hemagglutinin

GSK and Vir Biotechnology struck up their influenza R&D collaboration three years ago, aiming to build on a respiratory drug relationship forged at the start of the Covid-19 pandemic. The British pharmaceutical giant ended the Covid alliance last year. Now the influenza partnership is winding down too. The two companies have terminated their research collaboration on Vir’s antibodies for influenza, Vir said in its report of fourth quarter and full year 2023 financial results on Thursday. San Francisco-based Vir retains rights to these antibodies and is now free to seek other partners to advance their development. The end of the influenza collaboration follows the Phase 2 failure of one of the partnered programs, VIR-2482. This antibody, which came from Vir’s proprietary antibody discovery platform, is designed to target a region on the neuromindase protein found on the surface of both influenza A and B strains. A mid-stage clinical trial was evaluating VIR-2482 for the prevention of seasonal influenza A illness. Last July, Vir reported preliminary results showing the antibody did not meet either primary or secondary efficacy goals of the trial. In its report of financial results, Vir said it expects a full analysis of the trial data will publish in a scientific journal in the second quarter of this year. Leerink Partners analyst Roanna Ruiz wrote in Friday research note that the termination of the alliance makes sense, given the Phase 2 failure of VIR-2482. But she added that Vir executives said they are pursuing partnerships for their next-generation influenza programs, which span antibodies and antibody drug conjugates. VIR-2981, an antibody drug candidate for both influenza A and influenza B, is one of the programs Vir said it expects will have an investigational new drug application filed with the FDA in the next 12 to 24 months. The company is also developing VIR-2482 as a prophylactic for influenza A. This antibody targets hemagglutinin, a protein on the surface of the influenza virus. Vir said lab test results show that this antibody has been able to cover all major strains influenza A strains since the 1918 flu pandemic. When GSK and Vir began working together in 2020, the focus was Covid-19 drug R&D. The pharma giant made a $250 million equity investment in its new partner to begin that partnership, which yielded the antibody drug sotrovimab. Though the drug, brand name Xevudy, landed FDA authorization during the pandemic, the FDA later withdrew that regulatory status as the drug proved ineffective against the omicron strain. The influenza partnership began in 2021 with GSK paying Vir $225 million up front and increasing its equity stake by $120 million. Vir stood to receive up to $200 million more upon the achievement of milestones. Vir’s internal pipeline includes a drug candidate in Phase 2 testing for chronic hepatitis delta and another program in Phase 2 testing for chronic hepatitis B. VIR-1388, a T cell vaccine for preventing HIV, is in Phase 1 testing. Vir’s Covid-19 R&D is also continuing without GSK. VIR-7229 is a next-generation Covid antibody that Vir says is AI-engineered to have increased potency, breadth, and resistance to viral escape. The company expects to file the regulatory paperwork later this year to support evaluating this antibody in a Phase 1 clinical trial. Vir reported having $1.6 billion in cash, cash equivalents, and investments as of the end of 2023. “Our financial strength allows us to fund multiple clinical programs through major inflection points while enabling the flexibility to invest in external innovation opportunities,” Vir CEO Marianne De Backer said in a prepared statement. Image by Flickr user quapan via a Creative Commons license

Researchers have shed new light on how viral evolution, population immunity, and the co-circulation of other flu viruses shape seasonal flu epidemics. Researchers have shed new light on how viral evolution, population immunity, and the co-circulation of other flu viruses shape seasonal flu epidemics. The research, published today as a Reviewed Preprint in eLife, explores the relationships among evolutionary and epidemiological quantities in influenza, and presents fundamental findings that substantially advance our understanding of the drivers of influenza epidemics, according to the eLife editors. The authors used a rich set of data sources to provide what the editors say is compelling evidence on the roles of genetic distance, influenza subtype dynamics, and epidemiological indicators in predicting flu epidemics. The findings highlight genetic distance and subtype interference as key factors in determining the timing and severity of annual outbreaks. Influenza viruses continually accumulate genetic changes in two key proteins displayed on their surface -- called haemagglutinin (HA) and neuraminidase (NA) -- a process known as antigenic drift. Antigenic drift allows the virus to escape immune recognition in people who have been vaccinated or had a previous infection, leaving them exposed to re-infection. Of the two types of influenza viruses that routinely circulate together in humans (influenza A and B), influenza A, and particularly subtype A(H3N2), has the fastest rates of antigenic drift and causes the most severe