Virus World

Despite the major decline in COVID-19 vaccine sales since the 2022 peak, the infectious disease market is still expected to grow by 5.7% through 2029 with Pfizer, Gilead and GSK all set to be the dominant forces in this market. That’s according to a new report out by analysts at GlobalData, which found the infectious disease market is forecast to grow at a compound annual growth rate of 5.7% between 2023 and 2029 to reach $150 billion in annual sales by the decade’s end. Three Big Pharmas will also emerge as the dominant players: Pfizer, Gilead and GSK, which will, according to GlobalData’s estimates, collectively generate 62% of total infectious disease drug sales in that six-year period. And that comes despite a 63.8% decline in forecast sales for COVID-19 vaccines this year alone, with that partly offset by an “increasing demand for HIV drugs and continued high sales of COVID-19 therapeutics,” the firm said.

Pfizer will be boosted by its COVID med Paxlovid as well as its Prevnar pneumococcal disease vaccine franchise. Meanwhile, Gilead will rely on its major HIV products, and GSK, known for its strong presence in infectious disease, boasts a blockbuster shingles vaccine along with recent developments such as a new respiratory syncytial virus vaccine and an HIV pill. “Pfizer annual sales are forecast to decline by 9.2% from 2023 to 2029 due to easing pandemic pressures and the relaxation of government COVID-19 vaccination programs,” explained Kevin Marcaida, pharma analyst at GlobalData, in a release. Nevertheless, Pfizer is anticipated to retain its leading stance in the infectious disease market, primarily due to the sustained robust performance of its COVID-19 product lineup, spearheaded by the sales of Comirnaty, its COVID vaccine, and Paxlovid, according to the report. “This is due to strategic price hikes in 2023 for the U.S. market and persisting COVID-19 incidences in emerging economies. As a result, Comirnaty and Paxlovid are projected to achieve an astounding $122 billion in sales between 2023 to 2029,” Marcaida added. 

Gilead, meanwhile, is set to experience “steady infectious disease sales growth” of 12.4% from 2023 to 2029, the report finds, with HIV drug Biktarvy at the core of that, with GlobalData forecasting $92 billion in sales between 2023 and 2029. GSK, meanwhile, will grow out two blockbuster drugs: shingles vaccine Shingrix and HIV drug Dovato. Total sales for Shingrix are set to hit $41 billion between 2023 to 2029 while Dovato will do around half that, $20 billion, over the same period. “Pfizer, Gilead Sciences, and GSK are the three major companies driving growth in the infectious disease market” added Marcaida. “With their innovative products, these three industry leaders are well-positioned to capitalize on the expanding opportunities in the infectious diseases market.”

Sanofi and GlaxoSmithKline’s next generation Covid-19 vaccine could be used as a booster, after new data suggested that it elicited a strong immune response against the Omicron variant. The French healthcare company said the “next-generation” booster jab delivered a “strong immune response” against variants of Covid, including Omicron, after two trials. It was safe and well tolerated in the study of 247 people. The vaccine makers said their jab increased antibodies to tackle the BA.1 Omicron strain by 40-fold in participants who had received two messengerRNA shots, the technology used in popular vaccines from Moderna and BioNTech/Pfizer. They reported that the vaccine outperformed a third dose of the current BioNTech/Pfizer jab, eliciting double the number of neutralising antibodies to BA.1 and BA.2. Thomas Triomphe, executive vice-president of Sanofi Vaccines, said Covid kept evolving and waning immunity was likely to lead to the need for additional booster shots, at least in some populations....

Orchard Therapeutics said its gene therapy Strimvelis, approved by European authorities in 2016 to treat the rare inherited condition ADA-SCID, has been linked to a patient’s leukemia. No patients will be treated while Orchard investigates. The potential of gene therapies as cures for some hard-to-treat genetic diseases can be very attractive. But one such product is now suspected of causing a serious safety problem.  Friday, Orchard Therapeutics said its Strimvelis treatment, approved by European authorities in 2016 to treat the rare inherited condition ADA-SCID, has been linked to a patient’s leukemia. “Preliminary findings suggest this diagnosis may be attributable to an insertional event related to treatment with Strimvelis,” the company said. It’s now investigating whether there’s indeed a causal relationship.   Since its 2016 EU approval—when it was owned by original developer GlaxoSmithKline—only 16 patients have been treated with Stimvelis. The patient who developed leukemia had apparently been treated under a GSK compassionate use program in 2016. No more patients will get the therapy before the investigation is complete, Orchard said. The drug was never approved in the U.S. ADA-SCID is a condition marked by a mutation in the gene making the adenosine deaminase (ADA) enzyme, which is essential for maintaining normal white blood cells. ADA-SCID patients, with a dysfunctional immune system, have less than two years to live without effective intervention.

