President Trump has COVID-19, so what are the treatments that he has currently received?
This is a one shot intravenous drug with a half life of 22 days which he received prior to hospitalisation.
The company only announced its trial on 29 September and this showed that the antibody cocktail reduced viral levels and improved symptoms in non-hospitalised COVID-19 patients. The REGN-COV2 also showed positive trends in reducing medical visits.
The ongoing, randomised, double blind trails measures the effect of adding REGN-COV2 to usual standard of care compared to adding placebo to standard of care.
This trial is part of a larger programme and also includes studies of REGN-COV2 with the treatment of hospitalised patients and the for prevention of infection in people who have been exposed to COVID-19 patients.
The President and Chief Scientific Officer George D. Yancopoulos of the company announced that the Regeneron-S antibody cocktail REGN-COV2 rapidly reduced viral load and associated symptoms in infected COVID-19 patients. He went on to say the greatest treatment benefit was in patients who had not mounted their own effective immune response, suggesting that REGN-COV2 could provide a therapeutic substitute for the naturally occurring immune response. These patients were less likely to clear the virus on their own and were at greater risk for the lung symptoms. We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well tolerated safety profile, and we began discussing our findings with regulatory authorities while continuing our ongoing trials. In addition to having positive implications for REGN-COV2 trails and those of other antibody therapies, these data also support the promise of vaccines targeting the SARS-CoV-2 spike protein.
REGN-COV2 is a combination of two monoclonal antibodies and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19. To develop this product Regeneron scientists evaluated thousands of fully human antibodies produced by the company’s VelocImmune mice, which have been genetically modified to have a human immune system, as well as antibodies identified from humans who have been recovered from COVID-19.
These two potent, virus neutralising antibodies that form REGN-COV2 bind noncompetitively to the critical receptor binding domain of the virus’ spike protein, which then diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population.
Preclinical studies have shown that REGN-COV2 reduced the amount of virus and associated damage to the lungs of non-human primates. The trial included 275 patients and was designed to evaluate the antiviral activity with REGN-COV2 and identify patients most likely to benefit from treatment.
Patients in the trial were randomised one to one to one to receive a one time infusion of 8 g of REGN-COV2 high dose, others 2.4 g of REGN-COV2 low dose or placebo. All patients entering the trial had laboratory confirmed COVID-19 that was being treated in the outpatient setting. Patients also were prospectively characterised prior to treatment by serology test to see if that already generated antiviral antibodies on their own and were classified as seronegative non-measurable antiviral antibodies or seropositive measurable antiviral antibodies. Approximately 45% of patients were seropositive, 41% were seronegative and 14% were characterised as other due to unclear or unknown serology status.
- Serological status at baseline also predicted how rapidly patients had alleviation of their COVID-19 clinical symptoms – in the untreated placebo patients, seropositive patients had a median time to alleviation of symptoms of seven days, compared to seronegative patients who had a median time to alleviation symptoms of 13 days.
- REGN-COV2 rapidly reduced viral load through day seven in seronegative patients. For the patients who were treated with a high dose, the viral load at day seven was a 0.6 log10 copies/ml greater reduction. In patients treated with a low dose it was 0.51 log10 copies/ml greater reduction and in the overall population there was a 0.51 log10 copies/ml greater reduction in patients treated with a high dose and a 0.23 log10 copies/ml greater reduction in patients treated with a low dose compared to the placebo. Patients with increasingly higher baseline viral levels had correspondingly greater reductions of viral load at day seven with REGN-COV2 treatment.
- Patients who were seronegative and/or had higher baseline viral levels also had greater benefits in terms of terms of symptom alleviation. Among seronegative patients, median times to symptom alleviation was 13 days in placebo, eight days in high dose, and six days in low dose. Patients with increasing viral loads at baseline had correspondingly increase in benefit in time to symptom alleviation. There was a small number of medically attended visits given that most non hospitalised patients recover well at home. Patients in the seronegative group were at a higher risk of medically attended visits; 10 of the 12 medically attended visits occurred in patients who were seronegative at baseline. In a seronegative group, 15.2% of placebo treated patients, 7.7% of patients treated with high dose and 4.9% of patients treated with low dose required additional medical visits.
