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Eli Lilly have published a press release today stating that their neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 in US nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents.
Dr Andrew Garrett, Executive VP, Scientific Operations, ICON Clinical Research, said:
“BLAZE-2 is a randomized, double-blind, placebo controlled trial to evaluate the monoclonal antibody, bamlanivimab, in the nursing home setting. Eligible participants could be randomized to bamlanivimab 4200mg or placebo only if a nursing home recorded at least one confirmed case of SARS-CoV-2 infection among residents or facility staff from a sample collected within the last seven days. In this respect, the design aims to study bamlanivimab in a relatively closed environment where SARS-CoV-2 is known to be circulating. The press release reports prevention data (primary and secondary analyses) on 965 participants (299 residents and 666 staff) who tested negative for the SARS-CoV-2 virus at baseline and also treatment data on 132 participants (41 residents and 91 staff) who tested positive for the virus at baseline (exploratory analyses).
“The primary outcome measure was “cumulative incidence of COVID-19 defined as the detection of SARS-CoV-2 by RT-PCR and mild or worse disease severity within 21 days of detection”. The reported results are based on 8 weeks of follow-up for all participants and show a reduction in symptomatic COVID-19 with bamlanivimab versus placebo. The odds ratio of 0.43 points to a reasonably large effect by clinical trial standards with an associated small p-value of <0.001, which provides convincing evidence of an effect. For the pre-specified subgroup of nursing home residents, there was also evidence of efficacy with a large effect (odds ratio of 0.20, p-value <0.001).
“Further details of the analysis and modelling will be required to comment in more detail. It is reported that the secondary endpoints were also statistically significant.
“There appears to be no safety concerns at this stage, and the number of COVID-19 attributed resident deaths, although small, were all in the placebo groups (preventative and treatment groups). These data are very encouraging therefore.
“Prevention of symptomatic infection is currently focused on vaccine deployment, although there may also be an important role for preventative treatments in those known to be exposed to the virus. These positive results are to be welcomed and have the potential to extend the use of bamlanivimab and support the fight against SARS-CoV-2.”
Dr Peter English, Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice Magazine, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“The natural history of Covid-19 comprises several phases – a period from infection to the onset of symptoms (if there are any symptoms – the proportion of asymptomatic cases seems to depend in part on how hard you look for symptoms, and is higher at younger ages). Infectiousness appears to start up to 48 hours before the onset of symptoms, and ceases by about 8 days after the onset of symptoms. Those who have symptoms in the early stages of disease generally have flu-like symptoms. Roughly 10 days from the onset of symptoms some people start to develop more serious complications, which appear to be due to an over-reaction of the immune system. By this stage, the [viable, potentially infective, “active”) virus has usually been mostly or completely cleared, so disease progression from this point probably doesn’t require the ongoing presence of virus. For this reason, it is unclear what the value, at this point in the disease, of antibodies to the virus might be.
“So it seems likely that, if products like Bamlanivimab are to be effective, it would be very early in the course of the disease, ideally before infection.
“It is hard to make out exactly how Bamlanivimab was used in this trial, but it appears that it was, indeed, used primarily as a preventive treatment – rather like vaccination, although 132 of the 965 participants (41 residents and 91 staff) tested positive for the virus at baseline (suggesting either current infection, or previous infection with leftover, non-viable RNA being detected by RT-PCR testing).
“The difference between vaccination and the use of this product is that vaccines stimulate the body’s immune system to produce its own antibodies – and, indeed (if the vaccine works this way) to produce a broader immune response, including T-cells and so on. By contrast, Bamlanivimab is a monoclonal antibody against the virus, given by injection.
“In some ways, therefore, it makes most sense to compare it to vaccination. Vaccine trials are usually very large: the Moderna trial1 had 30,420 participants; the Astra-Zeneca trial2 enrolled 23,848 participants and extended to 74,341 person-months of safety follow-up; and the Pfizer-BioNtech trials3 enrolled 43,548 participants. This is partly because the ethics of giving a preventive treatment like vaccination are very different from giving a treatment for a disease. When somebody is ill, especially if the prognosis is poor, they may accept treatment with a poorer probability of success and a worse adverse event profile than when you offer a preventive treatment to somebody who is well. So, with vaccines, it is very important to detect even quite rare adverse events; and to be fairly confident about their efficacy.
“As a preventive treatment you might expect the same to apply to Bamlanivimab, but this phase III trial, with fewer than 1000 participants, is small compared to vaccine trials.
“However, I note that it was used in a care home population (residents and staff). Care home populations have been particularly hard-hit by Covid-19, so a poorer risk-benefit equation (and cost-benefit ratio) may be acceptable in such populations.
