Much work is ongoing to determine which patients might benefit the most from antibody-based therapies against Covid-19, but Astrazeneca seems to have already placed its bets. Further details emerged today on two pivotal trials of its antibody combo AZD7442 in prophylactic and post-exposure settings; both are due to start in the coming weeks, and results could emerge early next year.
This was according to Mene Pangalos, head of biopharmaceuticals R&D for Astra, who also told Evaluate Vantage that AZD7442 was poised to enter the NIH-sponsored Activ-2 and Activ-3 trials, in outpatient and hospitalised settings respectively.
However, the project’s long half-life and potential for intramuscular administration make it particularly suitable for earlier use, Mr Pangalos said, attributes that he believes will differentiate the project from rivals.
“Where we are really excited about this is outpatient settings – the Trump setting, as it were – and prophylactic use, where we have a really good profile,” Mr Pangalos said.
Astra has used half-life extension technology that it has already deployed effectively with another project, the RSV MAb nirsevimab; the company says this should help AZD7442 provide people with protection from infection for at least six months, and possibly out to 12 months. In a prophylactic setting this makes AZD7442 almost like “passive vaccination", Mr Pangalos said.
The advantages of an intramuscular injection, over the intravenous administration of antibodies from Regeneron and Lilly, are clear.
The Provent and Storm Chaser trials, described in greater detail today alongside Astra's third-quarter results, will test these theories. The former will recruit patients unsuitable for vaccination – for example those on chemotherapy or dialysis – while Storm Chaser will seek out potential infection events in locations such as care homes or meatpacking factories.
|Late-stage clinical programme for AZD7442|
|Provent||Prophylactic, in subjects unsuitable for vaccination. To start next week||300mg, IM|
|Storm Chaser||Post-exposure, in subjects exposed to infection, PCR -ve or +ve; start imminent||300mg, 600mg, IM|
|Tackle||Outpatient setting, further details tbc, starting 2021||600mg IM|
|Activ-2*||Outpatient setting, PCR +ve||Dose tbc (poss 600mg), IV and IM|
|Activ-3*||Inpatient setting, moderate to severe illness||Dose tbc, IV|
|IM = intramuscular, IV = intravenous. *NIH-sponsored. Source: Company statements.|
Astra is not ruling out a place for these therapies in hospitalised or sicker patients, however. Here, Mr Pangalos said that the design of the antibodies – specifically their deactivated Fc binding domain – might give them a better chance of showing efficacy, particularly in more severely ill patients, where both Regeneron and Lilly have had trials halted (Toxicity concerns now hit the Covid antibody approach, October 14, 2020).
“Hypothetically, an inactivated Fc binding domain may reduce any likelihood of antibody-dependent driven disease. When you are giving very high doses that might be a problem,” Mr Pangalos said.
As such, a much lower dose of AZD7442 is being considered for the Activ-2 and 3 trials versus doses of other MAbs. Activ-2 and 3 are designed to test many different antibodies from different drugmakers. Lilly, for example, tested 7,000mg of bamlanivimab in Activ-3, while Astra is considering 600-900mg.
“Given recent data with Regeneron and Lilly we need to be cautious. They tested some heroic doses, and there may be an opportunity to lower that and still see a benefit,” he said.
This too will need proving and it is unclear when these NIH-run trials might get under way; the AZD7442 Activ-2 and 3 substudies have yet to emerge on the NIH website or clinicaltrials.gov, as far as Vantage can determine.
The company is also starting its own trial in hospitalised patients, called Tackle, next year; details have yet to be confirmed.
It seems clear where Astra’s big hopes lie with this approach, although of course much still depends on the company proving that long-term protection can be achieved. Mr Pangalos pointed to 500,000 patients in the UK alone who are unable to receive a vaccine.
“Based on our data so far we hope that with a single dose – a relatively low dose, injected intramuscularly – we will be able to protect people for between six to 12 months. I think this is going to be a really important therapeutic platform for this disease,” he said.