Highlights

Beyfortus (nirsevimab) is a new drug indicated to prevent lower respiratory tract disease caused by respiratory syncytial virus (RSV) in neonates and infants during their first RSV season.

A single injection of Beyfortus, implementing passive immunization against respiratory syncytial virus for the entire RSV season, will provide reliable protection to a broad population of newborns, including healthy infants and babies with special diseases, those born at term and those born prematurely.

Beyfortus was developed by AstraZeneca in collaboration with Sanofi.

The European Medicines Agency (EMA) will soon decide on the marketing authorization of Beyfortus. In mid-September 2022, the Committee for Medicinal Products for Human Use (CHMP) recommended that the drug be approved.

Beyfortus (nirsevimab)

 

Medical Challenge of Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) usually causes mild cold-like symptoms. In most people who get sick, the ailment goes away in one to two weeks. However, in the case of infants, toddlers and the elderly, it can be much more serious: An underactive or weakened immune system cannot cope with the virus, leading to otitis media, bronchiolitis, respiratory failure, and pneumonia with a severe course.

Acute lower respiratory tract infections (LRTIs) caused by respiratory syncytial virus are the leading cause of hospitalization and death in children under one year of age. And the majority of hospitalizations due to RSV occur in healthy infants born at term. [1] [2] [3] [4]

Over 30 million cases of RSV-associated infections are reported each year, of which 3.2 million require hospitalization and nearly 120,000 are fatal in children under five years of age (usually before the age of six months). [5] RSV-related mortality is predominantly relevant in low- and middle-income countries (LMICs), [6] with half of the deaths occurring outside the hospital setting. [7]

In high-income countries (HICs), infants born prematurely as well as those with congenital heart disease or chronic lung disease, [8] Down syndrome, [9] neuromuscular disorders are at highest risk for RSV-associated infections. [10]

Maternal immunization is insufficient to protect premature infants because transplacental antibody transmission does not reach mature levels until the end of the third trimester. [11]

The burden of morbidity and mortality from RSV-associated infections in the elderly (over 60 years of age) was underestimated until recently. Now, according to modeling studies, the burden of RSV is similar to that of seasonal influenza in persons over 65 years of age. [12] [13] [14] Preliminary economic evaluations have confirmed the potential benefit of the RSV vaccine for the elderly, especially in HICs. [15] [16]

Despite the daunting burden of RSV-associated infections, the pharmaceutical industry has not been able to offer reliable protection against respiratory syncytial virus for six decades in a row; no effective and safe vaccines exist.

Moderate prophylaxis of RSV is now given with the monoconal antibody Synagis (palivizumab), which was approved in 1998 and is backed by AstraZeneca. Synagis is administered intramuscularly once a month throughout the RSV season, which in the Northern Hemisphere typically lasts from October–November through March–April. The reduction in the frequency of RSV-associated hospitalizations provided by Synagis relative to placebo is an objectively insufficient 45%–55%. [17] [18]

The situation with respiratory syncytial virus is further complicated by the fact that palivizumab (for a number of objective reasons, including economic) is approved for use in a very limited population of pediatric patients (approximately 2%). The conditions for prescribing Synagis by the start of the RSV season are as follows: with a history of premature birth and under 6 months of age; with bronchopulmonary dysplasia (BPD) and under 2 years of age; with hemodynamically significant congenital heart disease (CHD) and under 2 years of age. [19] [20] [21] [22]

In other words, nothing has been suggested for the prevention of RSV in healthy children.

The only approved treatment for respiratory syncytial virus infection is ribavirin, which is difficult to administer and of very mediocre efficacy. As a result, serious cases of RSV suggest solely supportive symptomatic therapy. [23]

 

Beyfortus: Mechanism of Action of Nirsevimab

Nirsevimab (MEDI8897) is a recombinant human monoclonal antibody (IgG1) that neutralizes respiratory syncytial virus (RSV) by binding to the highly conserved Ø site of the epitope on the virion’s antigenic envelope glycoprotein F necessary for pathogen fusion with the host cell followed by infection. Nirsevimab, unlike palivizumab, binds to the viral F fusion protein in a pre-fusion conformation rather than post-fusion conformation, thus locking the F protein and blocking virus entry into the cell. [1]

Nircevimab, which works on the principle of passive vaccination, is characterized (thanks to a modified Fc domain) by a long half-life, so one dose should be enough for the entire RSV season, which usually lasts 5 months in the fall-winter period.

AstraZeneca got hold of nirsevimab by buying it from Netherlands’s AIMM Therapeutics in 2014.

In March 2017, Sanofi tapped into the development of nirsevimab, paying AstraZeneca €120 million upfront and promising another €495 million if the project is successful. Costs and revenues are split in half.

In November 2018, AstraZeneca got rid of the U.S. rights to Synagis by selling it to Sweden’s Sobi (Swedish Orphan Biovitrum) for an advance of $1.5 billion and a promise of up to $470 million as the drug is sold. The Swedes have also joined the nirsevimab project: as it develops, Sobi will give AstraZeneca $345 million and get 50% of its sales in the U.S.

