Dave Hering, Invivyd CEO

Nearly two years after the Omicron variant bested the lead candidate of its predecessor company, Adagiocausing its stock to plunge 79%, its founding CEO to resign, and the company to rebrandInvivyd has picked up the pieces with a new pipeline anchor, a monoclonal antibody (mAb) for preventing COVID-19 derived from the one that failed.

VYD222 is a re-engineered mAb that differs from the failed ADG20, now called adintrevimab, by eight different amino acids. That allows VYD222 to shift slightly where it binds with the spike protein of SARS-CoV-2—a change that Invivyd reasons will make the antibody much better able than adintrevimab at preventing symptomatic COVID-19 as the virus rapidly evolves, forming new variants.

The re-engineering that wrought VYD222 reflects a change in strategy since Adagio became Invivyd, toward developing a continuous repertoire of SARS-CoV-2 neutralizing mAbs.

“We’ve really shifted this thesis from a singular antibody that would be designed, developed, and assumed to have ongoing activity, to one where we seek to meet viral evolution and the speed of viral evolution that we’ve seen in SARS-CoV-2,” Invivyd CEO Dave Hering told GEN Edge. “We need to do this continuously. We need to be able to provide antibodies on a regular updated basis that meet the new variants.”

In September, Invivyd dosed its first patient in the Phase III CANOPY pivotal trial (NCT06039449), designed to assess VYD222’s ability to protect against symptomatic COVID-19 at a 4,500 mg dose.

The trial will evaluate some 750 participants in two cohorts: One of about 300 significantly immunocompromised participants, the other about 450 participants at risk of exposure to SARS-CoV-2, randomized 2:1 to VYD222 or placebo. The primary endpoint for Cohort A is serum neutralizing titers against relevant SARS-CoV-2 variants at Day 28. For Cohort B, the primary endpoint is safety and tolerability.

Investors responded with a mini-surge that sent Invivyd’s stock price up 7%, from $1.77 a day before the announcement to $1.89 a day after. Since then, the stock has fallen 20%, closing at $1.51 on Monday.

However, Michael J. Yee, equity analyst with Jefferies, took a more positive view of the company over the summer, giving Invivyd high marks for its pivotal study design.

“We think the Phase III design is smart and aligned with FDA, which will allow them to quickly enroll the needed [patients] for the minimally sufficient 28 days titer level data and ‘all-comer’ safety data, while leveraging clinical data from the previous adintrevimab as a prototype drug, to put together a comprehensive data package for a potential EUA in a timely fashion,” Yee wrote in August.

Potential EUA filing

Initial primary endpoint data is expected to be released by the end of 2023 or early in the first quarter of 2024. Invivyd hopes that data will be positive enough to support a potential emergency use authorization (EUA) filing for VYD222, based on what the company calls its “general alignment” with an FDA regulatory pathway for that and anticipated follow-on mAb candidates.

Invivyd is not disclosing how many patients have since joined the initial participant in CANOPY, though Hering said the trial is going as planned, and is encouraged by what he called “a fair amount of outreach” to the company’s investor relations from patients interested in joining the study.

“Interestingly, even people not immunocompromised have been quite interested in enrolling in the trial. I attribute that to, among other things, the fact that people are still seeing COVID-19 cases in their communities and in their circles,” Hering said.

Over the summer, Invivyd said VYD222 generated positive initial data in its ongoing Phase I trial (NCT05791318) showing that a single administration of VYD222 was generally well-tolerated at all three dose levels tested with no serious adverse events. All dose levels tested showed robust neutralization activity against Omicron XBB.1.5 at Day 7.

“Given the dose-dependent strong 7-day titer data shown in Phase I earlier, we think the Phase III could easily replicate Phase I with stronger powering testing only the highest Phase I IV [intravenous] dose of 4500 mg,” Yee observed. “The titer levels may come down a bit going from Day 7 to Day 28, but the 4500 mg dose showed huge titer levels up to 16,800 or a ~121-fold increase in titer level vs baseline in Phase I which leaves enough ‘buffer’ and we should still see a strong effect at this readout.”

“In an optimal scenario, IVVD could be launching under EUA for immuno-compromised [patients] in the label—and have revenue come in as soon as the second half of 2024, Yee predicted, while maintaining his firm’s “Hold” rating and 12-month price target of $1.50.