Since its 2016 EU approval—when it was owned by original developer GlaxoSmithKline—only 16 patients have been treated with Stimvelis. The patient who developed leukemia had apparently been treated under a GSK compassionate use program in 2016. No more patients will get the therapy before the investigation is complete, Orchard said. The drug was never approved in the U.S. ADA-SCID is a condition marked by a mutation in the gene making the adenosine deaminase (ADA) enzyme, which is essential for maintaining normal white blood cells. ADA-SCID patients, with a dysfunctional immune system, have less than two years to live without effective intervention.  Besides Strimvelis, Orchard is also developing OTL-101, which uses a lentivirus to insert a functional copy of the ADA gene into a patient’s cells. The drug is currently undergoing a registrational trial and has won breakthrough and orphan drug designations from the FDA. All the gene therapy candidates in Orchard’s pipeline use lentiviral vectors that have been “specifically designed to avoid insertional oncogenesis after administration,” Orchard said, adding that no dangerous gene insertion has been reported around lentiviral vector-based stem cell gene therapy in any indication.

Company's Press Release (Oct. 30, 2020):

https://ir.orchard-tx.com/news-releases/news-release-details/orchard-statement-strimvelisr-gammaretroviral-vector-based-gene 

Although none of the coronavirus vaccines under development has proved its efficacy yet in clinical trials, at least 5.7 billion doses have been pre-ordered  around the world. First shipments of a COVID-19 vaccine created by Western laboratories have often been snapped up by the United States. Five vaccines — three Western and two Chinese — are in Phase 3 efficacy trials involving thousands of people. In a surprise announcement, Russian President Vladimir Putin claimed Tuesday that a vaccine dubbed Sputnik V — after the Soviet satellite — conferred “sustainable immunity” against the novel coronavirus. As research laboratories around the world race to develop a vaccine, manufacturers have received financing to help them prepare to have millions of doses ready to administer in 2021 or even before the end of the year.

Oxford University, working with the Swedish-British pharmaceutical group AstraZeneca, hopes to have results by September, while the US biotech company Moderna, partnering with the U.S. National Institutes of Health (NIH), is aiming for the end of the year, possibly November. U.S. President Donald Trump has launched “Operation Warp Speed” in a bid to develop, manufacture and distribute a COVID-19 vaccine to all Americans by January 2021. Hundreds of millions of dollars have been directed to vaccine developers, including nearly $500 million to Johnson & Johnson at the end of March. The United States has allocated funding to more companies than any other nation in the hope that one of them will come up with the vaccine to counter the highly contagious virus. So far, Washington has handed out at a total of at least $9.4 billion to seven vaccine developers and signed manufacturing contracts with five of them to provide 700 million doses. The companies involved are: Johnson & Johnson, Moderna, Oxford/AztraZeneca, Novavax, Pfizer/BioNTech, Sanofi/GSK, Merck Sharp and Dohme.  Two vaccine developers — Oxford/AztraZeneca and Sanofi/GSK — have signed or are in advanced negotiations with the European Commission to provide a combined 700 million vaccine doses. Britain, because of Brexit, is negotiating a separate pre-order of 250 million doses from four developers.  Japan is counting on 490 million doses from three suppliers, including 250 million from Novavax of the United States. Pharmaceutical giant Takeda bought the rights to a Novavax vaccine for Japan, which has funded the research. It would be produced locally.

