Eli Lilly have published a press release today stating that their neutralizing antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) together reduced risk of COVID-19 hospitalizations and death by 70 percent.
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
What is the difference between the different BLAZE trials? How do these results differ from the results last week?
“The BLAZE1 trial was an initial study investigating the impact of dual treatment with bamlanivimab (LY-CoV555) with/without etesevimab (LY-CoV16) vs placebo given as a single IV infusion to outpatients with mild-moderate covid 19 symptoms and a positive PCR test within the preceding 3days (72) hours. The primary endpoint was mean change in the various treatment groups on days 3, 7 and 11 post infusion and also on the rate of hospitalisation in the various treatment groups. In this study there was no significant difference between change in viral load between placebo and bamlanivimab monotherapy but the combination treatment resulted in faster reductions in viral load at all timepoints measured. Both monotherapy with bamlanivimab and combination treatment reduced the rate of hospitalisation relative to placebo, as well as alleviating the severity of symptoms faster than in patients receiving placebo infusions. Todays press release is the first phase III cohort which compares the combination treatment to placebo in patients with mild-moderate disease at higher risk of adverse outcomes (age, comorbidities etc) when given within 4 days of symptom onset. The need for hospital treatment or death from any cause was reduced from 7% in the placebo group to 2.1% in the antibody treatment group, a reduction of 70% in hospitalisation or death in the treated population; ten patients that received placebo died whereas none receiving the antibody therapy died.
“In contrast, the BLAZE2 trial is a trial in elderly care homes, which enabled investigation of treatment with bamlanivimab monotherapy in patients infected with SARS CoV2 and prevention of infection in patients negative for infection compared to placebo. This trial demonstrated prevention of illness, hospitalisation and death in bamlanivimab recipients who were uninfected at the time of infusion, as well as reduction in need for hospital care and death in those infected at the time of infusion when compared to those given a placebo infusion.
Were bamlanivimab and etesevimab tested as a preventive treatment in these trials?
“Yes in BLAZE2 which was a preventive trial in elderly residents of nursing homes.
Is this robust data; what are the strengths and limitations?
“The data generated are consistent across the studies and with previously published information.
Is there enough detail available to be able to assess the claims? Is there any overclaiming?
“The detailed data from the trial must be published, but based on the discussion during todays company webpresentation there are no imbalances between groups which detract from these data.
Are these results applicable to the general population?
“The population that participated were those with higher risk factors for severe disease needing hospital care and higher risk of death from COVID-19 and therefore were older, and had other comorbid conditions. While this also suggests that a general population may benefit from early intervention with the antibody combination, because the high risk population are those that are currently overburdening the health care services and dying from disease, this is the population which can benefit most from early intervention with these treatments.
Where does the 70% figure come from; is it accurate?
“It is an accurate reflection of the data presented and represents a reduction of 70% (from 7% to 2.1% ) in the composite outcome of death from any cause or need for hospitalisation in high risk COVID 19 patients treated within 4 days of symptom onset.
Any other comments?
“This product is already available for emergency use in Europe. The DHSC would do well to ask Lilly, which has a major research center in the UK, to consider applying for the EAMS program and submitting a dossier to the MHRA for emergency use authorisation for the combination in high risk subjects, particularly elderly care home residents and patients with other high risk factors.
“Lilly is continuing to investigate lower dose regimens which might be suitable for self administration via sc or IM injection, which would be easier to use in an outpatient setting and reduce need for home infusion services.”
Dr Kovilen Sawmynaden, Principal Scientist, LifeArc, said:
“The BLAZE-1 study aims to test how well the combination of the antibodies bamlanivimab and etesevimab works as a treatment among 1000 outpatients recently diagnosed with COVID-19, whereas the BLAZE-2 study looked at how well these antibodies work in preventing the elderly (in care homes) from catching the virus.
“The results from the BLAZE-1 study look promising and demonstrate the real therapeutic potential of using monoclonal antibodies as a part of a broader strategy to fight COVID-19. This was a good study size (~ 1000 patients) and there were significantly fewer patients either hospitalised or dying in the treatment group compared to placebo.
“It would be interesting to understand better whether etesevimab provides any additional benefit with respect to clinical outcome in this study. One would expect at the very least that the presence of two antibodies should offer protection in the event of a virus mutation or change in the future.”
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“These results are very encouraging. They are the first anti-viral drugs that demonstrably work in the first phase of the disease just after the virus has infected someone but before it has had time to cause a lot of damage. It is not shown to work at later stages where a patient is already in hospital (dexamethasone is a drug that, in contrast, does not provide benefit in early stages, but only at a very late stage in the disease process).
“These seem well-conducted trials, using lower doses than previously, but with bamlanivimab and etesevimab used together the benefit seen at higher doses can be achieved by their joint use at relatively low doses. The company also note they plan to try even lower doses.
“Although this is a press release and a full paper would be best to allow for more careful assessment, there is no reason to believe that any benefits have been exaggerated. The company suggest that even minor adverse effects are similar for placebo and no serious adverse reactions seem to have been observed. Reactions associated with infusing treatments are seen, including the potential for anaphylaxis.
“It is important to realise that the absolute risk reduction is worthwhile but not as dramatic as “70%” and it has uncertainty given the number of patients studied. The 70% relative risk reduction is probably in the range 40% to 84%. The absolute reduction of 5% in “events” (from 7% to 2%) has an uncertainty in the range of 2% to 7%. This is not solely due to reduction in hospitalisations but also in deaths, where the reduction of 2% has an uncertainty between 0.7% and 3%.
“These benefits seem real and worthwhile but there are limitations.
1. Identifying patients who test positive and are at high risk of hospitalisation and death prior to their admission to hospital is not simple. It is not clear whether this could be many tens of thousands of patients or relatively few.
2. The drugs at the moment have to be given by transfusion, though that may change to an injection in the future.
3. I do not know the costs per patient, but it could be very high and if the numbers needing treatment are very high this would be a problem. At the moment it would appear that 20 patients would need to be treated to prevent a hospitalisation or death (though it could be as many as 50 patients needing to be treated, or fewer than 20, larger studies are needed to be sure). There would be 50, or possibly more, needing to be treated to prevent a death. This is a good treatment, but it could be unaffordable.”
All our previous output on this subject can be seen at this weblink:
Dr Kovilen Sawmynaden: “LifeArc is a medical research charity. We are part of the BIA Antibody Taskforce to identify potential neutralising antibodies for Sars-Cov-2, donating our time and efforts on this project. We do not have a connection with Lilly on this antibody work.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs. I am a participant in the Oxford/Astra Zeneca trial, and on 13th January 2021 learnt I had received the active vaccine.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”