Limitations and challenges to the clinical use of niclosamide
Despite the interest in repurposing niclosamide for various diseases and infections, its ability to influence several signaling pathways may work to its disadvantage and lead to a widespread immunosuppressive effect. The favourable safety profile of niclosamide in treating humans with tapeworm infection could be due to the fact that the organ of interest was the gut and the drug did not need to be absorbed systemically, and therefore did not get the chance to negatively modulate systemic signaling cascades. Systemic delivery is required for infections, cancers and metabolic diseases that have shown to be responsive to niclosamide. The safety profile of niclosamide in these conditions is largely unexplored and future studies are required for a clearer picture of its toxicity. The oral dose of niclosamide as a cestocidal agent is 2g as a single dose, and this leads to a wide range of serum concentrations (Andrews et al., 1982), mainly due to variable absorption rates. The combination of a low oral bioavailability and a wide range of serum concentrations results in unpredictable efficacy in clinical studies. Additional studies with a formulation that gives high bioavailability are required before niclosamide can be used more widely. One of the obstacles in this direction is that a direct target of niclosamide remains undiscovered.
There is great interest in conducting studies to elucidate the structure-activity relationship of niclosamide and thereby to identify novel derivatives of niclosamide that might have better bioavailability (H. Chen et al., 2013). Recently, the high-resolution crystal structure of the 3CL protease, a key enzyme involved in the establishment of CoV infection and replication was discovered and will significantly facilitate the discovery of potent small-molecule inhibitors of COVID-19 via high-throughput screening (Z. Jin et al., 2020). Although these crystal structures provide useful new insights into drug discovery, extensive efforts are still needed to identify effective binding pockets for small molecules such as niclosamide and thereby validate the drug targets.
The challenges involved in repurposing niclosamide, begin with its stable crystalline structure and its lipophilicity that restrict its solubility in water. This resulted in high oral doses in pre-clinical trials and therefore raised safety concerns for clinical trials as it made therapeutically relevant concentrations of the drug difficult to achieve. For example, in a phase 1 dose-escalation study testing oral niclosamide plus standard dose enzalutamide for prostate cancer, subjects on the higher doses experienced dose limiting toxicities, however plasma concentrations at the maximum tolerated dose (500mg TDS) were not consistently above the expected therapeutic threshold (Schweizer et al., 2018).
Improvement in pharmacological and pharmacokinetic properties through reformulation can help overcome some hurdles and make use of the drug more mainstream. In a phase Ib prostate cancer trial, a novel reformulated orally-bioavailable niclosamide/PDMX1001 achieved targeted plasma levels when combined with abiraterone and prednisolone, and was well tolerated with no dose-limiting toxicities (Parikh et al., 2021). Zeyada et al., (2020) employed a novel oral niclosamide pluronic-based nanoformulation and tested its effect in hepatocellular carcinoma in rats. These nanoparticles had sustained release properties up to seven days and restored liver integrity, reduced α-fetoprotein (AFP) levels and showed better anti-cancer activities compared to the drug alone. Furthermore, the trials described above using intramuscular injection or novel formulations of oral niclosamide in COVID-19 will further elucidate its safety and efficacy, driven by systemic exposures.
Direct delivery of the drug into the lungs, such as the strategy in TACTIC-E, could overcome some such hurdles and generate high drug concentrations at the site of primary infection in COVID-19 infection, primarily the nasal cavity and lung tissue. Furthermore, this approach is thought to limit systemic exposure and hence decrease the risk of systemic side effects.