Brazil chose a similar model, ordering 100 million doses from AstraZeneca and partnering with China’s Sinovac to produce 120 millions of CoronaVac, which is already undergoing testing with Brazilians. Clinical tests of two Chinese vaccine candidates — Sinovac and Sinopharm — are well underway but only a few international partnerships have been announced, the one with Brazil and a possible one with Indonesia. Russia said 20 nations have pre-ordered 1 billion doses of Sputnik V and that with foreign partners it would be able to produce 500 million doses a year in five countries. The Coalition for Epidemic Preparedness Innovations, launched in 2017 by Norway, India, the Bill and Melinda Gates Foundation and the Wellcome Trust, seeks to ensure that there is “equitable access” to future vaccines. It has pre-ordered 300 million doses from AstraZeneca for dozens of developing countries in a partnership with The Vaccine Alliance. Billions of doses would be produced for Asia and elsewhere by the giant Serum Institute of India (SII), the largest vaccine producer in the world. Novavax and AstraZeneca have separately signed agreements with SII to produce a billion doses each for India and low- and middle-income countries on the condition that they prove their efficacy in clinical trials.

British drugmaker GlaxoSmithKline is giving up its work on developing three potential vaccines against the deadly Ebola and Marburg viruses, despite an ongoing Ebola outbreak in Democratic Republic of Congo.

While Ebola is a deadly and contagious disease, it is also still relatively rare, making the potential market for a vaccine sporadic and very likely unprofitable. This poses a dilemma for drug companies: With no real prospect of a financial return, can they justify the investment in expensive development and trials. GSK’s vaccine candidates - two designed to protect against Ebola and one against the Marburg virus - will be transferred to the Sabin Vaccine Institute in Washington, D.C., the British drugmaker said in a statement. There is no financial element to the agreement, a spokesman said.

The transfer agreement will see Sabin continue to develop the candidate vaccines, one of which - a potential Ebola shot known as ChAd3 - has been through mid-stage, Phase II, trials in Africa and could possibly be used to halt or limit future Ebola epidemics.  “Enabling Sabin to build on the scientific progress GSK has delivered up to Phase II increases the likelihood these candidate vaccines may help prevent potential future outbreaks,” Thomas Breuer, chief medical officer of GSK Vaccines, said in a statement.

GSK had put its Ebola vaccine work on hold after it was unable to progress the product through final stage, or Phase III, clinical trials toward the end of the 2014-16 epidemic, due to a dwindling number of Ebola cases.

Over the course of a two-day meeting, vaccine advisers to the US Food and Drug Administration voted in favor of approval for RSV vaccines for adults over the age of 60. The vaccine candidates, made by Pfizer and GlaxoSmithKline, could become the world's first approved vaccines against the common virus. On Wednesday, committee members voted 10-2 in support of the safety and unanimously in support of the effectiveness of GSK’s vaccine for the prevention of lower respiratory tract disease caused by RSV among older adults. For Pfizer’s shot, committee members voted on Tuesday with 7-4 with one abstention that there is adequate data to support the vaccine’s safety and effectiveness. The FDA, which typically follows the committee’s recommendations, is expected to decide on approval of the vaccines in May, ahead of RSV’s typical winter surge. Respiratory syncytial virus is a highly contagious virus that causes flu-like illness in people of all ages that increases in severity with age. According to the US Centers for Disease Control and Prevention, RSV is responsible for an estimated 177,000 hospitalizations and 14,000 deaths per year among adults 65 or older. GSK’s RSV vaccine candidate for older adults was 82.6% effective in preventing lower respiratory tract disease defined by either two or more symptoms or and one or more signs or three or more symptoms. The shot was 94.1% effective at preventing severe disease. The Pfizer vaccine was 66.7% effective at preventing moderated lower respiratory tract illness with two or more symptoms and 85.7% effective at preventing illness with three or more symptoms, according to Pfizer.

Focus on safety

Though a majority of the committee voted in support of the vaccines, some committee members expressed concerns over both vaccines’ risk of Guillain-Barre syndrome, a rare neurological disorder in which the immune system attacks its own nerves, causing muscle weakness and sometimes paralysis. The incidence of Guillain-Barre is about 1.5 to 3 cases for 100,000 adults over age 60 in the US annually, according to the FDA. Two adults among 20,000 vaccine recipients in Pfizer’s Phase 3 clinical trial developed symptoms consistent with the rare neurological disorder within nine days of receiving the shot. Of roughly 15,000 vaccine recipients of GSK’s Phase 3 clinical trial, one man developed Guillain-Barre syndrome within nine days of vaccination. “It seems to me that one case is a red flag. Two cases is very concerning,” said Dr. Marie Griffin, professor of health policy at Vanderbilt University Medical Center, who voted that the data demonstrated that both vaccines are effective but not safe

The FDA has called Guillain-Barre syndrome an “important potential risk” of Pfizer and recommended the company conduct a safety study for further evaluation of Guillain-Barre syndrome and other immune-mediated demyelinating conditions after potential vaccine approval, which the company has agreed to.

