Tamibaroterone inhalable dry powder shows broad-spectrum activity against SARS-CoV-2, MERS and H1N1

Researchers from the University of Hong Kong (HKU) have developed a dry powder formulation of tamibaroterone, which displays broad-spectrum antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and pandemic 2009 influenza A virus (H1N1), when delivered intranasally or through inhalation in mouse and hamster models.

Tamibarotene is an orally active retinoid for the treatment of acute promyelocytic leukaemia, which has been shown to suppress virus-induced lipogenesis within host cells, thereby affecting viral membrane block building, energy supply, and post-translational protein modifications ultimately disrupting propagation of a diverse group of viruses. [Nat Commun 2019;10:120; Front Immunol 2019;10:1533]

“When administered orally, tamibaroterone does not achieve robust antiviral activity in the respiratory tract due to inadequate lung distribution following oral administration,” wrote the researchers. “Therefore, higher doses would be needed to compensate for insufficient lung distribution. While tamibaroterone has an established safety profile in humans, with milder toxic effects than other retinoic acids, toxic effects are likely to occur with extensive systemic exposure. At the same time, pulmonary delivery could increase local drug concentration in the lung and reduce unintended distribution, thus maximizing the antiviral effect in the respiratory tract with a lower dose.” [Drugs Today (Barc) 2007;43:563-568]

The inhalable dry powder formulation of tamibarotene (A2-TFN) was prepared by spray freeze drying (SFD), a two-stage particle engineering technique, in which the drug solution is sprayed into a cryogen such as liquid nitrogen where the atomized particles are instantaneously frozen, followed by the sublimation of solvent at low pressure and temperature, leading to the formation of dried porous low-density particles, which can improve the rate of drug dissolution and aerosol performance. [J Control Release 2019;300:93-101]

The researchers subsequently established tamibaroterone’s prophylactic efficacy against clinical manifestation of SARS-CoV-2 infection by intranasally challenging golden Syrian hamsters with the virus. “As expected, vehicle-treated control hamsters developed clinical signs of lethargy, hunched back posture, and rapid breathing starting from 2 days post-infection, whereas hamsters treated with A2-TFN did not develop clinical symptoms. The viral RNA load and viral titres in lung tissues of hamsters who have received intratracheal A2-TFN were significantly [p<0.05] lower than those in controls,” they wrote. [Adv Therap 2021;4:2100059]

The broad-spectrum anti-coronavirus activity of A2-TFN was also shown in MERS-CoV–infected mouse model as pre-challenge prophylaxis. Moreover, A2-TFN’s anti-influenza activity was demonstrated by improved mouse survival rate and alleviated disease severity when administered either intratracheally as prophylaxis or intranasally as treatment.

“A single dose of SFD tamibarotene powder given by pulmonary delivery has successfully produced broad-spectrum prophylactic antiviral effect in animals, and the intranasal administration of reconstituted tamibarotene formulation also demonstrated therapeutic efficacy against influenza A virus,” commented the researchers.

“Currently, there is no inhalable antiviral powder formulation for coronavirus disease 2019 [COVID-19] treatment. Tamibarotene dry powder with broad-spectrum antiviral activity presents a new strategy for COVID-19 management, especially as prophylaxis and treatment for outpatients when inpatient healthcare cannot be provided,” said Dr Jenny Lam of the Department of Pharmacology and Pharmacy at HKU.