AbCellera and Eli Lilly have advanced into the clinic a second co-developed antibody designed to fight COVID-19—as well as several variants of the virus that have shown resistance to the companies’ first co-developed antibody, bamlanivimab (LY-CoV555).
The new, AbCellera-discovered antibody, LY-CoV1404, successfully neutralized SARS-CoV-2 and five regional variants of the virus, according to preclinical data included in a preprint posted on bioRxiv on Monday.
LY-CoV1404 entered the Phase II BLAZE-4 trial (NCT04634409), which was expanded to study the antibody’s safety and effectiveness in patients with mild-to-moderate COVID-19, alone and in several combinations—including one with bamlanivimab, and one with another antibody that Lilly is developing with Shanghai Junshi Biosciences, etesevimab (LY-CoV016 or JS-16).
“It certainly could be a next-generation antibody to those antibodies or other ones that are out in the market or that have emergency use authorization (EUA),” AbCellera CEO Carl Hansen, PhD, told GEN. “You have to temper that with the fact that it’s in clinical trials, we don’t have the data, and you never have the data until you do. But given what we know about it preclinically, we absolutely see this having a role for whatever [combination antibody] product lasts well into the future.”
Hansen added that Lilly will ultimately drive clinical and commercial decisions on LY-CoV1404—such as whether to pursue authorizations as monotherapy, in combination with other antibodies, or both, and when.
(A Lilly spokesperson at deadline had not responded to GEN questions about clinical and commercial development of the antibody.)
Lilly and AbCellera successfully developed bamlanivimab last year, with the FDA granting an EUA for the antibody alone in November—the first neutralizing monoclonal antibody to receive an EUA for treatment for mild-to-moderate COVID-19 Two weeks later, Regeneron Pharmaceuticals received an EUA for its two-antibody cocktail REGEN-COV.
More recently, the FDA granted another EUA for bamlanivimab in combination with etesevimab in February. But the following month, the U.S. government halted distribution of bamlanivimab monotherapy, citing a sustained increase in variants of SARS-CoV-2 that were resistant to the monotherapy, but is continuing to distribute the combination therapy.
During the first quarter, Lilly generated $810 million of net product revenue from both bamlanivimab monotherapy and bamlanivimab-etesevimab. Most of that revenue, $650.6 million, was generated in the United States.
Lilly and AbCellera estimate that more than 400,000 patients have been treated with either the monotherapy or combination, potentially preventing 11,000 deaths and more than 22,000 hospitalizations.
Last year, AbCellera received from Lilly $15 million in payments tied to achieving clinical and approval milestones, and $198.3 million in royalty revenue related to bamlanivimab, according to AbCellera’s Form 10-K annual report for 2020, filed March 30.
As for LY-CoV1404, AbCellera and Lilly have stated that they expect to shepherd that antibody through clinical development at least as quickly as they did bamlanivimab. From a single blood sample obtained from a convalescent patient, AbCellera said, it joined with partners within three weeks in identifying a viable antibody drug candidate that advanced into clinical testing 90 days after initiation of the program.
“Our goal is to have the clinical testing done by mid-summer and be applying for emergency use authorization shortly thereafter,” Hansen said.
Addressing analysts on Lilly’s quarterly earnings call on April 27, Daniel M. Skovronsky, MD, PhD, senior vice president and CSO, said Lilly had advanced LY-CoV1404 into clinical studies “in case new combinations are needed to fight variants.” Skovronsky said Lilly will spend $100 million this year toward the development of LY-CoV1404—one reason why the company narrowed, but raised the low end of its projected R&D spending range this year to between $6.9 billion and $7.1 billion, from the previous range of $6.5 billion to $7.7 billion.
LY-CoV1404, previously called LY3853113, has been developed from a fully human monoclonal antibody identified from a blood sample obtained two months after the onset of symptoms from a convalescent COVID-19 patient.
In the preclinical study, LY-CoV1404 was shown to bind to or neutralize the original strain of SARS-CoV-2 and variants first identified in the U.K. (B.1.1.7), South Africa (B.1.351), Brazil (P.1), California (B.1.426 and B.1.429), and New York (B.1.526).
It was in response to the South Africa variant that AbCellera began development work on LY-CoV1404. The company used the same platform with which it identified bamlanivimab last year, continuing to screen patient samples.
“At that point, we kept going,” Bo Barnhart, PhD, AbCellera’s scientific director, told GEN. “We kept looking for additional antibodies, and we have thousands of antibodies now to the spike protein for SARS-CoV-2. We had the ability to very quickly do an analysis of those antibodies that we had in hand when the variants really popped up and started taking over and causing problems within the pandemic.
“We were able to very quickly identify ‘1404. We knew that it was a very potent antibody, and we tested it against all of these variants, and we identified it as one that continued to be a strong neutralizer against the variants of concern,” Barnhart said.