illness and death. Amanda Perofsky, the lead author of the study and a research scientist at the Brotman Baty Institute, University of Washington, US, and Fogarty International Center, National Institutes of Health, US, says: "In theory, antigenic drift will lead to more susceptible individuals, which in turn should lead to more flu infections and larger or more severe epidemics. However, prior evidence for this in epidemiological data has been mixed. Mutations in HA are considered to cause the majority of antigenic drift, so surveillance efforts to monitor and predict influenza evolution focus on HA. There has been less focus on NA, even though antibodies against NA also correlate with immunity and influence infection severity. Moreover, outside of flu pandemics, little is known about how different cocirculating influenza subtypes potentially interfere with each other, affecting the size of outbreaks." In this study, Perofsky and colleagues from the Fred Hutchinson Cancer Center, the Icahn School of Medicine at Mount Sinai, US Centers for Disease Control and Prevention, and World Health Organization tracked A(H3N2) evolutionary dynamics -- measured by both genetic sequences and serological assays -- and linked this to epidemiological flu surveillance data in the US over 22 influenza seasons before the COVID-19 pandemic. They started out by identifying different indicators of flu evolution each season, using HA and NA genetic sequence data from the Global Initiative on Sharing Avian Influenza Data (GISAID) Epiflu database and serological data on immune cross-reactivity between viruses provided by World Health Organization Global Influenza Surveillance and Response System (GISRS) Collaborating Centres in Tokyo, London, Melbourne and Atlanta. They created phylogenetic trees showing lines of evolution of A(H3N2) viruses over time and measured genetic and antigenic distances between viruses circulating in consecutive seasons, to show how far apart the viruses evolved in that timeframe. Next, the team explored which of these measures of viral 'fitness' are most strongly related to variation across A(H3N2) flu outbreaks in different years. When comparing the predictive performance of sequence-based and serological evolutionary metrics, they found that genetic distances based on broad sets of antigenic sites ("epitopes") in HA and NA had the strongest, most consistent relationship with the disease burden of annual epidemics, rates of virus transmission, and severity of infection, and influenced the dominant subtype of influenza A -- A(H3N2) or A(H1N1) -- circulating in each season. When relating genetic distance in HA versus NA to A(H3N2) epidemiology, antigenic drift of H3 (the HA antigen of the A(H3N2) virus) was more strongly linked to epidemic size, viral transmissibility, the age distribution of cases, and the number of excess deaths caused by the A(H3N2) virus, while antigenic drift of N2 (the NA antigen of the A(H3N2) virus) was more strongly linked to the intensity of epidemics (the "sharpness" of the epidemic curve) and greater prevalence of A(H3N2) cases relative to A(H1N1) cases in the population. Increased drift in N2 was also associated with fewer days from epidemic onset to peak incidence (a measure of the speed of the epidemic). "The direct link between NA antigenic drift and A(H3N2) incidence patterns was a surprising and key result from our study," says Perofsky. "We expected HA to exhibit stronger associations with seasonal incidence, given that it elicits a stronger immune response than NA." Taken together, the authors' results showed that greater antigenic drift in both HA and NA was linked to larger, more intense epidemics, higher transmission, a greater dominance of the A(H3N2) subtype, and more cases in adults than children. Finally, the team applied machine learning models to assess the relative importance of viral evolution, prior population immunity, the co-circulation of other flu viruses, and vaccine coverage and effectiveness in predicting regional A(H3N2) epidemic dynamics. Using one of the models (called a random forest) they could accurately predict regional epidemic size, peak incidence, and subtype dominance patterns of seasonal outbreaks that occurred between 1997 and 2019. Surprisingly, they found that the incidence of A(H1N1) was more predictive of A(H3N2) epidemics than viral evolution, suggesting that interactions between different viral subtypes -- that is, subtype interference -- play a key role in influenza type A infection dynamics. "Our study shows that influenza epidemic dynamics are shaped in part by the virus' antigenic drift in both surface proteins, and that genetic sequence indicators of antigenic drift were more informative than serological (or antibody) data for predicting epidemics in the timeframe analysed," concludes senior author Cécile Viboud, a staff scientist at Fogarty International Center, National Institutes of Health, US. "Our work is the first to link NA antigenic drift to epidemic burden, timing, and the age distribution of infections. The connection between NA drift and seasonal incidence further highlights the importance of monitoring evolution of both HA and NA to inform the selection of strains for annual flu vaccines and epidemic forecasting efforts."

