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New data suggests the antibody therapies can have a big impact in preventing infection, or preventing at-risk individuals being hospitalized with severe COVID-19.(Source:Getty Images)

Developed on unprecedented timelines similar to the COVID-19 vaccines, monoclonal antibody therapies – once seen as central to the fight against SARS-CoV-2 – have only played a limited role so far since the US emergency use approvals of Regeneron and Eli Lilly’s products.

Now armed with new data, and seeking expanded emergency use authorizations (EUAs), that looks set to change soon; but the companies will still face challenges to the treatments truly assisting vaccines and public health measures to 'bend the curve' in the pandemic.

In November, the US Food and Drug Administration granted EUAs to both Regeneron’s REGEN-COV (casirivimab and imdevimab) and Lilly’s bamlanivimab for use in ambulatory patients with confirmed mild-to-moderate COVID-19 who are designated as ‘high risk’. This include a range of patients, including anyone over 65 years old, or anyone over 55 with co-morbidities such as obesity and hypertension.

But the therapies have faced some major practical barriers to the uptake, including the narrow window of 10 days after infection in which treatment can help at-risk patients. Added to this was the fact that hospitals, overwhelmed with severe COVID-19 cases, were not set up to administer the lengthy 60-minute infusion the antibodies required.

Also significant have been some serious misgivings among physicians about the limited amount of efficacy data that the FDA accepted for the EUAs, with no clear sign the drugs prevented mortality, and only modest reductions in the number of hospitalizations and emergency room visits compared with placebo.

But now that lack of enthusiasm for the therapies may well change on the back of new, and far more compelling studies presented in January.

The first of these is new data from Lilly’s BLAZE-1 study, showing that Lilly’s new two antibody cocktail (bamlanivimab plus etesevimab) reduced risk of COVID-19 hospitalizations and death by 70% in at risk patients with mild-to-moderate COVID-19. ()

Then data from Lilly’s BLAZE-2 study, where clinical teams went into nursing home across the US, and treated residents and staff prophylactically with bamlanivimab, showed an 80% lower risk of contracting COVID-19 versus residents in the same facility randomized to placebo.

Regeneron, meanwhile, carried out a similar study with REGEN-COV in people living in close contact with someone with a confirmed COVID-19 infection – the home being the most common place for transmission of the virus. A first analysis of interim data from 400 participants showed that ‘passive vaccination’ with REGEN-COV resulted in 100% prevention of symptomatic infection and around 50% lower overall rates of infection (symptomatic and asymptomatic). SC143698

Both companies are now talking to the US FDA about extending their EUAs and are addressing some of the frontline bottlenecks to access. Access in the rest of the world has also been extremely limited, with the European Medicines Agency only in recent weeks reversing its view that the products lacked sufficient evidence to grant a conditional marketing authorization. ()

The EMA has now begun its own reviews, and the EU and other international markets could see the first conditional marketing approvals within months.

Meanwhile, other Mab candidates are in the pipeline, with both Vir/GSK and AstraZeneca advancing towards readouts from pivotal trials with their offerings.

The antibody products are also vital for the significant numbers of patients who cannot be given the COVID-19 vaccinations, such as cancer patients receiving anti-B cell therapies that knock out the immune cells which generate neutralizing antibodies, as well as other individuals with immune defects who do not respond well to vaccines.

It is in this group where AstraZeneca is hoping to prove the value of its candidate, AZD7442, a combination of two long-acting antibodies being studied in the Phase III PROVENT study of around 5,000 people, including those with a compromised immune system, who cannot be vaccinated, vaccine hesitant, and those who are unlikely to respond to a vaccination.

Progess At Speed

As the pandemic took hold, both Regeneron and Lilly worked with the US National Institutes of Health (NIH) to generate evidence about how their treatments could help patients in a variety of settings.

