Respiratory Viral Infections The Next Frontier For Antiviral Drug Development

By Phillip Monk, Ph.D., chief scientific officer, Synairgen

Physicians and the public have long been aware that influenza can cause severe illness requiring hospitalization, but the pandemic wrought by SARS-CoV-2 has shown that other viruses can have a similarly significant impact on the global population. Meanwhile, technological advances enabling clinicians to test their patients for a panel of viruses have led to the realization that severe respiratory viral infections (RVIs) caused by many different types of viruses occur more often than previously thought. This realization is changing the way clinicians, academic researchers, and industry scientists look at viruses that cause RVIs.

Multi-viral testing is becoming increasingly common, especially in U.S. hospitals, and has introduced what I have elsewhere called a “virtuous cycle” of testing: the more we test for viruses, the better we understand which viruses are responsible for severe illness and the more we recognize the need to develop new strategies against them. Respiratory syncytial virus (RSV) is the most prominent example of how this heightened attention is changing the RVI landscape. For many years, most research on RSV focused on the pediatric population, but the more recent recognition of RSV’s impact on the elderly led to the development and — just this year — FDA approval of an RSV vaccine for people aged 60 and older.

However, while ribavirin is approved for pediatric patients with RSV and used off-label in immunocompromised patients with RSV,1 there is still no approved antiviral therapy for adults with RSV infections, and many other respiratory viruses, including human metapneumovirus (HMPV), parainfluenza virus (PIV), adenoviruses, rhinoviruses, and other coronaviruses (also known as “common cold viruses”), lack both vaccines and specific therapies. Thus, while testing has made clinicians more aware of the range of viruses that can cause RVIs, they still have nothing to give their patients. Clinicians urgently need new antiviral therapies, and this is especially true for treating vulnerable populations who are more susceptible to severe RVIs.

In this article, I discuss the extent of the RVI problem, with a particular focus on the medical need in multiple vulnerable populations, and Synairgen’s rationale for focusing the development of our clinical-stage product, SNG001, on these populations.

The medical need created by RVIs is unquestionably huge. In the U.S. alone, an estimated 3 million patients are hospitalized each year with an RVI. Influenza, SARS-CoV-2, and RSV collectively account for just over half of those hospitalizations, at 20%, 23%, and 9%, respectively. RVIs caused by HMPV, PIV, rhinoviruses, and other viruses account for the remainder.[2]

Indeed, while post-pandemic spikes in influenza and RSV cases led to predictions of a “tripledemic” of these two viruses plus SARS-CoV-2 in late 2022,3 lesser-known respiratory viruses should not be overlooked or underestimated — HMPV being one example. HMPV is a common cause of severe illness in older adults, having similar rates of ER visits, hospitalizations,4,5,6 ICU admissions, and death7 as influenza and SARS-CoV-2, and it is thought to be the second most prevalent cause of lung infection in young children after RSV.8

Cost is another important factor in RVIs that require hospitalization. The average length of a hospital stay for an RVI is three to six days,9,10,11 at an estimated cost of about $3,300 per day, for a total annual cost of $50 billion to the U.S. healthcare system.12,13 However, these numbers may underestimate the true financial burden because multi-viral testing is not routinely or universally conducted on every hospitalized patient. Moreover, the number of cases and length of stay imposes a huge burden on hospitals that negatively impacts routine care, surgeries, and other hospital procedures.

Despite all the foregoing statistics, there is still a paucity of data on the extent and burden of RVIs. The foregoing estimates of RVI incidence — which are based on just four published studies and data from the CDC and the Healthcare Cost and Utilization Project (HCUP) in the U.S. — may not capture the full extent of the problem or medical need posed by RVIs. As multi-virus testing and government tracking of viruses in circulation continue to increase, new data will further refine our understanding of the incidence and prevalence of RVIs.