“The odds ratio from the trial suggests that recipients were roughly two-fifths (0.46) as likely to develop symptomatic Covid-19 disease compared to the placebo group; and residents did even better, only one fifth (0.20) as likely. These are encouraging results – roughly comparable to a vaccine with 64% or 80% efficacy. No data are provided on protection against severe disease or hospitalisation, other than data on mortality. There were, it claims, four Covid-related deaths in residents, none of them in the treatment arm. (The relatively high death rate – four Covid-related deaths, and a total of 16 deaths – compared to the vaccine trials is to be expected, given that care home residents are likely to be much older and more frail than the populations in the vaccine trials.) The fact that all the Covid-19 related deaths were in the placebo arm of the trial is encouraging; but the rather small number makes it hard or impossible to calculate an odds ratio without a massive confidence interval.
“However, follow-up was for only 8 weeks and, as the recipients were receiving only passive antibodies, the level of which declines over time (as opposed to having a primed immune system with potentially very long term immunity), it is not clear how long this protection would last for.
“The press release doesn’t mention the cost of the treatment. My guess would be that a dose of Bamlanivimab will be a lot more expensive, and provide a shorter duration of protection, than vaccine.
“So it is not clear what the market for Bamlanivimab is or will be. It may well have a place in prophylaxis in care homes, where residents are at particularly high risk, following exposure. The cost-effectiveness of widespread use has yet to be established.”
1. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2020. (https://www.nejm.org/doi/full/10.1056/NEJMoa2035389).
2. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2020. (https://doi.org/10.1016/S0140-6736(20)32661-1 or https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext).
3. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020;383(27):2603-2615. (https://www.nejm.org/doi/full/10.1056/NEJMoa2034577).
Dr Kovilen Sawmynaden, Principal Scientist, LifeArc, said:
Is this robust data; what are the strengths and limitations?
“This appears robust, and achieved statistical significance. Study comprises a single-care home (comprising 299 residents). Careful extrapolation to others.
Is there enough detail available to be able to assess the claims?
“Yes.
Where does the 80% figure come from; is it accurate?
“Care home residents ONLY (i.e. excludes 666 staff). But, the group is predefined.
Is this good news; do we still need to know more?
“Great news. Demonstrates antibodies can be used prophylactically to prevent infection – and will complement vaccine strategy. People who are immunocompromised (or allergic to vaccine components) now have an alternative source of protection.
Do we know how applicable these findings may be outside nursing homes?
“No – but this was performed in a high-risk environment (i.e. nursing home). Hence, one could extrapolate these findings to low risk environments.
Is this the first potentially preventive treatment?
“No – we have vaccines.
Any other comments about this data?
“This is a single antibody (rather than a cocktail), which raises some concern of efficacy against new variants. A cocktail of different antibodies would mitigate this risk.”
Dr Nick Cammack, Covid-19 Therapeutics Accelerator Lead at Wellcome, said:
“The monoclonal antibodies developed for Covid-19 have always held great promise, as they are the first treatments that are specific to the disease. These results exceed our expectations, demonstrating that this class of treatments can be used to both prevent and treat disease. Reducing the risk of getting Covid-19 by up to 80% would be remarkable, and could have a dramatic impact on outbreaks among the most vulnerable groups globally.
“Monoclonal antibodies are traditionally the most expensive class of treatments in the world. Covid-19 must be the pivot moment where they move from the rich world to the whole world and become part of mainstream therapeutics.
“Early evidence suggests that the new variants that emerged in South Africa and Brazil may not respond to treatment by the first Covid-19 monoclonal antibodies. While this would be extremely disappointing, today’s findings prove that this class of treatments remain an important avenue to pursue. Now, we must invest in further research into a range of Covid-19 monoclonal antibody treatments that can work against any new variants that arise.”
Prof Eleanor Riley, Professor of Immunology and Infectious Disease, University of Edinburgh, said:
“Bamlanivimab is an antibody that binds with high affinity to the receptor-binding domain of the SARS-CoV-2 spike protein, thereby preventing the virus from being able to infect human cells. This trial suggests that it reduces the risk of contracting SARS-CoV-2 infection by 80% in nursing home residents and, when used to treat residents that have already contracted the virus, may reduce the risk of dying (although there were too few deaths in the trial to be absolutely sure of this).
“Whilst the successful roll out of COVID-19 vaccines should markedly reduce the need for such treatments there will always be a small proportion of the population who cannot be vaccinated or who will not respond well to vaccination due to underlying health conditions including immunodeficiencies and immunosuppressive therapies. Therapies such as Bamlanivimab could be very valuable for treating such individuals should they contract the infection and may also find use for prevention of infection in vulnerable, non-immune individuals prior to going into hospital or beginning a course of immunosuppressive therapy, for example.