That potency, AbCellera reasoned, could allow for a smaller dosage than the 700 mg dose authorized for bamlanivimab and 1,400 mg dose set for etesevimab, and potentially could enable subcutaneous injection rather than an infusion for either treatment of or protection from COVID-19.
“We believe that in the long run that’s going to be a game changer because it means you can much more easily get it to patients,” Hansen said. “You can manufacture more doses for a given amount of manufacturing capacity and can realistically think about rolling this out en masse in regions where COVID-19 is flaring up—examples like India. Wouldn’t it be wonderful if we had this ready for a country like that right now?”
In the preclinical study, LY-CoV1404 was shown to bind to those variants in the presence of 24 receptor-binding domain (RBD) mutations known to be resistant to other clinical-phase monoclonal antibodies. Two of those mutations, E484Q and L452R, appear in the B.1.617 variant first detected in October in India, which has seen a spike in cases in recent weeks.
“It is active to those mutations as well, which I think is really important,” Barnhart said. “We have confidence that this antibody will be active against that variant in addition.”
LY-CoV1404 was also shown to bind with high affinity to an epitope on the Spike (S) glycoprotein RBD, where it blocked interaction between ACE2 and the S protein.
That binding epitope includes amino-acid residues N501 and N439, the most prevalent mutations in the GISAID EpiCoV database. LY-CoV1404 neutralized two variants (B.1.1.7 and B.1.351) that both carry the N501Y mutation, as potently as wild-type virus in pseudovirus assays, while retaining full functional neutralization against pseudovirus with the N439K mutant, AbCellera said.
An in-depth assessment of mutations that could inhibit neutralization of LY-CoV1404 identified two other residues (444 and 445) that are very rarely mutated in the general population. Of the mutations tested, only K444Q, V445A, and G446V impacted LY-CoV1404 binding, and of these, only 0.005% of samples contained the known resistance V445A, while no occurrences of K444Q were observed.
“The unique binding epitope of LY-CoV1404, together with the low frequency of mutations observed within this epitope, indicate that this antibody could provide a highly effective solution to the spread of known variants and may provide a potent treatment against current VOCs [variants of concern], and emerging variants as a critical, complementary approach to vaccination,” the preclinical study concluded.
One trial, four antibodies
Based on the positive preclinical data, Lilly and AbCellera advanced LY-CoV1404 into BLAZE-4, a Phase II trial designed to assess—both individually and in combination—‘1404 with bamlanivimab, etesevimab, and VIR-7831, a monoclonal antibody being developed by Vir Biotechnology and GlaxoSmithKline.
“There is concern about variants, and I think it’s really commendable that companies that are playing in this space would consider combining forces to make sure that treatments are available not months from now, but right away or as soon as possible, at least,” Hansen said.
The placebo-controlled study’s estimated primary completion date is August 25. BLAZE-4 is projected to enroll 1,416 participants with early symptoms of mild-to-moderate COVID-19.
COVID-19 is one of the nine targets for which AbCellera and Lilly agreed to partner on antibody discovery through a multi-year strategic research collaboration and license agreement that was announced in May 2020, and whose value has not been disclosed.
The agreement expanded upon the collaboration launched in March 2020 when Lilly agreed to co-develop the most promising of 500+ fully human antibody sequences AbCellera identified from a blood sample of one of the first U.S. patients to recover from COVID-19. Those antibodies were assessed for potential against SARS-CoV-2 by the Dale and Betty Bumpers Vaccine Research Center of the NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
Lilly is one of 27 partners with which AbCellera has carried out “well over 100” discovery programs, Hansen said, of which two are in COVID-19; the rest cover a variety of therapeutic areas that include cancer, cardiovascular diseases, inflammation, and neurodegeneration.
AbCellera does not currently have manufacturing capability for antibodies: “One of the drivers for the partnership with Eli Lilly was that we could bring our front-end discovery engine, and connect it to their world-class capabilities, frankly, in manufacturing and clinical development, and in commercialization,” Hansen said.
That need will be addressed, AbCellera said, when it completes construction of the new global headquarters, breaking ground last month. The new two-building, 380,000-square-foot HQ will rise in Vancouver, developed by the company with Western Canada-based commercial developers Dayhu Group and Beedie. The facilities are expected to be completed in 2023 and 2024.
“I like to describe it as a technologically advanced factory that can take in therapeutic concepts and target ideas, and at greater speed, and with greater effectiveness and in many cases, in places where others have failed, create the molecules that then move into clinical testing,” Hansen said. “This would be a facility that could support, generally, Phase I and Phase II trials, and would have a capacity of doing somewhere between 35 and 40 batches per year.”
The new headquarters will enable AbCellera to add hundreds of new staffers to its current workforce of 250 people.
“Our business model is to work broadly with the industry, so we see ourselves as an enabler of biotech writ large,” Hansen added. “And to deliver on that goal we’re going to need to expand this company very considerably over the next few years.”