GSK has said they will closely monitor cases after approval. While Pfizer did not provide data on co-administration with other vaccines, GSK’s data showed potential safety risks when the RSV and flu shots were administered together. Two adults in their 70s who received both the flu and RSV vaccine developed acute disseminated encephalitis, a rare neurological disorder that involves swelling of the brain and spinal cord, and one of the individuals died. The FDA considers these cases as possibly related to either RSV or flu vaccination, but review is ongoing. “This is a disease with incidence 0.1 in 100,000 usually, the majority being in children and then a scatter in young adults. So two cases in elders within three to four weeks post-vaccine is highly anomalous from a statistical standpoint,” said Dr. Hana El Sahly, the FDA advisory committee chair, who voted against the GSK shot based on its safety profile but in favor based on efficacy. Dr. Adam Berger, who voted in favor of GSK’s vaccine based on safety and efficacy, says it seems to be an issue with co-administration and that concerns with acute disseminated encephalitis and Guillain-Barre syndrome won’t be answered until larger studies are conducted. “I suggest a heavy reliance on the postmarketing surveillance and not only just reliance but making sure there is an enforcement around the requirements about this,” Berger said. “At the moment, I think the profile seems to be within the acceptable range.”

Search for an effective RSV vaccine

Some vaccine advisers wanted to see more data on the Pfizer vaccine’s effectiveness at preventing hospitalization or death, especially among high-risk individuals including adults over 80, those with comorbidities, or those who are immunocompromised. “I think the data does support the effectiveness of this vaccine, it’s just the population was underrepresented by people who could most benefit from the vaccine,” Griffin said of Pfizer’s clinical trial. The available safety and efficacy data is from the first season of Pfizer’s clinical trial scheduled over two RSV seasons and the first of three seasons for GSK’s trial. Some experts want to wait for more data. “I’m desperately eager to have a vaccine that works for RSV. This has been a terrible disease my whole career. I would love to see it. No doubt about it,” said Dr. Jay Portnoy, professor of pediatrics at Children’s Mercy Hospital, who voted in support of GSK’s vaccine but against Pfizer based on efficacy. Portnoy said waiting for a second season of data would provide more robust numbers and complete analysis. “It’s not an emergency use authorization. We can take the time to finish the studies and get the information we need before licensing this product going forward. So I remain a little bit skeptical given the data that we have,” he said. Others think the benefits of the candidate vaccines outweigh the potential risks of deadly RSV infection. “Despite the challenges, despite the additional hurdles, our obligation is to do what’s right for the public,” said Dr. Daniel Kim who voted in favor of both shots. “And in this case, we have a bad disease, we have a good vaccine – so far, anyway, given the clinical trials – it’s a safe vaccine, and the vaccine can be used to prevent disease.”

Sanofi had previously projected it could produce 100 million doses of vaccine in 2020, and 1 billion doses in 2021. One of the world’s leading vaccine manufacturers has suffered a major setback in its work to produce a Covid-19 vaccine. The problem will push the timeline for deployment of Sanofi Pasteur’s vaccine — if it is approved — from the first half of 2021 into the second half of the year, the company said Friday. The news is not just disappointing for Sanofi and its development partner, GlaxoSmithKline, which is providing an adjuvant used in the vaccine. The companies have contracts with multiple countries, including the United States and Britain, as well as the European Union. Sanofi had hoped to start a Phase 3 trial of the vaccine this month and had projected it could produce 100 million doses of vaccine in 2020, and 1 billion doses in 2021. The problem relates to inadequate results in older adults in Sanofi’s Phase 1/2 trial, which the company traced back to an inadequate formulation of their vaccine, Su-Peing Ng, global medical head for Sanofi Vaccines, told STAT in an interview. Ng said both Sanofi and GSK are committed to continuing work on the vaccine, and plan to begin a Phase 2b trial in February. “We’re disappointed that there is a delay,” she said. “I think, though, that we’re encouraged that we have enough information, enough of the results from preclinical and clinical [studies] to tell us that we have a path forward. We need to optimize this formulation.”