In July, REGEN-COV became the first non-vaccine candidate to gain Operation Warp Speed backing, and seven months on, David Weinreich, Regeneron’s executive vice president, of global clinical development is proud of the huge progress made in bringing these products to the COVID-19 frontlines, but also clear-sighted about obstacles remaining to wider uptake.

Regeneron's David Weinreich

“I would hope that everybody wakes up and we really utilize these antibodies to get ahead of this disease while we're rolling out the vaccines,” Weinreich told Scrip.

“I don't want anyone to think Regeneron isn't completely rooting for the vaccines … This isn't competitive-speak this is science-speak. We should be utilizing these antibodies with a lot more fortitude than we than we currently are.”

Lilly's CEO David Ricks, when reporting its new data with chief scientific officer Daniel Skovronsky on 26 January, said, “Probably compared to any new drug that changes practice uptake and adoption has [never] been faster. In this case, it's just that, in a pandemic, we set expectations extremely high.”

Ricks said some early doubts were understandable. “Physicians, especially academics, are often trained to be skeptical. That's great in normal times, and sometimes good in pandemics, but in this case we've had to react quickly, often with partial information.”

But this caution was no longer necessary thanks to the stronger data, he said. “That final obstacle I think is removed here, and we expect to see utilization increase quite dramatically based on this dataset. I certainly hope that will happen [because] the impact on public health will be profound.”

Lilly’s Phase III BLAZE-2 trial recruited participants in US care homes where an outbreak of COVID-19 was underway where the advantage of the immediate protection from an antibody treatment over a vaccine is clear: immunity from vaccines take 2-3 weeks to build up, leaving residents and carers exposed.

Regeneron’s interim figures were also persuasive. For those that did still get infected after receiving REGEN-COV therapy, all were asymptomatic, with decreased peak virus levels and shortened duration of viral shedding. This suggests the therapy could therefore also minimize these individuals’ chance of passing the infection onwards.

Weinreich stressed out that the results were still interim, but was excited about their potential. “No one developed symptomatic disease. I don't know if it'll be perfect 100% when we read out the larger data set, but it's still a remarkable result. The period of transmissibility was also much smaller in the treatment arm.”

Also significant is its subcutaneous formulation, made possible by the lower dose used in the prophylactic setting, making it easier to distribute and administer.

The ultimate aim is a reduction in mortality – data that should mature over the coming weeks. Weinreich said this would eventually lead to the end goal: full US marketing authorization via a biologics license application (BLA) which he is sure will also help boost credibility of the treatments.

In Case Of Emergency – Lessons From The EUA

Weinreich said that operating via an EUA – accepting a lower evidence in the short term, in order to respond as fast as possible to the gravest global public health emergency in a century – was novel territory for biopharma companies, regulators and physicians alike.

“The whole point of this is to stop the pandemic. You're not going to have all the answers that we would typically have. Some physicians have said, ‘We get this’. Other physicians say ‘Well, why don't you have your final mortality data? That's what we really want to see.’ They're not wrong … that's what we would show up with for a formal approval. But the whole point of an EUA is we don't have all the answers.”

He adds that a non-business-as-usual mindset is needed during the pandemic, a "save the world" mode.”

Both Regeneron and Lilly note that many of the medical centers showing the fastest uptake of the therapies are not the renowned academic research institutions, but are regional hospitals who have shown determination to administer the therapies – what Ricks calls ‘flexibility’ – amid the pandemic.

South Africa Variant Evades Two Out Of Three Approved Antibodies

The emergence of new strains of SARS-CoV2 has added a whole new challenge – and some worrying results.

In vitro studies carried out by the University of Columbia last month found that Lilly’s bamlanivimab was entirely inactive against the South Africa variant (501Y.V2).

Meanwhile, casirivimab, one of the two antibodies in REGEN-COV, was 58-fold less effective at neutralizing the South Africa variant compared with the original virus. Fortunately, the second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail. 

For both companies the emergence of variants makes their job more difficult, but the risk was well understood at the outset.