- Both doses were well tolerated. Infusion reactions were seen in four patients to one placebo and to one REGN-COV2. Serious adverse effects occurred in two placebo patients, one low-dose patient and no high dose patients. There were no deaths in the trial. 2000 patients have been enrolled across the overall REGN-COV2 development programme and no unexpected safety findings have been reported by the independent data monitoring committee.
This trial is still ongoing, and Regeneron continues to enrol patients in the trial and also all other ongoing late stage trials evaluating REGN-COV2.
The data has not as yet been fully published in any journal. At least 1300 patients will be recruited further into the phase 2/3 portion of the outpatient trial overall. In addition to this trial in non-hospitalised patients, REGN-COV2 is currently being studied in a phase 2/3 clinical trial with the treatment of COVID-19 in hospitalised patients, the phase 3 open label recovery trial of hospitalised patients in the UK and a phase 3 trial for the prevention of COVID-19 in household contacts of infected individuals. Recruitment in all four trials is ongoing.
President Trump appears to have usurped the trial process and has fast tracked treatment for himself.
Remdesivir is an investigational nucleotide analogue with broad spectrum antiviral activity. At present it is not approved globally for use but has demonstrated in vitro and in vivo activity against the viral pathogens MERS and SARS, which are coronaviruses and structurally similar to COVID-19.
The limited preclinical data on Remdesivir in MERS and SARS indicate Remdesivir may have potential activity against COVID-19.
In the first published placebo controlled trial of Remdesivir for treating severe COVID-19 disease, Alice Dennis in The Lancet asserts that Wang and colleagues were unable to attain their primary endpoint of time to clinical improvement.
Although admittedly underpowered due to early trial termination, Remdesivir did not appear to affect rates of SARS-CoV-2 viral RNA low decline and mortality when compared with placebo.
Remdesivir appeared to inhibit early coronavirus lifecycle in vitro and in animal models and it is wondered whether Remdesivir might require initiation before the peak viral replication, which is difficult and probably not feasible in the clinical human presentation of COVID-19.
In cell cultures exposed to urine coronavirus, early Remdesivir initiation substantially decreased viral titres compared with control. However, this treatment effect was completely lost when initiation occurred just eight hours after infection.
In another study, mice administered early Remdesivir relative to inoculation with SARS-CoV-2 had substantially reduced lung damage compared with untreated cohorts, an effect that was lost when initiation was delayed by two days after inoculation. Another study published in The Lancet in April showed that Remdesivir was not associated with statistically significant clinical benefits.
A study published in the New England Journal of Medicine in May 2020 showed that Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalised with COVID-19 and evidence of a lower respiratory tract infection. This was published by Bagel and others in May.
Remdesivir went from potential Ebola treatment to offering a modest benefit for people with COVID-19.
In early June Gilead, the manufacturer, announced that other data showed that people with moderate COVID-19 recovered more quickly when given this drug for five days although the benefit was modest. A 10 day course of drug also improved patient outcomes, but the change was not statistically significant. Patients in this study were hospitalised but did not need mechanical ventilation. The data from the study has not yet been published in a peer reviewed journal so should be viewed with some caution.
Questions therefore still remain about Remdesivir such as which patients might benefit most from the drug.
The MHRA in the UK gave a positive scientific opinion for Remdesivir as one of the first COVID-19 treatments. The concluded that the various studies in their review suggested some benefit with Remdesivir compared with placebo for reducing supportive measures including mechanical ventilation and time to recovery in patients with mild or moderate, or severe COVID-19 disease or on supplemental oxygen treatment.
However, no statistically significant differences were found for mortality and serious adverse events. (Fewer were reported with Remdesivir compared with placebo).
More treatment discontinuations were reported with Remdesivir compared with placebo due to adverse events. A subgroup analysis reported in Bagel et al suggested that some groups may benefit more than others, however, they felt that this data needed to be interpreted with caution given the wide confidence interval and lack of adjustments for multiplicity. Therefore, this limited the applicability in clinical practice when assessing which patients are most likely to benefit from Remdesivir.
This all suggests that Remdesivir is an expensive option whose use needs to be carefully judged.
The London General Practice keeps abreast of all advances with SARS-CoV-2, both testing and treatments and wishes all those patients who have contracted it a satisfactory outcome.