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The ideal administration timing for the Phase III Synairgen nebulised SNG001 (interferon beta-1a) asset may prove challenging to evoke the best efficacy and safety in hospitalised Covid-19, experts say. They also note concerns surrounding its potential inflammatory effects in patients with advanced disease.

While nebulisation may be a more efficient form of SNG001’s administration than previously trialled subcutaneous injection, some experts questioned the asset’s practicality in Covid-19. Some experts add that SNG001 could perhaps perform better in milder, less-severe forms of Covid-19, considering the Phase III SPRINTER study’s (NCT04732949) focus on hospitalised subjects receiving oxygen.

Synairgen recently announced that the 610-patient SPRINTER trial has completed enrolment, with topline data expected early 2022. SNG001 is also investigated as one of the potential assets used against Covid-19 in outpatient settings in the ACTIV-2 Phase II/III study (NCT04518410) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The ACTIV-2 study has a December 2023 primary completion date. Synairgen has a market cap of USD 551.18m.

Timing of Synairgen treatment important

By using a localised, nebulised form of interferon, SNG001 should not lead to a systemic inflammatory reaction, University of Toronto immunology professor Eleanor Fish says. Yet the ideal efficacy window could prove challenging, as this would require capturing hospitalised patients at a time when they still have a significant viral load prior to entering an inflammatory phase, she says.

By focusing on patients that require oxygen, assessing the validity of the results could be easier, University of Virginia School of Medicine assistant professor Dr Patrick Evan Jackson says. Capturing the ideal application of SNG001 would require looking at the onset of patient symptoms, Fish adds. But disease onset remains variable, says Darragh Duffy, who leads the translational immunology lab at the Pasteur Institute in Paris. As such, immune responses in those infected with Covid-19 remain highly changeable, he adds.

Suggested use of SNG001 in patients who are at earlier stages of Covid-19 echoes previously published interim data from a Phase II study (NCT04385095). On 30 April, Synairgen shared combined data from the Phase II study, also known as the SG016 trial, which saw the participants split into two cohorts – 120 subjects tested at home and 101 hospitalised participants. At home, only two patients from the placebo group were taken to the hospital on grounds of worsening symptoms. Versus placebo, hospitalised subjects under SNG001 were 2.19 times more likely to recover to the level 1 mild stage on WHO Ordinal Scale for Clinical Improvement (OSCI) scale that ranges from 0 to 8. SPRINTER is recruiting patients on level 4.

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According to Fish, SNG001 should not play a role in the treatment of Covid-19 once the disease moves out of the viral phase due to the potential proinflammatory effects. This is partly based on previous results of the NIAID-sponsored ACTT-3 Phase III study (NCT04492475), which saw a worsening of respiratory status in seriously-ill subjects treated with subcutaneous injections of Merck’s Rebif (interferon beta-1a).

Investigators not asked by Synairgen to collect marker data

SPRINTER could review some potential inflammatory markers in the subjects, Fish says. But Dr Phillip Monk, chief scientific officer at Synairgen, says SPRINTER investigators have not been asked to measure such markers.

On September 2020, NIAID modified its study to halt the enrolment of subjects with advanced forms of Covid-19 who required high-flow oxygen on grounds of interim safety data. This decision was based on seeing a greater rate of severe adverse events (SAEs), namely the worsening of respiratory status, in participants on high-flow oxygen treated with Rebif, versus those who were not. Furthermore, the study found that the use of Rebif in combination with Gilead Sciences’ Veklury (remdesivir) was not superior to Veklury alone.

Jackson says there may be a patient population which could see a similar safety profile with nebulised SNG001 as it did with subcutaneous Rebif. This could be partly the result of type I interferons activating the immune cells, prompting an inflammatory response in the immune cells to kill and clear the virus, Fish says. However, ACTT-3 had studied subjects who placed on level 4, 5 and 6 of the ordinal scale.

Benefits in Synairgen’s nebulisation debated

Nebulisation could prove to be the preferred way of administering SNG001. By inhalation, the asset would be able to quickly hit the target site of the illness, Fish says. If used at early stages of Covid-19, SNG001 could treat the target site before the disease becomes completely systemic, she adds.

While more data remains needed to determine whether nebulisation is superior to subcutaneous injections, the mode of administration nonetheless have theoretical appeal in possibly being less toxic, Dr Leonard Calabrese from the Cleveland Clinic in Ohio says. Nebulisation as a mode of delivery minimises systemic exposure and the potential to increase inflammation in more severe patients, Synairgen’s Monk adds.

Nevertheless, the use of nebulisation as a method of administration has its own limitations. Rather than nebulisation itself, a potential issue remains in the fact that the mode of administration remains an aerosol-generating procedure, Jackson explains. In this sense, different institutions have slightly different standards as to their management of such procedures in Covid-19 patients, he adds, noting a potential limitation lies in the infection control practices in such settings.

Synairgen’s Monk argues its device manufacturing partner has conducted a study on the risk of secondary exposure to caregivers, concluding that placing a viral filter on the nebuliser’s exhalation port is effective. Yet, if faced with a potential surge, some institutions, due to limits in their physical infrastructure, would instead look for treatments with easier ways of administration such as capsules or pills, Jackson notes.

Potential for targeting specific patients

Nevertheless, owing to the ongoing appearance of new Covid-19 variants, therapeutic assets such as SNG001 remain needed, Weizmann Institute of Science biomolecular sciences Gideon Schreiber says.

If SPRINTER identifies specific patients, such as those with defects in interferon-signaling pathways, SNG001 could become a treatment with a specific subset of patients, Jackson adds. This includes individuals with rare genetic mutations in different pathways, Duffy says.

Another target population could be individuals with high autoantibody counts of autoantibodies against type I interferons, which increase with age and have been linked to severe cases of COVID-19, he adds. In this sense, the asset could be potentially deployed as a treatment in settings such as care or nursing homes if faced with a COVID-19 outbreak, he notes.

Finding a potential use in SNG001 could be important to using more pathogen-agnostic treatments to the wider antiviral therapy space. Interferon therapy could be a potential first-line of defence in treating other viruses and possible future pandemics, Duffy says. Seeing that many viruses interfere with interferon response, SPRINTER results could potentially lay the groundwork for other viral infections, he notes. Synairgen is planning to initiate additional studies with the asset to determine its efficacy against other respiratory viruses.