Researchers had always anticipated the likelihood of variants, and for that reason Regeneron and Lilly’s drug discovery partner AbCellera generated thousands of antibodies via its drug discovery screening platforms last year.

Regeneron believes it is well placed to develop another cocktail, which could include two or even three new antibodies to defeat emerging variants.

Lilly, meanwhile, has already responded by pairing bamlanivimab with etesevimab (discovered by Junshi Biosciences) and recently added Vir and GSK’s VIR-7831 to its BLAZE-4 trial. The hope here, as in other combinations, is that by binding to distinct epitopes on the SARS-CoV-2 spike protein, this cocktail will show efficacy even against the South Africa variant. ()

The company has indicated that it expects to phase out its bamlanivimab monotherapy product during 2021, while Lilly’s BLAZE 4 study is expected to produce data in the first half of the year.

Lilly's Dan Skovronsky

Daniel Skovronsky, Lilly's chief scientific officer, said studies have shown that the antibodies still work on the UK variant – currently more of a threat in the US than the South African variant – and so the immediate challenge was opening up access to existing products as rapidly as possible.

“The most important thing is getting access for patients today for these antibodies because the data show they prevent hospitalizations and prevent death,” he said.

With regards to making new antibodies to the South African and other variants “this is just something that we've gotten good at and we can move quickly now into clinical trials,” he said, although the matter of how much data the FDA would require remains unresolved.

De-Risked Thanks To US Government Money

Nevertheless, the entire enterprise has been substantially de-risked by major upfront payments from the US government, via Operation Warp Speed to support R&D and manufacturing.

Regeneron received $450m last July to supply 300,000 finished doses of its antibody cocktail by 30 June 2021 and the US government has now agreed to raise the total to 1.5 million doses at a contracted price of $2,100 per dose, with most delivering in the second quarter.

A similar deal has been agreed with Lilly, which received $375m for an initial 300,000 doses of bamlanivimab, followed with an extra $812.5m for 650,000 more doses through to the end of June 2021.

AstraZeneca was awarded $486m in October for supplies of its candidate. However, with President Biden re-modelling and renaming Operation Warp Speed, it remains to be seen whether any more funding for the antibodies will be forthcoming.

FDA Struggling To Keep Up?

One final obstacle of concern to the biopharma companies is a sense that the FDA is now struggling to review data from the antibody therapies amid a flood of new vaccine submissions, and the need to conduct ‘business as usual’ reviews of other new drug submissions.

Lilly submitted an FDA request for an EUA in November for its new two antibody combination of bamlanivimab and etesevimab (from its Phase II BLAZE-1 trial, the first of its studies to show more solid data on hospitalizations in ambulatory patients).

This submission rested with the US regulator for months, but a decision finally came on 9 February. The FDA expanded Lilly's EUA to cover the combination, based on the new BLAZE-1 data showing the therapy's 70% improvement of risk of hospitalization or death compared to placebo.

Speaking in late January, Ricks had noted the unprecedented speed of R&D appearing to outstrip “the ability of governments and healthcare systems to absorb new information and implement new protocols and practices.”

Weinreich expressed his desire to see an EUA decision rapidly for Regeneron's new data. “We have got to get ahead of this curve and even eight weeks to the [next] data sets, 12 weeks to the announcement, and maybe two quarters to filing [is a long time and] means unfortunately, a lot of people are getting sick with this disease and a lot of people dying. And that's, in my opinion, not acceptable.”

Skovronsky shares this sense of urgency and the company has ended all placebo controls on its antibody trials as unethical. “The public health implications of these results could be enormous. A 70% reduction in hospitalization or death if broadly applied, as well as a marked reduction in death for any cause can have a profound effect on the course of the COVID-19 pandemic,” Skovronsky said.

This article was updated on 10 February to include a reference to the 9 February decision from the US FDA regarding the bamlanivimab and etesevimab EUA.

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