News

Which company will win the competition of RSV therapy?

Which company will win the competition of RSV therapy? Respiratory syncytial virus (RSV) infection is an important cause of acute lower respiratory tract infections in children under 5 years of age worldwide and one of the main causes of infant deaths.

Respiratory syncytial virus infection may not only aggravate the original chronic respiratory diseases, but may also cause sequelae such as repeated wheezing episodes, and cause a significant impact and burden on global child health.

Clinically, there are fewer drugs used to prevent or treat respiratory syncytial virus infection.

Synagis (palivizumab, palivizumab), a monoclonal antibody developed by MedImmune (acquired by AstraZeneca) as an inhibitor of the F protein of the respiratory syncytial virus, was approved by the U.S. Food and Drug Administration (FDA) in 1998. The fact that no new drugs for this indication have been approved during the year highlights the challenges facing the field of respiratory syncytial virus drug development.

Despite repeated failures in the research and development of new drugs in the field of respiratory syncytial virus, there are currently many drugs that have entered clinical trials that have made positive progress.

Who will quit the competition?

Recent failures in the development of new drugs for respiratory syncytial virus include Novavax’s Resvax (which has failed in two key studies) and Regeneron’s suptavumab (which has entered phase III and was then abandoned in 2017). Ten years ago, Synagis’ potential alternative drug, motavizumab, was rejected by the FDA for safety reasons.

ResVax developed by Novavax is a RSV fusion (F) protein recombinant nanoparticle vaccine that uses aluminum phosphate as an adjuvant. The company hopes to develop an immunization method that can immunize pregnant women to give babies RSV resistance.

In February 2019, Resvax was hit hard in its second phase III Prepare study: The results of the test showed that it failed to reduce the incidence of medically important RSV lower respiratory tract infections within 90 days of the baby’s birth The primary endpoint of the rate.

In a larger phase III study in 2016, ResVax failed to meet the primary endpoint of preventing moderate to severe respiratory syncytial virus lower respiratory tract infection (LRTI) in the elderly patient population.

Regeneron’s suptavumab is a fully humanized monoclonal antibody developed using Regeneron’s Velocimmune technology to target the fusion protein of respiratory syncytial virus (RSV-F). In August 2017, NURSERY Pre-Term, a phase III clinical study evaluating suptavumab (REGN2222) for the prevention of respiratory syncytial virus infection, failed to reach the primary endpoint of preventing respiratory syncytial virus infection in infants.

In addition, suptavumab failed to show signs of efficacy in a subgroup of patients. In terms of safety, adverse events were similar between suptavumab and placebo.

Based on this result, Regeneron has decided to terminate the further clinical development of suptavumab.

Another research monoclonal antibody, motavizumab, obtained by AstraZeneca’s acquisition of MedImmune is used to prevent severe diseases caused by respiratory syncytial virus in high-risk pediatric patients. AstraZeneca originally intended to use motavizumab as an alternative to Synagis.

The FDA’s marketing applications for motavizumab were based on safety considerations in November 2008 (severe allergic reactions) and September 2010 (the drug was not tested in the US population, and motavizumab failed to show obvious superiority). Due to the non-inferiority of Synagis, which reduces the number of hospitalizations and causes more serious side effects than Synagis, it is necessary to increase other clinical trials to provide evidence to support the satisfactory risk/benefit in the population requiring preventive indications) Two complete reply letters were sent out.

Among them, in June 2010, the FDA Antiviral Drug Advisory Committee also voted 14 against and 3 votes in favor, not recommending approval of motavizumab.

Who will win the late project?

Although Synagis, which is currently on the market, is expensive, the five-month dosage regimen is complicated and the restrictions on its use mean that the antibody has not been widely used clinically.

However, according to the forecast of Evaluate Pharma, a leading industry consulting and market research organization in the global medical and health field, Synagis sales will still reach 735 million US dollars in 2026. Therefore, the huge potential market allows companies such as GlaxoSmithKline to try this field again.

Since many recent news about vaccine development have focused on Covid-19, on November 23, GlaxoSmithKline launched its Respiratory Syncytial Virus Candidate Vaccine GSK3888550A for the Phase III GRACE study (NCT04605159) on the safety and effectiveness of maternal immunity. Did not cause widespread concern in the industry.

In the GRACE study of GlaxoSmithKline, 10,000 pregnant women will be provided with GSK3888550A or placebo, and the primary endpoint is to reduce lower respiratory tract infections within six months after birth. The study is expected to be completed in early 2024, and the interim results will be announced in 2022.

GlaxoSmithKline is not the only one interested in this field, given that any successful product is expected to meet the high clinical needs of the disease. Pfizer and Sanofi also have drug candidates in the late development stage, and there are more drug candidates entering the phase II clinical trial stage. All participating companies hope to avoid the failure of their original competitors.

Pfizer, Merck and Moderna have also adopted this passive vaccination method, which aims to ensure that the child can be protected from respiratory syncytial virus infection at birth through the mother’s vaccination.

Pfizer is currently slightly ahead: the pivotal phase III trial of PF-06928316 (RSVpreF) started in June this year, and a placebo-controlled trial of approximately 6,900 18-49-year-old pregnant women in the United States and several other countries will be followed up Respiratory tract infection rate and potential side effects of respiratory tract infection within six months after birth.

It is expected to be completed in the second half of 2023, and interim data may be released in 2022. In November 2018, this RSV vaccine has been approved by the US FDA for fast track.

Merck and Moderna recently concluded their collaboration on adult respiratory syncytial virus vaccines and are currently working on a separate project. Among them, Moderna plans to combine its mRNA candidate vaccine RSV mRNA-1345 with the candidate vaccine mRNA-1653 against human metapneumovirus and type 3 parainfluenza virus in order to prevent all three diseases at one time. However, the project is still in its early stages.

The monoclonal antibody nirsevimab (SP0232) jointly developed by Sanofi and AstraZeneca, like Synagis, aims to provide a preventive environment for babies shortly after birth.

On July 30 this year, the international authoritative medical journal “New England Journal of Medicine” published the results of a phase IIb study of nirsevimab, which looked good. Serious lower respiratory tract infections were reduced by 70% and hospitalization was reduced by 78%.

Nirsevimab uses extension technology to extend its half-life; Sanofi claims that nirsevimab can provide protection for at least six months (equivalent to passive vaccination) and may protect against RSV-related lower respiratory tract infections for up to 12 months.

Compared with the parent vaccine, this may make nirsevimab more suitable for the seasonal characteristics of respiratory syncytial virus: the use of the drug can more accurately target the period of the year when the virus is more common.

Nirsevimab is currently undergoing two Phase III trials, a Synagis-controlled study (Medley) for high-risk preterm infants, and a placebo-controlled study (Melody) for healthy infants and young children. These studies will publish data in 2022 and 2023 respectively.

The history of drug development for respiratory syncytial virus shows that this is a high-risk area. But at least so far, there are several therapies in advanced trials that are extremely promising, and if they succeed, they will gain a huge market.

(source:internet, reference only)

Disclaimer of medicaltrend.org