Multi-billion-dollar market

If that happens, he added, VYD222 could share a multi-billion dollar market for COVID-19-preventing antibodies with AstraZeneca, which is studying its next-generation long-acting antibody (LAAB) AZD3152 in the Phase II/III SUPERNOVA trial (NCT05648110).

Derived from B-cells donated by convalescent patients after SARS-CoV-2 infection, AZD3152 is optimized with a half-life extension and reduced Fc effector function and complement C1q binding platform expected to confer protection from COVID-19 for six months. A similar platform was used by Evusheld (tixagevimab and cilgavimab), AstraZeneca’s COVID-19 antibody combination which gained EUA last year, then lost authorization in January due to lack of effectiveness against newer variants. AstraZeneca has said it could make AZD3153 available by year’s end via EUA, if data from the trial proves positive.

Hering said the market for VYD222 is large enough, depending on how immunocompromised is quantified and classified, to range from 8 to 18 million people. “We started, as you can imagine, doing work to look into the different populations that make up immunocompromised organ transplant patients: People with different oncology and cancers, in particular blood cancers. People on immune suppressants for rheumatoid arthritis, or multiple sclerosis dialysis,” Hering said.

Although not technically considered immunocompromised, he noted, older adults develop problems with their immune systems: “You could also see in some of those populations a need for additional products beyond vaccines.”

“There’s a huge unmet need in particular, in these populations we’ve been talking about, and a real need to supplement the medicine cabinet with products like ours,” Hering said. “So, we’ve been working with regulators on how to do this efficiently and how to do this on an ongoing basis, really, with that goal in mind.”

Invivyd was launched as Adagio Therapeutics, a spinout of Adimab, at the height of the COVID-19 pandemic in 2020. After raising $130 million in two financing rounds, Adagio initially sought to develop ADG2, an engineered antibody that successfully offered complete protection against severe SARS-CoV-2 and SARS-CoV in mouse models.

By December 2020, Adagio had shifted its focus to adintrevimab, a newer version of ADG2 that was engineered to offer a longer duration of protection by extending the antibody’s serum half-life.

The new antibody, then called ADG20, showed promise against not only COVID-19 but also other coronaviruses, including SARS-CoV-1 (SARS-CoV) and MERS. “Our view was, it’s great to have a treatment for this particular outbreak, but why not aim a little bit higher and figure out a way of finding antibodies that neutralize the entire clade of coronaviruses that target human ACE2?” Adagio co-founder and CEO Tillman Gerngross, PhD, told GEN Edge in 2020, referring to angiotensin-converting enzyme 2.

By February 2021, Adagio took adintrevimab into the clinic, dosing the first patient in a Phase I trial, and rapidly advancing the mAb into two late-phase studies, the Phase III EVADE trial (NCT04859517) assessing the antibody’s prevention of COVID-19; and the Phase II/III STAMP trial (NCT04805671), evaluating ADG20 as a treatment for COVID-19.

Hitting turbulence

Adagio hit turbulence in December 2021, when the company acknowledged that ADG20 had failed to effectively neutralize the Omicron variant of SARS-CoV-2 (B1.1.529) in lab testing as the company had publicly predicted a month earlier. After results failed to fulfill Adagio’s rosy prediction, which had sent shares near doubling, investors punished the company severely, sending its shares cratering 79% in a single day to $7.26 from $34.26.

Two months later in February 2022, Gerngross resigned. He was succeeded by Hering, who had joined Adagio seven months earlier as COO. In September 2022, Adagio rebranded as Invivyd, a name intended to reflect the company’s business focus of applying its discovery platform to develop and commercialize antibodies that transcend the limits of the human immune system to better prevent and treat infectious respiratory viral diseases, starting with COVID-19.

Invivyd re-engineered adintrevimab into VYD222 using its integrated discovery platform:

  • First, monitor viral evolution and map common mutational escape routes to predict future variants of concern.
  • Use deep B-cell mining capabilities licensed from Adimab to isolate broadly neutralizing antibodies that target rare viral epitopes that are not under strong immune pressure, thus increasing the probability of sustained utility.
  • Engineer antibodies to improve their potency, breadth, biophysical properties, and developability. Using affinity maturation, Invivyd can engineer candidates to have high activity against specific viral variants it identifies as potential future variants of concern.

