by Manasi Vaidya in New York and Reynald Castaneda in London.

Eli Lilly’s and Regeneron Pharmaceuticals’ bids to secure an FDA Emergency Use Authorization (EUA) for their respective monoclonal antibodies (mAbs) caused caution due to limited clinically relevant data. A premature EUA could hamper ongoing investigations needed to solidify efficacy data and offer better utility insight.

Despite data showing the mAbs led to a reduction in SARS-CoV-2 viral load, their primary endpoints, larger datasets on clinically-relevant secondary endpoints such as reduced hospitalisation are needed for stronger EUA consideration. However, regulatory experts did not entirely dismiss the possibility of an EUA since the FDA’s therapeutic benchmarks have been variable. The ability to manufacture adequate mAbs to provide access to patients is likely to be an issue in the event of a premature EUA.

On 7 October, Eli Lilly announced it had submitted an EUA request for LY-CoV555 monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate Covid-19. Later the same day, Regeneron released announced it had submitted a request for an EUA for its mAb cocktail REGN-COV2, although details are scarce on its setting. Regeneron’s REGN-COV2 cocktail consists of the mAbs REGN10933 and REGN10987. On the same day, US President Donald Trump, who had received REGN-COV2 in a compassionate use setting following a Covid-19 diagnosis, promoted both therapies in a video message and advocated for their authorisation.

Regeneron did not respond to questions posed in this article when contacted for comment. Eli Lilly did not return a request for comment by press time.

Early data supports application, but more needed for authorisation

To date, the FDA has been inconsistent about what safety and efficacy data are necessary for an EUA, said Efthimios Parasidis, professor of law and public health, Ohio State University, Columbus. It is difficult to say if the bar for an EUA is getting progressively tougher or more relaxed based on the three EUAs granted thus far, added a regulatory consultant who is a former FDA official. The first drug to get an EUA, hydroxychloroquine, had the weakest data, Gilead Sciences’ Veklury (remdesivir) had mediocre data, and the latest EUA recipient, convalescent plasma, had somewhat weaker data in comparison, the consultant added. The authorisations for hydroxychloroquine and chloroquine were later revoked.

At the FDA, there are career scientists who are likely to advocate evidence-based medicine, so FDA Commissioner Stephen Hahn would encounter pushback if he succumbs to political pressure to approve Eli Lilly and Regeneron’s EUA, the consultant added. However, because the President was treated with Regeneron’s cocktail, it could receive an EUA based on potentially weak data if he pushes for approval and the FDA caves to political pressure, noted the consultant.

Given the urgency of the pandemic, the EUA application for the mAbs is understandable, but the present dataset is only indicative of an efficacy signal, said Dr Robert Shafer, infectious disease professor, Stanford University, California. The two mAb therapies seem to be complementary and have an antiviral effect, said Dr Myron Cohen, associate vice chancellor for Global Health, University of North Carolina, Chapel Hill.

In the LY-CoV555 trial, the mAb did not meet its primary endpoint of viral load reduction at all three evaluated doses of 700mg, 2,800mg and 7,000mg. According to a 7 October presentation, the 11-day viral load reduction at all three doses of LY-CoV555 had a p-value of 0.87. LY-CoV555 appears active, but only the middle dose is statistically different from placebo, said the consultant. In persistently high viral load patients, viral load reduction with the 2,800mg dose versus placebo had a p value of 0.013. In the absence of peer-reviewed data it is difficult to understand if the success in the middle dose was only a statistical issue or another cause, said John Moore, PhD, professor of microbiology and immunology, Weill Cornell Medical College, New York.

REGN-COV2 reduced viral load through Day 7 in the seronegative patient group, which was described posthoc, compared with placebo in the high dose (p=0.03) and low dose (p=0.06), as per a 29 September presentation.