 

Beyfortus: Nirsevimab’s Efficacy in Protecting Against Respiratory Syncytial Virus

Several clinical trials have been conducted to obtain regulatory approval for nirsevimab, confirming the protective efficacy of Beyfortus against respiratory syncytial virus (RSV) in a broad pediatric population.

 

MELODY

The MELODY (NCT03979313) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial enrolled healthy children (n=1,490) under one year of age. Premature infants (at least 7 months old) were also invited to participate because they are at increased risk for RSV complications.

Subjects received intramuscular placebo or nirsevimab at a dose of 50 mg (under 5 kg) or 100 mg (over 5 kg).

The primary endpoint was the frequency of acute lower respiratory tract infections (LRTIs), the presence of which was recorded within 150 days of prophylaxis and confirmed by a positive PCR result for RSV, the presence of signs of infection, and an objective clinical criteria of severe respiratory disease.

Beyfortus outperformed placebo, providing a statistically significant reduction in LRTIs caused by RSV in healthy infants who were term or preterm. The disease was experienced by 1.2% of infants (n=12/994) in the nirsevimab group — versus 5.0% (n=25/496) in the control group. Thus, the protective efficacy of Beyfortus was 74.5% (95% CI: 49.6 to 87.1; p<0.001).

Infants who received prophylactic nirsevimab had a 77% reduced risk of developing RSV-associated LRTIs requiring medical care compared to placebo: hazard ratio (HR) 0.23 (95% CI: 0.12 to 0.47).

Beyfortus protected against the need for hospitalization by 62.1% (95% CI: −8.6 to 86.8; p=0.07).

 

NCT02878330

The NCT02878330 phase 2b (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial found that a single dose of nirsevimab reduced the incidence of requiring medical care for RSV-associated LRTIs in healthy preterm infants (n=1453) by 70.1% (95% CI: 52.3 to 81.2) compared with placebo at 150 days after prophylaxis: infection developed in 2.6% of subjects — versus 9.5% in the placebo group (p<0.001).

Beyfortus reduced the need for hospitalization by 78.4% (95% CI: 51.9 to 90.3): 0.8% of cases — vs. 4.1% (p<0.001).

 

MEDLEY

The MEDLEY (NCT03959488) phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial compared nirsevimab with palivizumab among high-risk children (n=925), either born prematurely and facing their first-ever RSV season, or with chronic lung disease (CLD) or hemodynamically significant congenital heart disease (CHD) and facing their first or second RSV season .

Based on the results, medical care due to RSV-associated LRTIs was required for 0.6% of patients (n=4/616) in the nirsevimab group — versus 1.0% (n=3/309) in the palivizumab group.

Serum levels of nirsevimab after 150 days were comparable to those observed in the MELODY clinical trial. This indicated that the protective efficacy provided by Beyfortus to high-risk infants was similar to that it provided among healthy or premature infants.

 

Expert Comments

The key issue with nirsevimab’s commercial future lies in pricing. Pharma developers will have to convince health systems that the cost of Beyfortus, which like any other monoclonal antibody, will cost more than the respiratory syncytial virus (RSV) vaccines that have yet to be offered.

During RSV season, pediatric hospital wards are overcrowded with children with the disease, so states will have to balance the possibility of reducing the burden of infection but allocating substantial money from the budget. Overall, there is great interest in nirsevimab, the World Health Organization (WHO) may also be interested.

While the market for RSV prevention was estimated at $455 million in 2020, it is forecast to grow to $6.3 billion by 2030, thanks to the emergence of both nirsevimab and vaccines alike. Half of the sales will come from Beyfortus.

Meanwhile, clesrovimab (MK-1654), a monoclonal antibody developed by Merck & Co., is in its final clinical trials, targeting F protein in pre-fusion and post-fusion conformations, binding it in a highly conserved site IV and having an Fc modification for a prolonged half-life. [1] [2] [3]

Clesrovimab is being tested in two clinical trials, NCT04767373 phase 2b/3 and NCT04938830 phase 3, in healthy infants (including those born preterm) and infants at high risk for severe disease, respectively. The first study compares clesrovimab with placebo, the second with palivizumab.

The NCT04086472 phase 2 clinical trial confirmed the efficacy of clesrovimab during challenge of healthy volunteers with intranasal inoculation with the Memphis 37b strain of RSV serotype A.

In late 2018, the University Medical Center Utrecht (UMCU) of Netherlands launched the NTR7403 phase 2 clinical trial to test an intranasal formulation of palivizumab, which was administered daily into the noses of premature infants. Results are unknown.

The NCT05118386 phase 1 clinical trial, sponsored by the Bill & Melinda Gates Foundation and studying the monoclonal antibody RSM01 in infants, is ongoing. RSM01, which targets the Ø site of the F protein in the pre-fusion conformation, is targeting low- and middle-income countries (LMICs), and therefore the estimated price per dose of the drug, which, due to the Fc modification, should protect throughout the RSV season, will not exceed $5.

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Julia Mardi

BioPharma Media’s Scientific Editor.

Julia strives to recognize in advance in which direction the pharmaceutical industry is moving. Her professional interests include gene therapy, immune checkpoint inhibitors, molecular biology, and drug repurposing.

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