Lead onychomycosis therapeutic


Hexima is conducting a phase I/IIa clinical trial to assess the safety and preliminary efficacy of its lead antifungal molecule, HXP124 as a treatment for onychomycosis.

Value proposition for HXP124

HXP124 is a water soluble small peptide that has been formulated for efficient nail penetration. This is expected to allow HXP124 to reach the site of infection in amounts that effectively kill the fungus that are responsible for the infection. Furthermore, HXP124 has a fungicidal mode-of-action and kills fungal cells within 30 minutes. HXP124’s novel mode of action also prevents fungi from becoming highly resistant to HXP124 treatment over time. These key features make HXP124 an outstanding candidate to treat onychomycosis, with the potential to be effective over a shorter treatment time than current therapies.

HXP124 rapidly kills fungal cells

For the treatment of onychomycosis, a fungicidal mode of action is beneficial as it will likely eradicate fungal cells at the site of infection and help prevent reinfection. HXP124 rapidly kills fungal cells (within 30 minutes) and testing undertaken by Hexima to date appears to indicate that it does so at lower concentrations than competitor molecule.

Cells of the pathogenic yeast Candida albicans were treated with HXP124, efinaconazole, tavaborole, terbinafine or ciclopirox at 100 µg/mL for 30 minutes.

Propidium iodide was used to fluorescently label dead cells, which were detected by flow cytometry.

The percentage of living cells after treatment for 30 minutes with antifungal drugs.

Fungi do not readily develop resistance to HXP124

A major problem facing health professionals when treating bacterial or fungal infections is the rapid development of resistance to antimicrobial treatments. In contrast to current antifungal treatments, HXP124 has properties which have the potential to prevent fungi becoming highly resistant to the molecule (Figure 3).
Cells of the pathogenic yeast Candida albicans were cultured in the presence of HXP124 and efinaconazole at sub-inhibitory concentrations (which means at concentrations which only partially inhibit the growth and replication of Candida albicans). At these concentrations, yeast cells quickly developed resistance to efinaconazole but did not develop strong resistance to HXP124 (*MIC: minimum inhibitory concentration; the minimum amount of drug required to inhibit growth of the fungus).

HXP124 Penetrates the Human Nail Plate

For a molecule to serve as a potent and effective treatment for onychomycosis, it must readily penetrate the human nail plate and reach the site of infection. This has been an enormous hurdle for many products. HXP124 penetrates the human nail plate and preliminary data indicates that it does so with greater efficiency than current therapies used to treat onychomycosis. On average, over 16% of the applied dose penetrated through the nail plate by day 10 compared with less than 3% for efinaconazole (Jublia®). High amounts of HXP124 can also be detected in the nail plate, both at the site of dosing and 5 mm from the dosed area, demonstrating that HXP124 moves laterally through the nail plate. This is important as HXP124 is likely to reach areas of the nail that are under the nail folds where fungal cells may evade topical products with poor nail penetration and diffusion. The faster and more efficient penetration of HPX124 through nails makes it a superior candidate for the treatment of fungal nail infections and may allow for shorter treatment times.
Schematic depicting how nail penetration is assessed. HXP124 was added to human nails using the method developed by Professor Howard Maibach, a dermatologist and researcher at University of California San Francisco Medical Centre. Briefly, (1) nails were sealed in an adapter over saline-soaked cotton wool and HXP124 (10 µL of 1% solution) was applied to the top of the nail plate daily for up to 14 days (2). (3) Penetration was assessed by analysing the amount of HXP124 that had reached the cotton wool by RP-HPLC.
HXP124 penetrates human nails faster and more efficiently than competitor molecules.
Following permeation assays, the dosing site (yellow arrow) and a region 5 mm away from the dose white (white arrow) were drilled out to determine how much HXP124 was inside the nail.
The amount of HXP124 at the dose site and the lateral non-dosed site of the nail was determined using an enzyme-linked immunosorbent assay using antibodies specific for HXP124.

HXP124 performs as well as the best topical therapy in an infected nail model.

HXP124 was tested in an infected nail model (conducted by independent contract research organisation (CRO), MedPharm, UK) to demonstrate that HXP124 is able to penetrate the nail plate and kill fungus present on the underside of the nail. Two currently marketed products, Jublia® and Penlac® were used as comparators in this study. Jublia® is the most effective topical product currently available. The test showed HXP124 is as effective at permeating and killing fungus in this model as Jublia® and substantially more effective than Penlac®.
Human nail clippings that had been infected with the fungus Trichophyton rubrum (most common causative agent of onychomycosis) were treated daily with HXP124, Jublia® or Penlac®. Adenosine triphosphate (ATP) levels were used to indicate the level of viable fungus. HXP124 reduced the level of viable fungus by more than 95% within 7 days and was as effective as Jublia® in this study.

HXP124 was very well tolerated in a dermal toxicity study in minipigs.

After repeat dosing for 42 days, HXP124 had a No Observable Adverse Effect Level (NOAEL) of 50 mg/kg which represented the highest dose tested and >750-fold higher than the intended clinical dose.