As many in the field have said before, what we really need are antifungals with a truly novel MoA, not minor changes to well-established classes.[1] There is a shortage of new antifungals for invasive disease. Small improvements in PK will hardly move the field forward or excite investors to engage. Our current armamentarium is still very limited.
Do we really need a longer-acting azole or candin? The azole class of agents has been tinkered with for over 40 years, and gave us azoles with greatly improved properties, broader spectrum, better PK and cleaner DDI profile than ketoconazole. As such, opelconazole, an inhaled triazole, and oteseconazole, a drug for RVVC are just minor variations on a theme.
We do not want to belittle the efforts that led to incremental improvements and eventually gave us drugs with aspergillus coverage, but it seems that azole chemistry is now as good as it gets. All are ergosterol inhibitors, fungistatic, and besides this, newcomers now also need to compete with generic fluconazole.
In the group of echinocandins, the latest arrival is rezafungin. It has a very similar structure to other candins, but its PK allows weekly instead of daily dosing. While this may sound like a significant improvement, rezafungin is still an IV only drug. We see it as a treatment for Candida auris (now Candidozyma auris) infections, as other candins do not have activity against this emerging pathogen. Is this sufficiently innovative?
It is all reminiscent of the tinkering with glycopeptide, trying to replace vancomycin with longer half-life competitors. Telavancin, oritavancin and dalbavancin require less frequent dosing but still could not replace cheaper off-patent vancomycin which still works just fine. All these newcomers were injectables and differentiated only by half-life. In acute care, and for the sick ICU patients, convenience factors are just not all that important.
For amphotericin B (AMB), we have 3 liposomal me-toos on the market. All 3 promise a better safety profile despite higher dosing. As much as we like the liposomal approach to drug delivery, their claim – even many years after approval – is still unsubstantiated by hard clinical data.
What clinicians really want is an oral candin, with cidal activity, or an oral AMB with no renal toxicity. This, however, is wishful thinking.
We still see a market for new antifungals with good activity against endemic mycoses and invasive mold infections, or with fungicidal instead of fungistatic properties. Neither azoles nor candins really work all that well in immunocompromised patients.
We discussed olorofim, ibrexafungerp and nikkomycin in prior blogs. These are antifungals with a novel MoA and would seem to address some of the existing high-need areas. However, despite in-vitro antifungal efficacy, many encountered problems at later stages of development. Sometimes PK, sometimes safety/tolerability issues emerged. All struggle(d) to find partners to help fund next steps.
We will skip 5-FC (as there is no news!), and will postpone discussion of the encochleated AMB from Matinas (which seems interesting!) to a time when more data has been published. Today’s blog centers on fosmanogepix, a promising novel antifungal currently in Phase 3 of development. Its name is almost unpronounceable, so we will refer to this Gpt1 inhibitor as FMGX from now going forward.
Here a brief introduction to FMGX, an ex-Eisai, ex-Amplyx, ex-Pfizer, now Basilea drug formerly known as E1210 or APX001A or MGX.
FMGX is a prodrug; the active moiety is MGX after dephosphorylation. FMGX competitively inhibits the biosynthesis of glycosylphosphatidyl inositol (GPI), an essential protein of fungal cell membranes that anchor mannoproteins to the cell walls.
MGX attaches to and blocks Gwt1, an acyl transferase in fungal ER membranes, thereby preventing the binding of palmitoyl-CoA.[2] Gwt1 is an essential enzyme in the cascade of steps, leading to the formation of a functional GPI anchor.