“When the omicron mutations occurred and reduced activity, this engineering re-established those bindings and recreated the activity and the binding. That has been really useful for a couple of reasons,” Hering said.

First, the re-engineering allowed Invivyd to apply a new regulatory framework for its Phase III trial allowing “immunobridging” through the use of data from serum-neutralizing titers as well as previously generated clinical trial data from a prototype mAb—in this case, adintrevimab (ADG20).

Second, adintrevimab met the FDA’s three criteria for a prototype mAb—it was initially established as a mAb; it completed pivotal, double-blind clinical trials; and it uses the same manufacturing platform and has activity against new current circulating variants, which VYD222 has shown. Adintrevimab remains within Invivyd’s pipeline, with trials having concluded and a package of data ready to submit for an EUA filing dependent on variant susceptibility: “If the virus mutates in a way that generates activity for ADG20, we still have inventory of the product.”

Adintrevimab and VYD222 are the only two named candidates listed in Invivyd’s pipeline. The company has three other COVID-19 mAb candidates, identified only as #3, #4, and #5, in discovery and preclinical phases—plus a mAb combination candidate for prevention of influenza, in the early discovery phase.

As new variants emerge, Hering said, Invivyd envisions developing several new antibodies in response. “Our approach is to look at a set of, basically, a family of different antibodies. VYD222 comes from this ADG20 lineage. We do see that ‘222 can be re-engineered further,” Hering said.

Zigging and zagging

“We’ve done some of that work already looking at it versus the current variants now, but we’re starting to look at this as, maybe we have a handful of families of model antibodies that are on different parts of the spike, protein, different areas of the receptor binding domain, non-overlapping epitopes that would give us coverage,” Hering explained. “So, if the virus zigs, we can zag. If it zags, we can zig.”

Hering said the annual model for availability of COVID-19 and flu vaccines could serve as a similar model for generating antibodies that keep pace with newer variants and any older ones that may re-emerge.

“We’re talking with regulators now about how that could work, but really thinking through that again, on a yearly basis, we would provide updated antibodies that work against that year’s variants,” he added.

Since COVID-19 emerged in late 2019, the FDA has granted EUAs to 13 treatments, only to withdraw five of those approvals as the treatments proved unable to combat newer variants of SARS-CoV-2. The withdrawn treatments include Regeneron Pharmaceuticals’ REGEN-COV combination (casirivimab and Imdevimab), Eli Lilly’s combination bamlanivimab and etesevimab, GlaxoSmithKline (GSK)’s sotrovimab, AstraZeneca’s Evusheld, and Lilly’s bebtelovimab.

Of the COVID-19 drugs on the market, the bestseller by far is Pfizer’s antiviral pill Paxlovid®, which generated $4.4 billion in revenues in the first nine months of this year. But that’s down 74% from the $17 billion Pfizer racked up during January-September 2022.

The drug most recently granted an EUA for COVID-19 covers a niche population. InflaRx’s mAb Gohibic (vilobelimab) was authorized in April to treat COVID-19 in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).

Invivyd’s headcount now stands at about 80–90 people, Hering said, in line with the 84 full-time employees reported as of February 1 but below the 101 disclosed a year earlier, according to regulatory filings. However, Invivyd plans to grow its staff further should it need additional people to commercialize VYD222.

“That’s still in the planning stages and we’re looking to see how that all unfolds,” Hering cautioned. “Certainly, we’re starting to build inventory to be ready for a launch, doing all of the different market access and different components that you would expect so that we could be ready for potential launch.”

Does Invivyd envision standing alone in infectious disease, or evolving into the infectious disease subsidiary of some biopharma giant?

“Too early to tell right now,” Hering said. “We’re very excited for what we’ve accomplished so far, and we’ll certainly look at that when and if that situation occurs. But right now, we’re focused on VYD222 and getting ready to potentially launch it.”

“Our belief is that COVID-19, unfortunately, is here to stay. And year after year people are going to need products like ours—hopefully, fingers crossed—to provide protection and prevention on an ongoing basis,” Hering added.

Alex Philippidis is senior business editor of GEN.

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