The antiviral effect or viral load reduction with both mAb therapies is unsurprising given preclinical evidence, but more data is needed to justify an EUA, noted Moore. The viral load reduction data still need to be analyzed in a peer-reviewed journal to be convincing on the clinical meaningfulness of the secondary clinical endpoints, said Dr Michael Dougan, assistant professor, Medicine, Harvard Medical School, Massachusetts.

In the Eli Lilly study, LY-CoV555 demonstrated an improvement in the Covid-related hospitalisation and emergency room visit secondary endpoint in all doses, Shafer noted. Among 309 patients who received LY-CoV55 at three different doses, the secondary endpoint of the rate of hospitalisations or emergency room (ER) visits was 1.6% compared to 5.8% with 156 patients on placebo (p=0.02). While the patient numbers are small and the trial was not designed for clinical efficacy, the reduction in hospital stay with LY-COV555 is impressive and has meaningful potential, said Dougan.

Regeneron’s mAb cocktail showed efficacy in seronegative patients, indicating mAbs are ideal for patients who have not generated their own immune system response, Shafer said. However, its EUA is unlikely to be restricted to these patients, as these tests are not standard in diagnosing Covid-19 patients, he noted. Still, it could trigger talks for such a test to be integrated in practice, he added.

Eli Lilly’s EUA is focused on high-risk patients, crudely defined as those over age 65 years or with a body mass index (BMI) greater than 35, but the precise definition is awaiting discussions with the FDA, as per a 7 October company call. This high-risk subgroup contains a significant number of patients, said Cohen. It is reasonable for Eli Lilly to limit the EUA to high-risk patients, but detailed data from the group is needed to weigh in on an EUA and guide medical decisions, said Dougan.

Guidelines on how to identify patients who are at risk of progression and should receive the mAb therapies are likely to emerge quickly from physician associations if the therapies get authorised, noted Cohen. Nevertheless, more efficacy data is needed as it would be awkward in practice to only have an EUA for outpatients but not in more severe cases, added Shafer. While more data is needed, there is a possibility additional data may be collected but not publicly released, noted Dougan. Regarding safety, there is a higher standard in the outpatient setting versus in a hospital setting where patients are constantly monitored, said Chad Landmon, chair, Intellectual Property and FDA Practice Groups, Axinn, Veltrop and Harkrider, Washington DC.

EUA may negatively impact trials, possible supply challenge

If an EUA is granted based on the publicly available data released so far, it could diminish the potential to learn how these mAbs work in the long term, said Shafer. There is the risk people would prefer to access therapies via an EUA rather than be in a trial where they could get placebo, added Shafer and Parasidis. The consultant agreed, adding it has been difficult to get clinical evidence on convalescent plasma since its EUA.

Granting an EUA based on inadequate data would have a long-term effect in diminishing public confidence on approved drugs, said Moore. Many surveys have indicated consumer scepticism on using vaccines due to low public confidence in the process, and the same applies to therapeutics, he said. If a vaccine is perceived to have been granted an EUA just because of the election, there will be even more patient reluctance to take it to avoid the virus, said Landmon. However, if a patient already has Covid-19, they are likely to want to take a drug with an EUA, he added.

An overall challenge with mAbs is the difficulty to meet demand since there are huge manufacturing requirements, Shafer said. Once an EUA is granted, mAbs are unlikely to be available right away, he added.

Manufacturing capacity is the main constraint for mAbs, said an Eli Lilly spokesperson on the investor call. Eli Lilly plans to study its lowest dose of 700mg to stretch its supply and can provide only one million 700mg doses in 4Q, as per its investor call. Regeneron only has doses for 50,000 patients but expects to have 300,000 doses available in the next few months, as per its 7 October statement. President Trump has said the drug will be free of cost to patients and the military will be responsible for its distribution. If the drugs are in short supply, those with underlying illnesses will have to be prioritised, said Shafer, adding the same was done with Veklury.

Manasi Vaidya is a Senior Reporter and Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.