Hospitalizations resulting from RVIs are disproportionately high among vulnerable populations, who are more susceptible to severe viral infections due to multiple factors. One factor is age: while adults over the age of 70 constitute about 11.3% of the U.S. population,14 they account for the majority of patients hospitalized with RVIs15 and up to 31% of deaths (in or out of hospital) due to RVIs.16 Other factors include comorbidities, underlying lung diseases such as asthma and chronic obstructive pulmonary disease (COPD),17,18,19 and immunocompromised status.

RVIs are especially concerning for immunocompromised individuals, who are affected by many different respiratory viruses beyond influenza, SARS-CoV-2, and RSV. Patients may be immunocompromised as a result of an underlying immune deficiency or as a consequence of treatment for disease, including stem cell transplantation, chemotherapy, treatment with B cell-depleting therapies such as rituximab for cancer or autoimmune disease, and the use of immunosuppressants in solid organ transplant patients. Not only are these immunocompromised patients more susceptible to viral infections, but they also have a harder time clearing them. Without specific treatment, they may be severely ill for many weeks, increasing the likelihood of hospitalization, progression to the ICU, lung damage due to long-term infection, and even death.20,21,22

We also know from our first-hand discussions with physicians that difficult-to-treat RVIs in patients receiving immunosuppressive therapies create a dilemma: Halting the immunosuppression could help the patient’s body fight and clear the infection. But in the meantime, the patient’s cancer or autoimmune disease isn’t being treated, or the patient cannot proceed with a bone marrow or solid organ transplant procedure, or the risks of graft-versus-host disease (GvHD) and transplant rejection increase in a patient who has already received a transplant.

Additionally, because immunocompromised individuals have weakened immune systems, vaccines against respiratory viruses are less likely to induce strong and highly protective immune responses. For these and other vulnerable populations, there is a good argument to be made for focusing on the development of new, preferably broad-spectrum, antiviral therapies rather than vaccines.

Antiviral therapies can be grouped into two main categories: virus-directed and host-directed.

Virus-directed therapies target specific viral proteins involved in infection, replication, and survival. The chief drawback to a virus-directed therapy is the potential for the virus to develop resistance that renders the therapy ineffective.

There are two types of host-directed antivirals. One type targets proteins in the host (patient) that viruses use to infect cells, replicate, and be released to infect other cells. Because many viruses may depend on a common host protein or pathway, these types of host-directed antivirals could potentially have broad-spectrum effects. But, as with virus-directed antivirals, viruses could still develop resistance to them.

The other type of host-directed therapy boosts the patient’s own antiviral responses, offering the potential for broad-spectrum activity against most viruses — including those such as RSV, HMPV, PIV, future pandemic viruses, and others for which specific therapies don’t exist — with no concern for the development of resistance. This is the approach Synairgen is taking with SNG001, a formulation of interferon-β (IFNβ) for inhalation that is delivered directly into the lungs. IFNβ is a naturally occurring protein that orchestrates the body's antiviral defenses, both locally at the site of infection and systemically by recruiting immune cells that clear the virus-infected cells and inducing adaptive immune responses that lead to long-term immunity against the virus, all while avoiding the risk of resistance.

At Synairgen, we intend to conduct clinical trials of SNG001 in populations that are vulnerable to RVIs, such as immunocompromised patients, the elderly, and those with certain comorbidities. By targeting the host antiviral response, we could conceivably have activity against any respiratory virus, and for this reason I think host-directed antivirals will be a tremendously important component of the antiviral armamentarium of the future.

References

About The Author:

Phillip Monk, Ph.D., joined the respiratory company Synairgen in October 2006 as head of bioscience development to develop an inhaled formulation of interferon-beta targeting severe viral lung infections. He was appointed to the Board as chief scientific officer in September 2009. Previously, he was director of the respiratory and inflammation biology group at Cambridge Antibody Technology and was discovery/early development project manager for tralokinumab, an anti-IL-13 therapeutic antibody, now an approved treatment for moderate-to-severe atopic dermatitis. Prior to that, he worked at Bayer AG within the respiratory disease therapeutic area, focusing on the development of novel therapies for asthma, COPD, and cystic fibrosis.

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