for REGN10987 is located on the side of the RBD, away from the REGN10933 epitope, and has little to no overlap with the ACE2 binding site.
Baum A, Fulton BO, Wloga E, et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020 Aug 21;369(6506):1014-1018. PubMed: https://pubmed.gov/32540904 . Full-text: https://doi.org/10.1126/science.abd0831
Proof-of-principle in a cell model, using vesicular stomatitis virus pseudoparticles expressing the SARS-CoV-2 spike protein. Simultaneous treatment with REGN10933 and REGN10987 precluded the appearance of escape mutants.
Thus, this cocktail did not rapidly select for mutants, presumably because escape would require the unlikely occurrence of simultaneous viral mutations at two distinct genetic sites, so as to ablate binding and neutralization by both antibodies in the cocktail.
Regeneron. REGN-COV-2 Antibody Cocktail Program Updates, September 29, 2020. https://investor.regeneron.com/static-files/a596a85e-e72d-4529-8eb5-d52d87a99070
The first clinical data on REGN-CoV-2 (REGN10933 + REGN10987), published online a few days ago (not peer reviewed). Regeneron called it “a descriptive analysis on the first ~275 patients”, derived from a broad ongoing clinical development program. Adult, non-hospitalized COVID-19 patients with symptom onset ≤ 7 days from randomization and not on any putative COVID-19 therapies, were randomized to receive single doses of REGN-CoV-2 at 2.4 g IV (lower dose), at 8 g IV (higher dose) or placebo. Mean age was 44 years (49% male, 55% hispanic, 42% obese, 65% with > 1 risk factor for severe COVID-19). Before treatment, serology was used to divide patients into positive (n=123) versus negative (n=113). As expected, “viral load” in nasopharyngeal (NP) swabs was higher in seronegative patients (7.18 versus 3.49 log10 copies/mL). Main results showed a modest viral load reduction mainly in seronegative patients and a lack of a numerical dose-response relationship:
- REGN-CoV-2 appeared to reduce viral load through day 7 mainly in seronegative patients: the mean NP viral load reduction was -1.98 (high) and -1.89 log10 copies/mL (low dose), compared to -1.38 with placebo (difference versus placebo -0.56 for both dosage groups, p = 0.02).
- If all patients were included (including seropositives), the reduction was -1.92 and -1.64 log10 copies/mL, compared to 1.41 with placebo (difference versus placebo -0.37, significance only seen with high dose).
- Patients with higher baseline viral levels had correspondingly greater reductions in viral load
- Median time to symptom alleviation for the overall population (median) was 8, 6 and 9 days for high dose, low dose and placebo, respectively (seronegative only: 8, 6 and 13).
- As for medically attended visits, there was a numerical reduction versus placebo, but with just 12 visits in total there was no way of discerning the relevance. Most non-hospitalized patients recovered well at home.
- Both doses were well-tolerated. Infusion reactions and severe adverse events were balanced across all groups, no deaths occurred.
That’s what we have: half a log in NP swabs, after a week. There is no doubt that more data are urgently needed, in patients with more severe disease and in older patients. If approved, Regeneron will distribute REGN-CoV-2 in the US and Roche will be responsible for distribution outside the US.
Additional references
Padmanabhan P, Desikan R, Dixit NM. The quantitative landscape of the neutralizing antibody response to SARS-CoV-2. Full-text: https://doi.org/10.1101/2020.09.25.20201996
This article is a pre-print and has not been peer-reviewed. The study collates, compares, and ranks available NAbs (including REGN10987 and REGN10933), laying out the landscape of NAb responses currently observed including in patients, and informs ongoing efforts to develop NAb-based interventions for SARS-CoV-2 infection.
Sajna KV, Kamat S. Antibodies at work in the time of severe acute respiratory syndrome coronavirus 2. Cytotherapy. 2020 Aug 31:S1465-3249(20)30846-X. PubMed: https://pubmed.gov/32988772 . Full-text: https://doi.org/10.1016/j.jcyt.2020.08.009
In this nice review, the authors discuss up-to-date advances in immune-based therapy for COVID-19.
Wan Y, Shang J, Sun S, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020 Feb 14;94(5):e02015-19. PubMed: https://pubmed.gov/31826992 . Full-text: https://doi.org/10.1128/JVI.02015-19. Print 2020 Feb 14
Antibody-dependent enhancement (ADE) of viral entry has been a major concern for antibody-based drug therapy. ADE of viral entry has been studied extensively in other viruses and has been observed in coronaviruses for decades. Some advances on molecular mechanisms.
Dyer O. Covid-19: Trump tests positive as US cases climb. BMJ 2020; 371 October 2, 2020. Full-text: https://doi.org/10.1136/bmj.m3861
For the record: Trump is the eighth national leader believed to have contracted the virus, joining some others who were notably dismissive of its gravity. The leaders of the UK, Brazil, Bolivia, Guatemala, Honduras, and Armenia have all had the disease, with varying symptoms. The president of Burundi, Pierre Nkurunziza, who insisted that “God will spare Burundi” from the pandemic, is believed to have become the first national leader and first Burundian to die from COVID-19 in June (though his government claimed he died from heart failure).
Perano U, Baker S. Trumpworld coronavirus tracker. https://www.axios.com/trump-republicans-coronavirus-covid-positive-0c465d3b-b1df-4096-a1b8-6df63efbf2f7.html
Current overview about the White House outbreak.
Physician to the President. Health Update on President Donald J. Trump October 2, 2020. https://twitter.com/PressSec/status/1312122950133272576
Official statement on Trump’s initial treatment, given by Sean P. Conley, physician to the president. Well, “polyclonal”? Are we mistaken?
WHO. Corticosteroids for COVID-19, living guidance September 2, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1
WHO suggests NOT to use corticosteroids in the treatment of patients with non-severe COVID-19. WHO recommends systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). However, the panel noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary and should be interpreted cautiously when used for determining which patients should be offered systemic corticosteroids. For example, clinicians must use their judgement to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient suffering from chronic lung disease. Similarly, a saturation above 90–94% on room air may be abnormal if the clinician suspects that this number is on a downward trend.