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Lilly’s EUA Timeline For COVID-19 Combo Antibody Depends On Safety Data, Manufacturing

Lilly’s EUA Timeline For COVID-19 Combo Antibody Depends On Safety Data, Manufacturing

Source : 'The Pink Sheet'

Eli Lilly and Company ’s next step in its strategy for COVID-19 monoclonal antibodies is about doubles: The timing of when it will seek an emergency use authorization for its two-antibody combo regimen depends on two factors – safety data and manufacturing confidence.

Getting the EUA from the US Food and Drug Administration might also double the number of Lilly’s COVID antibody products. The firm announced on 7 October that it had filed for an EUA for its single-antibody product, the SARS-CoV-2 spike protein neutralizing antibody therapy LY-CoV555.

An EUA for the combination therapy – which pairs LY-CoV555 (bamlanivimab) with another neutralizing antibody, LY-CoV016 (etesevimab) – could be filed in November after Lilly compiles more safety data and has more certainty about production capabilities.

The announcements, which included positive data about the combo’s impact on viral load, come about three weeks after interim Phase II data for the single-antibody showed viral clearance and reduction in hospitalization, but still left analysts hoping for the combo data.("Lilly Claims Proof Of Concept For Neutralizing Antibodies In COVID-19 Therapy" "Scrip" )

The rapid-fire announcements underscore the swift pace of COVID science, but also the race to market between rival firms’ antibody cocktails. Regeneron Pharmaceuticals, Inc.’s initial data from 275 patients in a Phase I/II/III study of its REGN-COV2 therapeutic regimen showed an ability to reduce viral load and cut time to alleviation of symptoms for non-hospitalized people infected with the virus. ("Regenerons COVID19 Antibody Cocktail Shows Early Promise But Does It Merit An EUA" "Scrip" )

The REGN-COV2 cocktail then garnered even bigger headlines after being administered to US President Donald Trump in early October after he contracted the virus. ("Executive Privilege How Giving Trump Special Access To Experimental COVID Treatment Could Backfire" "Pink Sheet" )

Analysts generally expect an EUA for the Regeneron regimen shortly, especially with the US biotech’s production capacity boosted thanks to a manufacturing tie-up with Roche Holding AG announced in August. ("Regeneron and Roche Await Data On Potential COVID-19 Blockbuster" "Scrip" )

While the race is good for patients, the numerous potential competing antibody products, along with other factors, likely mean that monoclonal antibodies won’t command the same soaring pricing in COVID that they have in cancer. (See sidebar.)

Trump himself endorsed the Regneron cocktail as a “cure” in a video posted to Twitter on Wednesday evening that also praises the Lilly product and promises free treatments for patients.

Lilly assured listeners during its investor call that it is increasing manufacturing capacity for COVID-19 therapies as well.

If Lilly’s EUA application for LY-CoV555 monotherapy is approved, the company says it could provide 100,000 doses at 700mg this month and up to 1 million doses before the end of 2020.

The firm expects to have 50,000 doses of the combination regimen available during this quarter, with increased capacity in place in early 2021 thanks to partnerships, including a recent manufacturing alliance with Amgen, Inc.. ("Coronavirus Update Moderna And Pfizer Respond To Vaccine Trial Transparency Demands" "Scrip" )

Lilly is also exploring lower doses of the combination to potentially stretch supply, as well as alternative delivery options since the single-antibody’s current standard dose of 2.8g – yes, that’s just a “g” – is time-consuming to manufacture and infuse.

To manage supply of the therapies, Skovronsky says Lilly’s current sense is that priority should go to infected patients who either are 65 or older and/or have body mass index of 35 or higher.

“That's sort of a crude way to get it at high-risk patients,” he admitted. “I think it makes sense to focus limited supply [of] antibodies on those patients. I think the precise definition of that population will come with discussions with the FDA, which, of course, will need to balance sort of the equitable distribution of drug and availability of drug with helping those who need it the most.”

Lilly’s most recent data concerns the combination therapy cohort of the Phase II BLAZE-1 study, which randomized 112 recently diagnosed patients with mild-to-moderate infections to a LY-CoV555/LY-CoV016 cocktail and 156 patients to placebo. The study met its primary endpoint: patients receiving the combination significantly reduced viral load by day 11 (p=0.011), achieving near complete viral clearance. In addition, treatment-arm patients also achieved significant reductions in viral load at day three (p=0.016) and day seven (p<0.001).

“This trial was designed primarily as a safety and biomarker study,” Lilly chief scientific officer Daniel Skovronsky told the call. However, “we did see very meaningful clinical efficacy signals. … Importantly, for both monotherapy and combination therapy, we really helped the outliers. We think COVID-19 is a disease of outliers. It's the people who don't clear their virus naturally, who are at highest risk of getting into trouble with this disease. And both monotherapy and combination therapy showed dramatic reductions in the percent of patients with persistently high viral load at day seven.”

Skovronsky pointed to another datapoint as potentially especially important – an exploratory analysis showed only 3% of treatment-arm patients had persistent high viral load at day seven of treatment, compared to 20.8% in the placebo arm.

In a same-day note, Canaccord Genuity analyst John Newman called the p-values reported by Lilly impressive but said more detail is needed on viral load reduction and magnitude of benefit. He noted that like Regeneron’s study, most patients receiving either study drug or placebo achieved near viral clearance by day 11 of treatment.

In a 7 October note, ISI Evercore analyst Umer Raffat said Lilly’s viral load-reduction data with the cocktail merits attention. “Notice how a combination of LY-COV555 and LY-COV016 (two different neutralizing antibodies) shows a >1 log benefit on viral load vs placebo by day seven,” he said.

“That’s a big deal. This will get attention. Recall remdesivir [Gilead Sciences, Inc.’s Veklury] was unable to show a benefit on viral load,” Raffat said. ("Gilead Sets Remdesivir Price Commits Nearly All NearTerm Supplies To US" "Scrip" )

Mizuho Securities USA analyst Vamil Divan called the cocktail data more promising than what Lilly’s monotherapy has shown so far, although the clinical meaningfulness of viral load reduction is debatable. “We are more encouraged by other benefits seen in the trial, including a greater than six-fold reduction … the rate of COVID-19-related hospitalizations and ER visits over placebo,” he wrote in a 7 October note.

As in the monotherapy portion of BLAZE-1, Lilly’s antibody cocktail also reduced risk of hospitalization. COVID-19-related hospitalization or emergency room visits occurred in 0.9% of patients receiving the combo and in 5.8% of patients on placebo, a relative risk reduction of 84.5% (p=0.049), Lilly noted.

Divan also pointed to a benign safety and tolerability profile and the fact that Lilly has seen no emergent putative resistance variants in patients treated with the combo regimen. Skovronsky noted during the investor call that Lilly had seen some potential resistance issues in the LY-CoV555 monotherapy data from BLAZE-1 that might correlate to 9% of patients in a more mature dataset.

“Consistent with our theory that the combination therapy would not have resistant variants, we've not seen any in preclinical experimentation, and the two antibodies have different amino acids that they contact and, therefore, different susceptibilities to resistance,” Skovronsky said. “We did not see a significant number of resistant variants in combination therapy, less than 1% right now.”

Lilly’s ongoing efforts with the neutralizing antibody therapies includes a BLAZE-1 confirmatory cohort in recently diagnosed patients with mild-to-moderate disease to test the cocktail’s ability to reduce hospitalization risk and persistent high viral load.

The pharma also hopes to have sufficient data to file a biologics licensing application for the combo as early as the second quarter of 2021.

By Joseph Haas