Eli Lilly and Co. announced that the monoclonal antibody bamlanivimab (LY-CoV555) significantly reduced the risk of contracting symptomatic COVID-19 among inpatients and staff in long-term care facilities. The phase-3 BLAZE-2 COVID-19 prevention study was conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the COVID-19 Prevention Network (CoVPN) in the UK.
BLAZE-2 is a randomised, double-blind, placebo-controlled trial to evaluate the monoclonal antibody bamlanivimab in the nursing home setting. Bamlanivimab is a monoclonal antibody licensed for emergency use by the U.S. Food and Drug Administration for the treatment of mild to moderate COVID-19 in high-risk patients.
The phase-3 BLAZE-2 study included 965 participants who tested negative for SARS-CoV-2 at baseline (299 inpatients and 666 staff) in the primary and secondary endpoint analyses to assess the preventive potential of bamlanivimab, while 132 participants (41 inpatients and 91 staff) who tested positive for the virus at baseline were included in exploratory analyses to assess treatment potential. All participants were randomised to take bamlanivimab or placebo.
After eight weeks of follow-up, there was a significantly lower frequency of symptomatic COVID-19 (the primary endpoint) in the bamlanivimab treatment arm compared to placebo (odds ratio 0.43, p=0.00021). For the pre-specified subgroup of nursing home residents, a significantly lower frequency of symptomatic COVID-19 was observed in those treated with bamlanivimab compared to placebo (odds ratio 0.20; p=0.00026).
These results suggest that inpatients randomised with bamlanivimab have up to an 80% lower risk of contracting COVID-19 than inpatients in the same facility randomised to placebo. Over the course of the entire study, there were a total of 16 reported deaths, including deaths not related to COVID-19, and all deaths involved inpatients (11 deaths in the placebo arm and 5 in the bamlanivimab arm).
An independent data and safety monitoring committee supervised the BLAZE-2 study. In the study, the safety profile of bamlanivimab was consistent with observations from the Phase-1 and Phase-2 studies. Serious adverse events were reported at a similar frequency in the bamlanivimab and placebo groups.
"The results of this groundbreaking study further support the belief that bamlanivimab - and potentially other monoclonal antibodies - can reduce symptoms and may even prevent COVID-19," said Dr. Myron S. Cohen, M.D., CoVPN co-principal investigator and director of the Institute for Global Health and Infectious Diseases at the University of North Carolina (Chapel Hill, USA). "The antiviral activity seen with bamlanivimab treatment underscores the importance of early intervention to help counteract the devastating impact the virus has had in this vulnerable population and other high-risk patients", he added.
Dr. Andrew Garrett, Executive VP of Scientific Operations, ICON Clinical Research, said: "Prevention of symptomatic infection is currently focused on vaccine uptake, although there may also be an important role for preventive treatments in individuals 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, editor of the journal Vaccines in Practice and former chair of the British Medical Association's public health medicine committee, said: "It appears that products such as bamlanivimab may be effective at a very early stage of the disease, ideally even before infection. It is difficult to understand exactly how bamlanivimab was used in this study, but it appears primarily as a preventive treatment - a bit like vaccination - even though 132 of the 965 participants at baseline were virus positive”. This may hint at ongoing infections or previous infections with residual non-viable RNA detected by RT-PCR testing.
In a sense, therefore, it makes more sense to compare it with vaccination. Vaccine studies are usually very large. As a reference, the Pfizer-BioNtech studies enrolled 43,548 participants. This is partly for ethical reasons, because giving a preventive treatment such as vaccination in a healthy patient is very different from giving a treatment for a disease. When someone is ill, especially if the prognosis is not good, they may accept a treatment with a lower probability of success and a worse adverse event profile than when you give a preventive treatment to someone who is well. Hence with vaccines, it is very important to detect even quite rare adverse events and to be very sure of their efficacy.
As a preventive treatment one might expect the same to apply to bamlanivimab, but this phase-III study, with less than 1000 participants, is small compared to vaccine studies. It must be said that it was used in a specific population, that of nursing homes. Nursing home populations have been particularly affected by COVID-19, so it may be acceptable to make different considerations about risk-benefit and cost-benefit ratios.
The results are encouraging - roughly comparable to a vaccine with 64% or 80% efficacy. However, the follow-up was only eight weeks, and since the recipients received only passive antibodies, whose levels decrease over time, as opposed to having an immune system primed with potentially long-term immunity). It is unclear how long this protection would last.
Dr. English added: “The study press release does not mention the cost of the treatment. My guess is that a dose of bamlanivimab will be much more expensive, and provide a shorter duration of protection, than the vaccine. So it is not clear what the market for bamlanivimab is or will be. It might have a place in prophylaxis in nursing homes, where inpatients are at particularly high risk, after exposure. The cost-effectiveness of widespread use has yet to be established."
Professor Eleanor Riley, Professor of Immunology and Infectious Diseases at the University of Edinburgh, said: 'The launch of COVID-19 vaccines should greatly reduce the need for these treatments (monoclonal antibodies, ed), but there will always be a small proportion of the population who cannot be vaccinated or who do not respond well to vaccination due to health conditions, including immunodeficiencies and immunosuppressive therapies. Therapies such as bamlanivimab could be very valuable in treating such individuals should they become infected, and could also find use in preventing infection in vulnerable, non-immune individuals before going to hospital or starting a course of immunosuppressive therapy, for example.”
For Prof. Riley, this news is particularly encouraging given that two major studies on hyperimmune plasma have been halted due to lack of efficacy. The high efficacy of bamlanivimab is due to the fact that it is a single antibody selected for a high neutralising effect among the very wide and varied mixture of antibodies present in hyperimmune plasma, many of which have little or no neutralising ability. She added however that, “the highly specific binding of bamlanivimab to a particular variant of the spike protein means that it may be less effective against some variants of the virus and this will need to be monitored”.