In effect, participants in the trial received too little vaccine. While the too-small dose generated adequate levels of neutralizing antibodies in adults aged 18 to 49 in the trial, adults 60 and older generated lower levels of neutralizing antibodies than are seen in the blood of people who have recovered from Covid-19 infection, Ng said.  Perplexed by the findings, the company set out to figure out why the vaccine underperformed. It discovered two commercial reagents used to measure how much antigen — active vaccine — was included in each dose were giving false readings. In fact, Ng said, the concentration of the antigen “was insufficient.” A revised formulation, tested recently in non-human primates, showed the vaccine prevented damage in the lungs, which is what triggers severe Covid disease in people, and led to rapid clearance of the virus. The vaccine’s path will be more challenging because of this delay; the Covid vaccine landscape is changing daily and placebo-controlled trials may not be feasible for much longer, with the first vaccines soon to be deployed. If people know they may soon have access to an authorized vaccine, there is less motivation to enroll in a trial where they might get a placebo. Sanofi knows this and is proposing to the Food and Drug Administration that its Phase 2b trial compare its vaccine to one that is already authorized, not a placebo. “To continue to provide confidence that we’re going to have a vaccine that meets the expected standard of care, we propose the comparison with an authorized Covid-19 vaccine instead of placebo control,” Ng said. That would set a very high bar for the Sanofi vaccine. Pfizer and Moderna, the front-runners in the vaccine race, have reported vaccine efficacy of about 95% in their Phase 3 trials. If the Sanofi vaccine doesn’t reach that level of efficacy, can it be brought to market, STAT asked Ng.

“That will be up to the regulators,” she said, adding that “for the public to be confident in the choice of a vaccine, it would have to be pretty close to what’s been established now. The Sanofi vaccine would have one advantage compared to the Pfizer and Moderna vaccines: It wouldn’t require ultracold storage and could instead be kept in standard refrigerators, making it easier to distribute Pfizer and Moderna are poised to receive emergency use authorizations from the FDA this month — an FDA advisory panel endorsed the Pfizer shot on Thursday — and vaccine rollout in the United States is expected to begin within days of the FDA’s green light. The Phase 3 trial for Johnson & Johnson’s vaccine — the only one-dose vaccine currently in clinical trials in the U.S. — is about to finish enrollment; if it is effective, it could get an EUA in the first quarter of 2021. The Sanofi vaccine is made with an approach the company uses for one of its flu vaccines, Flubok. That in theory is an advantage; the FDA knows how this vaccine system works. It’s called a recombinant protein vaccine, with the spike protein of the SARS-CoV-2 virus, which cases Covid-19, generated in insect cells. Sanofi is also developing a second vaccine, a messenger RNA vaccine, like the Pfizer and Moderna shots. For this project, it is collaborating with Translate Bio, a Lexington, Mass.-based biotech. Clinical trials for that vaccine have not yet begun.

An antisense drug developed by GlaxoSmithKline has been shown to suppress the hepatitis B virus (HBV) in a  phase 2 trial, raising hopes of a “functional cure” for the widespread disease. HBV affects an estimated 260 million people worldwide, according to GSK. While drugs to treat it are available – such as Gilead’s polymerase inhibitor Viread (tenofovir) – there is still no curative treatment, and the company hopes that GSK3228836 could fill that void. Most people are able to shake off HBV infection in time, but in a majority of children and a minority of adults, HBV infection can become chronic and lead to cirrhosis as well as liver cancer, whilst also allowing transmission of the virus to others. Chronic HBV kills around 900,000 people every year. In the phase 2a trial, GSK3228836 was able to reduce two biomarkers of chronic HBV infection – hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA – compared to placebo after four weeks treatment. The trial involved four patients previously treated with antivirals and 12 who were new to drug therapy for HBV, and across both groups there were six patients who had a 3-log (99.9%) or greater reduction in HBsAg levels after 29 days. 