The GPI pathway is highly conserved in fungi and exists in humans as well. Therefore, species-selective inhibition of the fungal Gwt1 target was a key concern early on as MGX should not also block its human homologue, PIGW. As described by Mutz and further investigated by Dai, binding of MGX to fungal Gwt1 is indeed selective. MGX had negligible inhibitory activity on PIGW, even at high doses.[1],[2] Similarly, gepinacin, another Gwt1 inhibitor, has been shown to be specific for the fungal target.[3]
We are not sure whether this rules out any and all interference with human enzymes. Any degree of cross-over inhibition of the mammalian enzyme would be rather consequential. After all, more than 150 different human proteins are GPI anchored; they function as enzymes, adhesion molecules, receptors, protease inhibitors, transporters, and complement regulators.[4] With antifungal therapy often administered for prolonged periods, species selectivity is a must. This will become a review issue, if not by the FDA, then by us.😊
The other concerns are related to development of resistance by a single mutational event. Based on in-vitro studies, this does not appear to be too frequent, occurring in the range of 10-7 – 10-8.[5] Past experience tells us not to rely on these tests too much – in bacteriology, such in-vitro tests are not really predictive, and we would assume that the same holds true for fungi. Clinical practice will provide real-world answers soon enough.
As far as FMPG’s anti-fungal spectrum is concerned, it is broad, comprising not just Candida and Aspergillus, but many more rare fungi as well. As would be expected for an NCE drug, organisms resistant to candins or azoles are fully susceptible.[6]
For fungistatic drugs we are usually provided with MIC values. However, for candins and also for FMGX, MEC values are commonly listed on antifungal susceptibility testing (AFST). This practice merits a word of caution.
Determining fungal MICs or MFCs is very difficult, esp. for molds. Plagued by reproducibility issues, testing has become more standardized over the last 10 years, with CLSI and EUCAST guidelines stipulating test parameters. Nonetheless, technical difficulties abound and reproducibility is still problematic even in experienced hands. For instance, four-fold differences (ie. 2 dilution steps) in MIC testing are still within the acceptable bandwidth.[7]
Difficulties with MIC testing became evident when the candin class was introduced into clinical practice. Since then we have the MEC category which indicates morphologically suppressed hyphal growth but not total inhibition. We still don’t know how MECs correlate with clinical efficacy. So far, they are merely values indicative of partial in-vitro efficacy.
“Minimum effective concentration (MEC) is the lowest concentration of an antimicrobial agent that results in morphologic changes (aberrant growth) against filamentous fungi” PFALLER
We plan to talk more about FMGX, its ongoing clinical program, and the results of published studies in an upcoming blog.
ABBREVIATIONS
AFST antifungal susceptibility testing (not routinely done for molds)
ECOFF epidemiologic cut-off [9],[10]
ER endoplasmatic reticulum
GPI glycosylphosphatidylinositol
MEC minimum effective concentration
MFC minimum fungicidal concentration
MIC minimum inhibitory concentration
RVVC recurrent vulvovaginal candidiasis
TDM therapeutic drug monitoring
REFERENCES
[1] Mutz M. The GPI anchor pathway: A promising antifungal target. Future Med Chem. 201; 8: 1387
[2] Dai X. Structural insights into the inhibition mechanism of fungal GWT1 by manogepix. Nature Communications 15:9194, 2024
[3] Liston S. Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability. Antimicrob Agents Chemother 64:e00899-20
[4] Kinoshita T.. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J. Lipid Res. 2016; 57:6
[5] Kapoor M. Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species. Antimicrob Agents Chemother. 2019 Dec 20;64(1): e01387-19
[6] Almajid A. Fosmanogepix: The Novel Anti-Fungal Agent’s Comprehensive Review of in Vitro, in Vivo, and Current Insights From Advancing Clinical Trials. Cureus 16(4): e59210, 2024
[7] Otto W. A Practical Guide to Antifungal Susceptibility Testing. JPIDS 2023:12: 214
[8] Pfaller M. Antifungal susceptibility testing. Uptodate. Accessed Oct 15, 2025
[9] Defined as “MIC above which isolates have phenotypically detectable acquired resistance mechanisms”
[10] Kahlmeter G. How to: ECOFFs – the why, the how, and the don’ts of EUCAST epidemiological cutoff values. Clin Microbiol Infection 28 (2022): 952
