A University of Washington (UW) spinout focused on developing vaccines for COVID-19 and other respiratory illnesses says the $100 million in Series B financing it just completed will enable it to bring its first two candidates into the clinic this year.
Seattle-based Icosavax plans to launch Phase I studies of its COVID-19 vaccine IVX-411, as well as of IVX-121, a respiratory syncytial virus (RSV) candidate. Proceeds from the financing will support development of both programs through early clinical development. Icosavax hopes to evolve IVX-121 into a bivalent vaccine that will also target human metapneumovirus (hMPV).
Both candidates, and others being developed by the company, use a virus-like particle (VLP) technology developed at UW’s Institute for Protein Design (IPD).
“[VLPs] work well with related pathogens, and hMPV and RSV are in fact related. If you could have a vaccine that would protect you against one the leading causes of pneumonia, versus a vaccine that would protect you against two leading causes of pneumonia, what would you want?” Icosavax CEO Adam Simpson told GEN Edge.
“We think we have a technology that’s particularly suited to both the combination approach and then targeting older adults,” Simpson said. “The challenge has been a protein-folding problem: How do you use VLPs as a modality for other different antigens or heterologous antigens?”
The solution, developed by IPD, uses a two-component, computationally designed protein structure that self-assembles, without interfering with the critical three-dimensional conformation of the displayed antigens. The individual protein components are expressed and purified using traditional recombinant protein techniques, then spontaneously self-assemble into VLPs when mixed together.
The protein components have generated high yield and stability, according to Icosavax, suggesting that manufacture of these VLP vaccines will be highly scalable. Icosavax licenses the IPD technology from UW for a variety of infectious diseases—although for COVID, the company also holds worldwide rights and an exclusive option for North America and Europe.
The technology is designed to address a challenge that has impeded wider use of VLP vaccines: How to construct and manufacture VLPs capable of displaying complex viral antigens that have been difficult to successfully produce at scale, including for RSV and hMPV.
VLPs are icosahedral or rod-shaped structures formed through self-assembly of viral structural proteins. The nanoparticle-sized structures were first identified in 1968 in the sera of patients with Down’s syndrome, leukemia and hepatitis.
High neutralizing titers in adults, long duration of protective immunity, and the ability to be used as combination vaccines are qualities shown by naturally occurring VLPs such as those used in the most popular marketed vaccines based on the technology.
The best-selling of those is Pfizer’s Prevnar 13® / Prevenar 13® (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]), which generated $5.85 billion in total revenues last year, all but flat from $5.847 billion in 2019. Next-highest is Merck & Co.’s Gardasil® (Human Papillomavirus quadrivalent vaccine, recombinant) and next-gen version Gardasil® 9 (Human Papillomavirus 9-valent Vaccine, Recombinant), which racked up a combined $3.94 billion in 2020, up 5% from a year earlier.
“RSV and hMPV are each individually of similar [market] size as pneumococcal as a trigger of pneumonia, but there are no licensed or approved vaccines for either RSV or hMPV, so we think there’s a major unmet medical need here,” Simpson said.
In a study published in January, Fortune Business Insights predicted more than six-fold growth in the total RSV therapeutics market in this decade, surpassing $4 billion in 2027 from $609.2 million last year, driven by vaccines as well as drugs. The hMPV market appears smaller, estimated in 2016 to be $1 billion ($1.1 billion in today’s dollars) according to ViroNovative, the Dutch developer of vaccines, antibodies, antivirals, and diagnostics for hMPV that spun out of Erasmus Medical Center, where the virus was discovered in 2001.
Among drug developers setting their sights on both respiratory diseases is Moderna—whose mRNA-based COVID-19 vaccine has won FDA and European emergency authorizations.
Moderna’s wholly owned vaccine candidate mRNA-1653 is designed to protect against both hMPV and Parainfluenza virus type 3 (PIV3). In February, Moderna completed enrolling its first cohort in a Phase I study of seropositive children 1–3 years old (NCT04144348). The study has an estimated primary completion date of September 2022.
Moderna is also studying a wholly owned mRNA-based vaccine candidate for RSV, mRNA-1345. In January, Moderna updated its protocols for its Phase I trial (NCT04528719) to include evaluation of mRNA-1345 in adults over age 50 (for which dosing has begun) and a wider range of children (12–59 months from 12–36 months). Moderna also said it intends to assess combinations of mRNA-1345 with its vaccine candidates against other respiratory pathogens in children and in older adults.
Further along in Phase II and III trials is nirsevimab, a monoclonal antibody being co-developed by AstraZeneca and Sanofi to prevent lower respiratory tract infections (LRTI) caused by RSV. Nirsevimab was granted a Promising Innovative Medicine (PIM) Designation by the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) in January, six months after generating positive Phase IIb data. Sanofi has agreed to pay AstraZeneca up to €615 million (up to $733 million) under a partnership launched in 2017.
Target of choice
Icosavax’s RSV vaccine candidate IVX-121 incorporates a stabilized prefusion F antigen licensed from the NIH’s National Institutes of Allergy and Infectious Disease (NIAID). In a 2019 Phase I proof of concept study published in Science, a team of NIAID researchers showed how the antigen, called DS-Cav1, evaluated as a vaccine, elicited substantially more high-quality antibody titers than those typically generated using earlier RSV immunogens in mice and macaques.
“The learning was that people went after RSV F as the target of choice for RSV because the only approved product in the RSV space targeted RSV F,” Simpson said, referring to Synagis® (palivizumab), a monoclonal antibody marketed by Arexis (Swedish Orphan Biovitrum) and indicated for preventing serious lower respiratory tract disease caused by RSV.
