SARS CoV viruses block interferon production in infected cells, allowing the virus to continue replicating unabated. Treatment with interferons may overcome that block, potentially restoring cells normal anti viral activity.
Why inhalation route?
- simple application, self-administration at home, patient-friendly
- high bioavailability of drugs in lungs
- avoidance of systemic adverse effects
- rapid onset of action due to the availability of huge pulmonary surface area
- local delivery better target organ, dose reduction, lower costs
Promising clinical results on inhaled Interferon-beta to treat COVID-19
On 20 July 2020, the Southampton-based biotech company, Synairgen announced promising results from its Phase II double-blind, placebo-controlled trial in hospitalised COVID-19 patients (100 patients), using their interferon beta protein (IFN-beta) administered by inhalation using a nebulizer.
The repurposing of Interferon-beta protein for the treatment of COVID-19 aimed at the direct pulmonary delivery of the protein into the lungs of patients with coronavirus, using a nebuliser, in the hope that it will stimulate an immune response. The initial findings suggest the treatment cut the odds of a Covid-19 patient in hospital developing severe disease (such as requiring ventilation) by 79%. Synairgen claims that patients were two- to three times more likely to recover to the point, where their everyday activities were not compromised by the virus infection. The trial also indicated a “very significant” reductions in breathlessness among patients who received the treatment.
Interferon beta (IFN-beta) is a naturally occurring, 20 kDalton protein, and has been commonly used in the treatment of multiple sclerosis. (Betaferon™ a 250 microgram/mL injectable product)
The IFN-beta also governs the body’s antiviral responses since it belongs to a group of signalling proteins made and released by the host cells in response to the presence of viruses. In a typical scenario, a virus-infected cell will release interferons which causes the nearby cells to alarm and to heighten their anti-viral defenses. There is evidence that deficiency in IFN-beta production by the lung could explain the enhanced susceptibility of these at-risk patient groups to developing severe lung disease during respiratory viral infections. Furthermore, viruses, including coronaviruses, have evolved mechanisms which suppress endogenous IFN-beta production, thereby helping the virus evade the innate immune system.
Under laboratory in vitro conditions IFN-beta (Synairgen code: SNG001) has been shown to protect cells from infection with a broad range of respiratory viruses including highly pathogenic coronavirus strains, including MERS-CoV (see Figure 1 below), SARS-CoV and SARS-CoV-2, the virus which causes COVID-19.
Figure 1. SNG001 reduced viral load following MERS-CoV infection in cell-based assays with a similar potency to that seen against other respiratory viruses
Synairgen is developing a formulation of IFN-beta, called SNG001, for direct delivery to the lungs via nebulisation, to treat and/or prevent severe respiratory illnesses caused by SARS-CoV-2, the virus which causes COVID-19.
Inhaled interferon alpha2b by Better Life Pharma
Another clinical trial with inhaled interferon is planned by a Canadian clinical stage pharmaceutical company BetterLife Pharma, later this summer. This will be a 150-patient, Phase II study where interferon alpha2b drug (called AP-003) will be administered directly to lung of patients with pre-existing conditions early after COVID-19 infection using a nebulizer. Better Life Pharma hopes that its inhalation device, an experimental delivery system, already used during the Wuhan crisis, along with its patent pending interferon alpha2b drug AP-003 will help patients by bolstering their own immune systems, to prevent them progressing to severe stages of the disease and help avoid potential damage to their lungs, and then eventually heart, kidneys and the brain – the leading cause of death amongst COVID-19 patients. AP-003 will contain BetterLife’s patent-pending and highly purified composition of IFNa2b, which the human body produces during a viral infection. A number of recent studies have investigated the use of interferon alpha 2b (IFNa2b) on patients with cases of COVID-19 and found that the drug significantly accelerated clearance of the virus from the airways of patients. If the IFNa2b interferon drug is inhaled via a handheld nebulizer, then it can be delivered directly to the lungs where it can help fight COVID-19 at the source.
In BetterLife’s planned trial, which is being designed with FDA guidance, patients will be treated within five days of being assessed and tested and before they develop dyspnea (when patients develop breathing problems and are rushed to hospital).
The premise being put forward by the company is that an intervention with AP-003 within seven days of exposure will inhibit the viral proliferation and allow the immune system to respond and prevent organ damage, thereby preserving life.
The company hopes that an inhaler delivering AP-003 directly to a patient’s lungs could make a difference by not only treating those who are seriously ill in hospital, but by eventually also being used as a coronavirus prophylaxis/prevention, allowing sufferers and those at high risk the ability to treat themselves at home before even becoming ill.
The compositions of the interferon formulations used in these clinical trials are not public. The protecting effect of cyclodextrins on interferons has been widely studied and patented.
- Mantlo E, Bukreyeva N, Maruyama J, Paessler S, Huang C. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020 Apr 29;179:104811
- Rowlatt, Justin (2020-07-20). “Covid treatment trial described as ‘breakthrough‘“. BBC News Online. Retrieved 2020-07-20.
- Mohl, S.; Winter, G. (2006) Continuous Release of rh-Interferon alpha-2a from Triglyceride Implants: Storage Stability of the Dosage Forms. Pharm. Dev. Technol. 11(1), 103-110