TrialSite shared that Eli Lilly’s (Lilly) monoclonal antibody program targeting COVID-19 appeared to be working, at least according to some trial site reports. Now Lilly is moving to secure an emergency use authorization for its monotherapy (LY-CoV555) to the U.S. Food and Drug Administration (FDA), as its primary COVID-19 monoclonal antibody competitor Regeneron also just submitted an EUA request to the FDA. The Midwestern American company starts with an EUA request for LY-CoV555 monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19. What’s Lilly’s basis? They report now on engagement with FDA and other global regulators based on new data both for the monotherapy and of the combination therapy (LY-CoV016) that met primary and secondary endpoints, reducing viral load, symptoms and hospitalizations. The company plans to initiate a large open-label pragmatic study in COVID-19 patients in October. TrialSite acknowledges the monumental collaborative effort involved—for the monotherapy thanks to A) breakthrough technology developed by AbCellera, a University of British Columbia spinoff, B) a partnership with the National Institutes of Allergy and Infectious Diseases (NIAID) Vaccine Research Center, and, importantly, C) the work of Lilly scientists, working tirelessly around the clock to find the right targets. Moving forward, the investigational products will be known as bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016).
Lilly is working with two monoclonal antibodies, including one that it developed based on the powerful discovery technology from AbCellera and the second originates from China. LY-CoV555 was made possible due to a collaboration with AbCellera and NIAID Vaccine Research Center and Lilly scientists while LY-CoV016 was picked up in a co-development licensing deal with China’s Shanghai Junshi Pharma.
What is an emergency use authorization?
According to the FDA, the EUA authority enables FDA to help strengthen the U.S. public health protections against threats such as COVID-19 by facilitating the availability and use of Medical Countermeasures Initiative (MDM) required during public health emergencies. The authority comes from section 564 of the Federal Food, Drug and Cosmetic Act (FD&C Act), authorizing the FDA Commissioners to allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by threats such as COVID-19.
What Therapies has FDA granted EUA targeting COVID-19 thus far?
To date, the FDA has accepted only two EUAs targeting COVID-19, including Remdesivir and convalescent plasma.
What’s the basis for the EUA?
Data from a new interim analysis of the BLAZE-1 clinical trial showed that combination therapy with two of Lilly’s SARS-CoV-2 neutralizing antibodies reduced viral load, symptoms and COVID-related hospitalization and ER visits. The randomized, double-blind, placebo-controlled Phase 2 study evaluated LY-CoV555 and LY-CoV016, which bind complementary regions of the SARS-CoV-2 spike protein, for the treatment of symptomatic COVID-19 in the outpatient setting. The combination cohort enrolled recently diagnosed patients with mild-to-moderate COVID-19, who were assigned to 2800 mg of each antibody (n=112) or placebo (n=156).
The combination therapy significantly reduced viral load at day 11 (p=0.011), meeting the primary endpoint of the study. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11. Further, combination treatment reduced viral levels at day 3 (p=0.016) and day 7 (p<0.001)—earlier time points during the course of infection when higher viral loads are typically seen. Combination therapy also significantly reduced the time-weighted average change from baseline from day 1 to 11. An exploratory analysis showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0 percent) versus placebo (20.8 percent), corresponding to a nominal p value of p<0.0001 without multiplicity adjustment. No emergent putative resistance variants have been observed thus far in patients treated with combination therapy.
Combination therapy also met prespecified clinical endpoints, including the time-weighted average change from baseline in total symptom score from day 1 to 11 (p=0.009). The improvement in symptoms was observed as early as three days after dosing and was similar in magnitude and timing to improvements previously seen with LY-CoV555 monotherapy. The rate of COVID-related hospitalization and ER visits was lower for patients treated with combination therapy (0.9 percent) versus placebo (5.8 percent), a relative risk reduction of 84.5 percent (p=0.049). This was also similar to observations for LY-CoV555 monotherapy. Note this material is not peer reviewed yet. Lilly is working to publish the monotherapy and combination therapy data in peer-reviewed journals as soon as possible.
No Material Safety Concerns
Combination therapy has been generally well tolerated with no drug-related serious adverse events. In LY-CoV555 monotherapy studies, there have been isolated drug-related infusion reactions or hypersensitivity that were generally mild (two reported as serious infusion reactions, all patients recovered). Treatment emergent adverse events were comparable to placebo for both LY-CoV555 monotherapy and combination therapy.
Is Lilly read to commence manufacturing of the investigational product?
Yes. That’s because, as Lilly shared in their recent press release, the Indianapolis-based pharmaceutical company invested in large-scale manufacturing of both antibodies at risk—meaning they started investing the money in production before data demonstrated their potential to become a meaningful therapeutic option for COVID-19.