“RSV F is a shape shifter, so it looks one way postfusion, after it’s already invaded the cell, versus how it looks in its prefusion version,” Simpson explained. “If you’re immunizing against what the virus looks like after it has already invaded the cell, it’s too late.”
Icosavax’s other clinic-bound candidate is IVX-411, a SARS-CoV-2 receptor binding domain VLP vaccine incorporating a self-assembling protein nanoparticle that displays 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain in a highly immunogenic array.
Preclinical data has suggested that Icosavax’s VLP COVID-19 vaccine may offer the potential for one-dose administration and thermal stability, which Simpson said would allow for their storage at conventional freezer temperatures rather than at ultra-low temperatures, as required of some COVID-19 vaccines. Those qualities are expected to be studied further in the clinic, as is how well IVX-411 can protect against variant strains of SARS-CoV-2.
In a preclinical preprint posted February 11 on bioRxiv, Icosavax’s COVID-19 vaccine, combined with any of five different adjuvants studied, induced substantial neutralizing antibodies and CD4 T-cell responses after two consecutive immunizations in non-human primates.
When combined with AS03—an alpha-tocopherol-containing squalene-based oil-in-water emulsion used by GlaxoSmithKline (GSK) in its A/H1N1 pandemic flu vaccine Pandemrix—IVX-411 showed geometric mean titers, relative inhibitory concentration of 50% (GMT IC50) of 1,568 and 1,108 on day 126 and 154, respectively, compared with 775 for Moderna’s FDA emergency-authorized COVID-19 vaccine (mRNA-1273) in healthy young adults, in a focus reduction neutralization test (FRNT) assay.
High yield and stability
Last year, IVX-411 and precursor candidates were shown in mice to induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a five-fold lower dose, according to a study published October 30 in Cell. The study’s corresponding authors included Neil King, PhD, a UW assistant professor based at IPD who also chairs Icosavax’s Scientific Advisory Board.
King co-founded the company with David Baker, PhD, IPD’s director and a Howard Hughes Medical Institute (HHMI) investigator.
“The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable,” King and colleagues observed. “These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.”
Soon after that study, Icosavax initiated GMP manufacturing, with Amgen agreeing to manufacture a key intermediate for the initial clinical studies.
Icosavax isn’t the only vaccine developer applying VLPs to fight COVID-19. Medicago and GlaxoSmithKline (GSK) recently launched Phase III clinical testing of Medicago’s plant-derived COVID-19 vaccine candidate in combination with GSK’s pandemic adjuvant, as part of an ongoing Phase II/III study. Medicago uses the leaves of a plant as bioreactors to produce the S-spike protein which self-assemble into VLPs for use in the CoVLP vaccine candidate.
Another vaccine developer, VBI Vaccines, has applied enveloped virus-like particles (eVLPs) designed to mimic the structure of viruses to develop two vaccines against COVID-19: VBI-2901, a trivalent pan-coronavirus vaccine candidate expressing SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins on the same particle; and VBI-2902, a monovalent vaccine candidate expressing the SARS-CoV-2 spike protein. Last month, VBI began enrolling participants in an adaptive Phase I/II trial of VBI-2902, adjuvanted with aluminum phosphate.
Last year, Icosavax won two grants toward its COVID-19 vaccine program: The Bill & Melinda Gates Foundation awarded $10 million toward supporting the program through the planned first in human Phase 1 clinical trial in young and older adults. And Open Philanthropy, whose main funders include Facebook co-founder Dustin Moskovitz, awarded $6.5 million to support development of Icosavax’s vaccine platform technology as well IVX-411.
Open Philanthropy’s $6.5 million was included within the $100 million Series B round. Icosavax also plans to use proceeds toward pipeline expansion, though the company isn’t saying if it will do so within the respiratory space, in other therapeutic areas, or both.
“The exciting thing is that the platform can be can be used for all kinds of areas,” Simpson said.
The Series B brings to $161 million the total Icosavax has raised since it was established in 2018 as the fourth spinout to emerge from IPD’s Translational Investigator Research Program. Simpson joined the company that year while continuing as CEO of IPD’s second spinout, PvP Biologics, which was acquired last year by Takeda Pharmaceutical for $330 million. Icosavax emerged from stealth mode in 2019 with $51 million in Series A financing.
The Series B was led by RA Capital Management. RA Capital’s founder and Managing Partner Peter Kolchinsky, PhD, is joining Icosavax’s board in conjunction with the financing. RA Capital was joined by new investors Janus Henderson Investors, Perceptive Advisors, Viking Global Investors, Cormorant Asset Management, Omega Funds, and Surveyor Capital (a Citadel company). Icosavax’s earlier investors also participated, including Qiming Venture Partners USA, Adams Street Partners, Sanofi Ventures, and ND Capital.
Icosavax is among growing companies that have completed financings or initial public offerings large enough to help reinvigorate Seattle’s life sciences cluster, long known for its top-flight universities and institutions like the Gates Foundation. The region ranks eighth among GEN’s Top 10 U.S. Biopharma Clusters.
With its latest financing, Icosavax plans in part to continue growing its staff, now at 17 full-time employees. “Our goal is to hire eight to 10 people over the next year. We are absolutely looking to grow to support the operations in Seattle,” Simpson said.
“Setting aside COVID as an indication, there has been a reinvigoration of the vaccine space, and a recognition, frankly, that the world needs vaccines,” Simpson observed. “When you look at things like RSV and hMPV that are major causes of viral pneumonia with no vaccines, I think there’s a renewed interest in or appreciation in technologies that that can help in indications like that.”
Is that interest strong enough for Icosovax to consider going public?
“We’re certainly aware of the market and, as well as the resurgence of interest in the vaccine space,” Simpson said. “The near-term plan is just to execute based on the financing that we raised.”