In four of the big responders, levels of the biomarker fell below the limit of detection, and in one case that persisted for six months. Meanwhile, five of 12 previously-untreated patients had 2-log (90%) or a greater reduction in HBV DNA. The results are still preliminary but according to GSK show clear signs of a therapeutic effect that will be tested in a phase 2b programme, due to start before the end of the year. The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” Experts talk about a functional cure in HBV – defined as the complete loss of HBsAg – because it is impossible to tell biologically if the virus has been eliminated from the body. That is because viral DNA fragments can lurk in cells, hiding from current drug therapy and evading the immune system. GSK3228836 is designed to target viral DNA directly, which could give it a chance of targeting all traces of the virus in the body, and prevent it from becoming a chronic infection. GSK licensed the drug from longstanding partner Ionis as part of a two-drug deal last year, paying $25 million upfront with milestone payments taking the value of the deal up to $262 million.

If either of the antisense drugs covered by that license make it through to market, that would look like a very good deal, particularly given the sheer scale of HBV infection worldwide. The first drugs that were able to effect a cure for chronic hepatitis C virus (HCV), such as Gilead’s Harvoni (sofosbuvir/ledipasvir), quickly amassed blockbuster revenues, although that tailed off quickly as the pool of available patents declined. Analysts at William Blair have suggested that the market for an HBV cure could be around the same size as HCV, which peaked at around $10 billion a year. There’s competition coming through the industry pipeline though. Last year, Roche paid a whopping $200 million upfront to license an RNA interference drug for HBV from Dicerna called DCR-HBVs (now RG6346), with another $1.47 billion in potential milestones. The drug is in phase 1/2 development. Meanwhile, Johnson & Johnson paid $175 million upfront for Arrowhead Pharma’s RNAi candidate ARO-HBV (now JNJ-3989) which is also in a phase 2 trial.

The arrangement brings the Trump administration’s investment in coronavirus vaccine projects to more than $8 billion. The head of the federal effort is a former GSK executive. The French drug maker Sanofi said on Friday that it had secured an agreement of up to $2.1 billion to supply the U.S. federal government with 100 million doses of its experimental coronavirus vaccine, the largest such deal announced to date. The arrangement brings the Trump administration’s investment in coronavirus vaccine projects to more than $8 billion. This sprawling, multiagency effort, known as Operation Warp Speed, is placing bets on multiple vaccines and is paying companies to manufacture millions of doses before clinical trials have been completed. “The global need for a vaccine to help prevent Covid-19 is massive, and no single vaccine or company will be able to meet the global demand alone,” Thomas Triomphe, executive vice president and global head of Sanofi Pasteur, the company’s vaccine division, said in a statement.

Under the deal announced, Sanofi and its partner, the British pharmaceutical company GlaxoSmithKline, will receive federal funding to pay for clinical trials as well as for manufacturing the vaccine. Sanofi said the deal also includes an option for the company to supply an additional 500 million doses. The company expects to begin clinical trials to test for safety in September, followed by late-stage efficacy trials before the end of this year. Sanofi said it could apply for regulatory approval in the first half of next year. Under the deal announced, Sanofi and its partner, the British pharmaceutical company GlaxoSmithKline, will receive federal funding to pay for clinical trials as well as for manufacturing the vaccine. Sanofi said the deal also includes an option for the company to supply an additional 500 million doses. The company expects to begin clinical trials to test for safety in September, followed by late-stage efficacy trials before the end of this year. Sanofi said it could apply for regulatory approval in the first half of next year. 

The head of Operation Warp Speed, Moncef Slaoui, is a former GSK executive who as of May held just under $10 million in GSK stock. Dr. Slaoui’s financial ties to some of the companies that are pursuing coronavirus vaccines have raised questions about conflicts of interest. Dr. Slaoui is not a federal employee, instead working under a $1 contract that exempts him from federal rules that would require him to list his outside positions, stock holdings and other potential conflicts. Dr. Slaoui said in an interview in May that he was determined to avoid any conflicts of interest, but that his GSK stock represented his retirement from 29 years at the company, and that he had told federal officials he would not take the job if he had to sell it...