Pandemic mutations prompt antibody collaborations

A trial testing a combination of Lilly and Vir antibodies is the latest attempt by developers to stay ahead of the virus that causes Covid-19.

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Several new variants of the pandemic virus are causing alarm around the world, in case existing vaccines, monoclonal antibodies and natural immunity become less protective. Drug developers are racing to stay ahead of these mutations, and a collaboration announced yesterday between Lilly, Glaxo and Vir was the latest example of these efforts.

The groups will test a new combination of Lilly’s bamlanivimab plus Vir’s VIR-7831; however, staying ahead of variants is only one of the problems that these antibody developers face. Usage has also failed to take off as expected, and it is not inconceivable that the virus could render some of these MAbs ineffective before they can become entrenched.

Lilly’s existing combination – bamlanivimab plus etesevimab – seems to be particularly vulnerable, if academic research released this week holds up to scrutiny. The MAbs’ effectiveness was found to be markedly reduced against the so-called South African variant (B1351), which is causing the most concern for its potential for increased transmissibility and ability to cause more severe disease.

The researchers also tested Regeneron’s antibody cocktail, casirivimab and imdevimab, and found this did manage to knock down the B1351 variant, although the latter antibody was responsible for the knockdown. Both MAb combinations held up well against the UK variant (B117).

It should be remembered that this paper, from Columbia University, is only available as a pre-print. There are also questions around the extent to which results obtained via lab assays translate to the real world.

It is also far from clear whether the South African variant will become widespread and present a problem; however, some believe that the results do not bode well for Lilly. Leerink analysts went as far as to say that it will be hard to justify continued use of bamlanivimab once other antibodies are available, and that monotherapy with this antibody should be phased out.

Leading anti-Covid-19 antibodies

 Product (company)

Authorisation setting Ongoing or confirmatory trials
Casirivimab + imdevimab (Regn-COV2; Regeneron) Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation Subcutaneous formulation; prevention; confirmatory in mild to moderate; hospitalised
Bamlanivimab (LY-CoV555; Lilly) Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation Prevention study (Blaze-2); + etesevimab mild to moderate (Blaze-1)
Bamlanivimab + etesevimab (LY-CoV016; Lilly) Filed for patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation Prevention study (Blaze-2); mild to moderate (Blaze-1)
Source: Company statements.

It seems likely that Lilly had already anticipated bamlanivimab’s weaknesses, and indeed this week the company said that the monotherapy product will be phased out as the combination with etesevimab comes on line. The company anticipates emergency use authorisation for the combo on the back of new data from the Blaze-1 trial, reported this week, which showed a remarkable 70% reduction in the risk of death among non-hospitalised high-risk patients.

On a call this week, Lilly executives insisted that the bamla + ete combo could knock down variants being found in the US right now. A novel project thought to be highly potent against the South African variant is “moving towards human trials” in case that becomes widespread, said Dan Skovronsky, the group's chief scientific officer.

Guarding against future variants is also no doubt the aim of the Vir collaboration. The company's antibody, which is being developed in partnership with Glaxo, will be tested in combination with bamla in a new arm of Blaze-1.

Lilly has several other preclinical projects in the wings, Mr Skovronsky said. “We may need antibodies that are more variant specific in the future. We might need cocktails of three or more antibodies.” 

This is one reason why Lilly is trying to drive dosages down, he said: the successful data from Blaze-1 was derived from two huge 2,800mg doses each of bamla and ete, which require infusion times of over an hour.

Logistics

The logistical problems associated with long infusion times, on top of the novelty of such a therapy to treat an infectious disease, have been major brakes on uptake of these antibody therapies. Lack of data was another barrier, according to the Lilly execs, but the Blaze-1 results should change things.

“We’ve removed that obstacle and we think uptake should improve dramatically based on this dataset,” Mr Skovronksy said.

Lilly has forecast sales of $1-2bn this year from its Covid-19 products, most of which will be from antibodies, an estimate that seems extremely bullish considering the limited use so far. Success in accelerating infusion times is surely going to be needed for these numbers to be met.

Lowering dosages could help for another reason: more people can be dosed with the same amount of raw product. Global antibody manufacturing capacity is finite, Mr Skovronksy pointed out, and developers for now only have leverage on dose.

Mr Skovronksy also said that the lead time for identifying and manufacturing a new antibody is five or six months, at a minimum. Of course MAbs have yet to win a place at the forefront of the fight against this virus, despite data suggesting they should be used more widely. But that time lag should probably be considered another hurdle for these therapies against this incredibly fast-changing virus.

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