What is Australia’s potential new COVID treatment?

Pfizer Australia has confirmed it will supply at least 500,000 treatment courses of its investigational COVID-19 oral antiviral candidate, provided it passes ongoing phase 2/3 clinical trials and is approved by the Therapeutic Goods Administration (TGA).
 
Should it prove effective, the treatment – PF-07321332 – will be administered in combination with HIV protease inhibitor ritonavir as an early treatment or potential prophylaxis for people exposed to COVID-19.
 
It would also add to the number of frontline treatments available to Australian clinicians, following prior deals for sotrovimab, molnupiravir (anticipated to be approved and arrive in 2022), and the recent announcement of 15,000 doses of the monoclonal antibody treatment, ronapreve.
 
How does it work?
According to Pfizer, PF-07321332 is designed to slow the virus down by blocking the activity of the main SARS-CoV-2 protease, an enzyme essential for viral replication.
 
‘Co-administration with a low dose of ritonavir is expected to help slow the metabolism, or breakdown, of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus,’ a release from Pfizer stated.
 
‘Ritonavir has been used extensively in combination with other antivirals to help slow metabolism in a similar way.’
 
How does it differ from molnupiravir?
PF-07321332 was designed specifically to target the virus, after scientists discovered a small molecule that appeared to reduce the replication of a range of coronaviruses, including SARS-CoV-2, in cells in the lab.
 
This contrasts with molnupiravir, which was originally developed to target Venezuelan equine encephalitis virus (VEEV), and prior to COVID was showing promise against viruses like influenza and Ebola.
 
The latter also uses a different mechanism to inhibit replication of the virus; rather than blocking the 3C-like protease (3CLpro) that plays a crucial role in SARS-CoV-2’s replication process, it instead incorporates RNA-like building blocks into the RNA genome of the virus itself.
 
If this genetic material is further replicated, defective RNA copies are produced and the pathogen can no longer spread.
 
Both medications are designed to be taken orally early in the course of disease to try to limit symptoms and hospitalisations, and early clinical trial results suggest molnupiravir is able to reduce the risk of hospitalisation or death by up to 50%.
 
However, one potential advantage PF-07321332’s approach compared with molnupiravir is that it does not rely on causing genetic mutations to hamper the virus.
 
While Merck, the developer of molnupiravir, has said data shows the drug is not capable of inducing genetic changes in human cells, trial participants have been told to abstain from heterosexual intercourse or agree to use contraception.
 
According to Nicholas Kartsonis, a senior vice president of clinical research in Merck’s vaccines and infectious disease department, the restriction is because until reproductive toxicology study results are available, ‘we don’t know if there’s any potential effect of [the] drug on sperm’.
 
How far into development is PF-07321332?
The medication is in the middle of a phase 2/3 development program, which began in July and is designed to test efficacy against specific cohorts, namely infected patients who are at either a high risk or low risk of severe illness.
 
A third trial aimed at preventing SARS-CoV-2 infections in adult household contracts of symptomatic COVID-19 patients is also underway.
 
Results are not expected until 2022.
 
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