For the monotherapy, LY-CoV555 (bamlanivimab), Lilly is focused on the 700 mg dose because similar clinical effects were observed across all dose levels teste in the clinical trial known as BLAZE-1. Lilly reports that it could supply as many as 1 million doses of 700 mg LY-CoV555 monotherapy in Q4 2020, with 100,000 available in October.
As far as the supply of the combination therapy, Lilly anticipates it will have 50,000 doses available in Q4 2020. The supply of this combination therapy will increase substantially starting in Q1 2021 as additional manufacturing capacity is available via the Lilly partnership with Amgen (NASDAQ: AMGN). Lilly is also pursuing partnerships to offer antibodies to resource-limited countries.
What is the regulatory update?
Based on the combination therapy data, along with the previously disclosed findings for LY-CoV555 monotherapy, Lilly has engaged global regulators, including the FDA regarding potential EUA. Lilly has now submitted an initial request for EUA for LY-CoV555 monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19. We expect to submit a subsequent request for EUA for combination therapy in November, pending clinical trial enrollment, once additional safety data accumulate and sufficient supply is manufactured. Lilly anticipates having data to support a biologics license application (BLA) submission for combination therapy as early as Q2 2021. Conversations with global regulators are ongoing.
The BLAZE-1 clinical trial (NCT04427501) continues to enroll a confirmatory cohort of higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19, testing the ability of the antibody combination to reduce the number of patients with persistent high viral load and reduce COVID-related hospitalizations. In addition, Lilly is studying lower doses of combination therapy and alternative delivery options in planned or ongoing clinical trials. Other ongoing clinical trials include a Phase 3 study of LY-CoV555 monotherapy for the prevention of COVID-19 in residents and staff at long-term care facilities (BLAZE-2, NCT04497987). In addition, LY-CoV555 monotherapy is being tested in the National Institutes of Health-led ACTIV-2 and ACTIV-3 studies of ambulatory and hospitalized COVID-19 patients. Data from these other ongoing trials are not yet available. Thus far, over 850 trial participants have been dosed with LY-CoV555 (alone or in combination with LY-CoV016), contributing to the safety data supporting this potential treatment.
Open-label pragmatic study in COVID-19 outpatients
To generate additional efficacy and safety data, Lilly plans to initiate a pragmatic, open-label study in the coming weeks, enrolling patients treated with either monotherapy or combination therapy, with a focus on collecting data regarding hospitalizations, deaths and safety.
About the Investigational Products
About bamlanivimab (LY-CoV555)
LY-CoV555 is a potent, neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. LY-CoV555 emerged from the collaboration between Lilly and AbCellera to create antibody therapies for the prevention and treatment of COVID-19. Lilly scientists rapidly developed the antibody in less than three months after it was discovered by AbCellera and the scientists at the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center. It was identified from a blood sample taken from one of the first U.S. patients who recovered from COVID-19.
Lilly has successfully completed enrollment and primary safety assessments of LY-CoV555 in a Phase 1 study of hospitalized patients with COVID-19 (NCT04411628) and long-term follow-up is ongoing. A Phase 2 study in people recently diagnosed with COVID-19 in the ambulatory setting (BLAZE-1, NCT04427501) is ongoing. Lilly recently initiated a Phase 3 study for the prevention of COVID-19 in residents and staff at long-term care facilities (BLAZE-2, NCT04497987). In addition, LY-CoV555 is being tested in the National Institutes of Health-led ACTIV-2 and ACTIV-3 studies of ambulatory and hospitalized COVID-19 patients.
About etesevimab (LY-CoV016)
LY-CoV016 (also known as JS016) is a recombinant fully human monoclonal neutralizing antibody, which specifically binds to the SARS-CoV-2 surface spike protein receptor binding domain with high affinity and can effectively block the binding of the virus to the ACE2 host cell surface receptor. Point mutations were introduced into the native human IgG1 antibody to mitigate effector function. A SARS-CoV-2 challenge study was conducted in rhesus macaques and showed LY-CoV016 is effective for both prophylactic and therapeutic venues against SARS-CoV-2 infection. Lilly licensed LY-CoV016 from Junshi Biosciences after it was jointly developed by Junshi Biosciences and Institute of Microbiology, Chinese Academy of Science (IMCAS). Junshi Biosciences leads development in Greater China, while Lilly leads development in the rest of the world.
Lilly has successfully completed a Phase 1 study (NCT04441931) of LY-CoV016 in healthy U.S. volunteers to evaluate the safety, tolerability, pharmacokinetics and immunogenicity. LY-CoV016 has been well tolerated and no drug-related severe adverse events (SAEs) have been observed to date.
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