Inflation remains a top consumer gripe, but the higher cost of milk and eggs is negligible when compared to insulin. Spending on insulin has tripled in the past decade, topping $22 billion in 2022, according to research from the American Diabetes Association. While some of that increase is due to a growing patient pool, it’s also due to rising prices. The inflation-adjusted cost of insulin increased 24% from 2017 to 2022. Lower-cost insulin is becoming available to more Americans with diabetes. Implementation of the Inflation Reduction Act last year was a catalyst. One of the federal law’s provisions set a $35 cap on the monthly out-of-pocket cost for insulin. Though the price cap applied only to insulin for Medicare beneficiaries, it established a template that insulin manufacturers followed. Eli Lilly announced it would slash prices and cap a patient’s monthly cost at $35, changes that phased in during 2023. Novo Nordisk and Sanofi followed with announcements of similar price cuts and caps on out-of-pocket costs that took effect at the start of this year. These changes are significant because those three drugmakers account for an estimated 90% of the insulin market. Sanofi, Novo Nordisk, and Eli Lilly already had alternative insulins: unbranded versions that are the same as their branded insulin products, but with a lower price. The companies also developed follow-on biologics, which are versions of another company’s insulin products. These insulins are essentially biosimilars. Insulin, which had historically been regulated like a drug made from chemicals, transitioned to the biologics regulatory pathway in 2020. The congressionally mandated change was intended to open the doors to competition by establishing a pathway for others to develop biosimilar insulins. But so far, the vast majority of available insulin still comes from the big three insulin manufacturers. By offering lower-cost insulins along with their branded products, the big insulin manufacturers retain market share, Sally Yanchus, senior research analyst at Water Tower Research, told MedCity News. Other companies have yet to dent this share. Biocon is a dominant seller of biosimilar insulins in emerging markets, Yanchus said. But the India-based company, which secured its place in U.S. insulin biosimilars with the $3.3 billion acquisition of the biosimilar business of its partner Viatris in 2022, remains a small player in the U.S. “Since Lilly and Sanofi and Novo also make biosimilars of their brand, they’re going to capture most of the market, at least in the developed market, which is exactly why they decided to do it,” Yanchus said. New biosimilar alternatives are still in development. Civica Rx announced its biosimilar plans in 2022, pledging to commercialize insulin priced at $30 per vial and $55 for a box of five cartridges. It said it would be able to provide insulin at these prices because it is a nonprofit organization. Civica Rx has constructed a 140,000 square-foot facility in Petersburg, Virginia, with the capacity to produce about 90 million vials and 50 million pre-filled syringes per year. When Civica Rx unveiled its plans two years ago, it set a 2024 target date to bring its insulin products to the market. Yanchus said Civica Rx’s impact on the market will depend on its ability to secure regulatory approvals and successfully launch its products. Debbi Ford, chief communications and public affairs officer for Civica Rx, said in an email that the nonprofit is committed to bringing low-cost insulin to all Americans as soon as possible. She added that test runs of insulin have already begun at the Virginia manufacturing site. “We have met with the FDA and have a clear path forward for the insulin program,” Ford said. “We will provide a filing timeline as we progress.” Biosimilars have drawn startup interest as well. Houston-based synthetic biology company rBIO claims it can produce biosimilars at greater yields than is possible with current technologies. The startup is based on technology licensed from Washington University. Its platform, which uses a new genetic coding process to synthesize proteins and peptide hormones, has yielded a pipeline of preclinical biosimilars for antitrypsin, erythropoietin, uricase, and hemagglutinin. The most advanced rBIO program is biosimilar insulin, but it still needs to go through clinical testing. The startup’s founders have a goal of lowering the cost of insulin by 30%. New biosimilar options could also come from some states. Washington state and Maine have explored the possibility of manufacturing generic drugs, including insulin. California is much further along with an initiative called CalRx. Signed into law in 2020, CalRx empowers the state to develop, manufacture, and distribute lower-cost generic and biosimilar products. California’s goals include boosting competition for drugs that have little competition or are susceptible to shortages or supply chain disruptions. With insulin as its first focus, California put $100 million behind CalRx—$50 million for developing biosimilar insulin and $50 million for construction of a manufacturing facility. Civica Rx will play a key role in California’s plans. Last March, CalRx announced a partnership with the nonprofit to develop and manufacture three of the most commonly used types of insulin. Gov. Gavin Newsom said this insulin will cost Californians $30 for a 10 mL vial—the same price it will cost the state to manufacture and distribute the drug. The plan is for CalRx insulin to become available through local pharmacies and mail order pharmacies. While CalRx insulin will initially come from Civica Rx’s Virginia facility, the partners aim to eventually develop a manufacturing site in California. “There are only three major players [in the insulin market] and they tend to follow each other,” Newsom said in the broadcast announcement of the Civica Rx partnership. “Time for disruption—and that’s where California comes in.”