“This news is particularly encouraging given that two major trials of convalescent plasma have been halted due to lack of efficacy. The high efficacy of Bamlanivimab is because it is a single antibody selected for high neutralising effect from among the very large and varied mixture of antibodies present in convalescent plasma, many of which have little or no neutralising capacity. However, the highly specific binding of Bamlanivimab to one particular variant of the spike protein does mean that it may be less effective against some variants of the virus and this will need to be monitored.”
Prof Daniel Altmann, Department of Immunology and Inflammation, Imperial College London, said:
“This Lilly press release offers positive news from the BLAZE-2 trial in which the SARS-CoV-2 neutralising monoclonal antibody, LY-CoV555, was given to prevent infection to 965 uninfected people in care-homes, as well as to 132 who were already PCR-positive for the virus. The monoclonal antibody had been defined as one able to bind at high affinity to the receptor binding domain of virus spike, blocking entry to the cell
“The investigation reports a very significant impact – reducing both symptomatic disease and deaths. This is a big result when one considers the massively disproportionate disease burden and fatalities around the world in care-homes. Earlier results in severe patients in a hospital setting had been disappointing, perhaps reflecting the point that at that later stage of disease, other disease processes are implicated, rather than just virus entry.
“So, good news. Since the antibody might stay in the system for a few months, this offers a means of seeing vulnerable groups through a high risk period.”
Prof Chris Butler, Professor of Primary Care, Nuffield Department of Primary Care Health Services, University of Oxford, and Co-Lead of the PRINCIPLE Trial, said:
Is this robust data; what are the strengths and limitations?
“These preliminary findings are very exciting, in that they appear to show a benefit from monoclonal antibody treatment for prevention of SARS-CoV-2 infection. While the potential findings about mortality or intriguing, there’s not enough data to come to any firm conclusions apart from that more research appears well justified.
Is there enough detail available to be able to assess the claims?
“The study included 299 residents of nursing homes and 686 staff in their prevention study, and 41 residents and 91 staff in the treatment study. So far, they report odds ratios with P values. Knowing the actual numbers of outcome events by group and seeing the raw would help interpret the importance and potential impact of these findings, if replicated in usual care.
Where does the 80% figure come from; is it accurate?
“This is probably a relative risk reduction, so without knowing the actual proportions who developed symptomatic COVID-19 disease, it’s difficult to know exactly how dramatic this reduction is. We do not know the proportions allocated to the different intervention groups.
Is this good news; do we still need to know more?
“This is tremendous news, in that nursing home residents and residents of long term care facilities have been hardest-hit by the pandemic and here we have an intervention that may well prevent the illness, as well as possibly be useful as an early treatment, in both staff and residents. However, follow-up was for eight weeks and the sample size was, out of necessity, fairly small in this efficacy study. On the face of it, this study looks like that it justifies a much larger trial. Critically, the intervention appears safe. The investigators are to be congratulated for successfully conducting this research in a context which is traditionally challenging to do complex and long term trials, especially under pandemic circumstances.
Do we know how applicable these findings may be outside nursing homes?
“Research should be done among those who are the potential recipients of the intervention that is being investigated. Nursing home residents have a huge amount to gain from effective treatment and prevention strategies so it is clear why and appropriate that investigators focus initially on this group. However, with these promising findings, future studies should include a broader range of people in the community, where the reach and impact of this kind of treatment and prevention strategy is likely to be greatest. While finding ever more effective treatments for those who are very ill with COVID-19, keeping people out of hospital is the critical challenge we face right now. More research of treatments for use in the community is urgently needed.
Is this the first potentially preventive treatment?
“No, vaccination is the first preventative treatment!
Any other comments about this data?
“We are really looking forward to seeing the full data with the actual numbers!”
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organization. ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries. ICON conducts clinical trials on behalf of Sponsors, including vaccine trials. I am a member of the UK Statistical Authority’s (UKSA) Research Accreditation Panel.”
Dr Peter English: “No conflicts of interest to declare.”
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.”
Dr Nick Cammack: “Wellcome is co-convenor of the Covid-19 ACT-Accelerator and co-founder of the Covid-19 Therapeutics Accelerator, which has secured manufacturing capacity and supply of Bamlanivimab for low-and-middle-income countries.”
Prof Eleanor Riley: “No Conflicts of interest.”
Prof Daniel Altmann: “DMA has received consultancy remuneration from Oxford Immunotec.”
Prof Chris Butler: “I am the chief investigator of the principal trial of treatment in the community for syndrome make COVID-19 illness.”