{"id":5576,"date":"2025-10-17T10:13:27","date_gmt":"2025-10-17T16:13:27","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=5576"},"modified":"2025-10-21T16:57:12","modified_gmt":"2025-10-21T22:57:12","slug":"the-antifungal-landscape-2","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2025\/10\/17\/5576\/the-antifungal-landscape-2\/","title":{"rendered":"The Antifungal Landscape – 2"},"content":{"rendered":"
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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]<\/a>  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.<\/p>\n\n\n\n

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.<\/p>\n\n\n\n

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.<\/p>\n\n\n\n

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?<\/p>\n\n\n\n

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.<\/p>\n\n\n\n

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 \u2013 even many years after approval \u2013 is still unsubstantiated by hard clinical data.<\/p>\n\n\n\n

What clinicians really want is an oral candin, with cidal activity, or an oral AMB with no renal toxicity. This, however, is wishful thinking. <\/p>\n\n\n\n

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.<\/p>\n\n\n\n

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<\/em> 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.<\/p>\n\n\n\n

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\u2019s 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.<\/p>\n\n\n\n

Here a brief introduction to FMGX, an ex-Eisai, ex-Amplyx, ex-Pfizer, now Basilea drug formerly known as E1210 or APX001A or MGX.<\/p>\n\n\n\n

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.<\/p>\n\n\n\n

MGX attaches to and blocks Gwt1, an acyl transferase in fungal ER membranes, thereby preventing the binding of palmitoyl-CoA.<\/span>[2]<\/a>  Gwt1 is an essential enzyme in the cascade of steps, leading to the formation of a functional GPI anchor.<\/span> <\/p>\n\n\n

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FMGX structure and function.  From: Dai<\/figcaption><\/figure>\n<\/div>\n\n\n

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]<\/a>,[2]<\/a> Similarly, gepinacin, another Gwt1 inhibitor, has been shown to be specific for the fungal target.[3]<\/a><\/p>\n\n\n

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GPI structure. From: Kinoshita <\/span><\/figcaption><\/figure>\n<\/div>\n\n\n

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]<\/a>  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.\ud83d\ude0a<\/p>\n\n\n\n

The other concerns are related to development of resistance by a single mutational event. Based on in-vitro<\/em> studies, this does not appear to be too frequent, occurring in the range of 10-7 <\/sup>\u2013 10-8<\/sup>.[5]<\/a>  Past experience tells us not to rely on these tests too much \u2013 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.<\/p>\n\n\n\n

As far as FMPG\u2019s 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]<\/a><\/p>\n\n\n\n

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.<\/p>\n\n\n\n

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]<\/a> <\/p>\n\n\n\n

<\/p>\n\n\n\n

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\u2019t know how MECs correlate with clinical efficacy. So far, they are merely values indicative of partial in-vitro <\/em>efficacy.<\/a><\/p>\n\n\n\n

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\u201cMinimum effective concentration (MEC) is the lowest concentration of an antimicrobial agent that results in morphologic changes (aberrant growth) against filamentous fungi” PFALLER<\/p>\n<\/blockquote>\n\n\n\n

We plan to talk more about FMGX, its ongoing clinical program, and the results of published studies in an upcoming blog. <\/span><\/p>\n\n\n\n

<\/p>\n\n\n\n

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ABBREVIATIONS
<\/strong>AFST       antifungal susceptibility testing (not routinely done for molds)
ECOFF   epidemiologic cut-off [9]<\/a>,[10]<\/a>
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<\/p>\n\n\n\n

REFERENCES
<\/strong>[1]<\/a> Mutz M. The GPI anchor pathway: A promising antifungal target. Future Med Chem. 201; 8: 1387
[2]<\/a> Dai X. Structural insights into the inhibition mechanism of fungal GWT1 by manogepix. Nature Communications 15:9194, 2024
[3]<\/a> Liston S.  Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability.  Antimicrob Agents Chemother 64:e00899-20
[4]<\/a> Kinoshita T..  Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J. Lipid Res.  2016; 57:6
[5]<\/a> 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]<\/a> Almajid A.  Fosmanogepix: The Novel Anti-Fungal Agent\u2019s Comprehensive Review of in Vitro, in Vivo, and Current Insights From Advancing Clinical Trials. Cureus 16(4): e59210, 2024
[7]<\/a> Otto  W.  A Practical Guide to Antifungal Susceptibility Testing.  JPIDS 2023:12: 214
[8]<\/a> Pfaller M.  Antifungal susceptibility testing. Uptodate. Accessed Oct 15, 2025
[9]<\/a> Defined as \u201cMIC above which isolates have phenotypically detectable acquired resistance mechanisms\u201d
[10]<\/a> Kahlmeter G. How to: ECOFFs – the why, the how, and the don’ts of EUCAST epidemiological cutoff values. Clin Microbiol Infection 28 (2022): 952<\/p>\n\n\n\n

<\/p>\n","protected":false},"excerpt":{"rendered":"

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 Continue reading The Antifungal Landscape – 2<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":5586,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[227,3,18],"tags":[2514,1271,1580,471,2456,403,650,595,2504,2505,2502,41,66,2429,689,646,626,1495,2512,2431,2515,1347,1585,2517,1583,2464,2508,610,927,2433,2513,1342,2501,641,2462,2510,67,2509,655,2516,2506,2507,2496,2518,979,74,1582,48,928],"class_list":["post-5576","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-afst","tag-allphase-pharma-consulting","tag-ampho-b","tag-amphotericin-b","tag-amplyx","tag-antibiotic-blog","tag-aspergillus","tag-basilea","tag-candida-auris","tag-candidozyma-auris","tag-candins","tag-clsi","tag-dalbavancin","tag-echinocandins","tag-eisai","tag-endemic-mycoses","tag-eucast","tag-fluconazole","tag-fmgx","tag-fosmanogepix","tag-fungal-susceptibility-testing","tag-fungicidal","tag-fungistatic","tag-gpi","tag-harald-reinhart","tag-ibrexafungerp","tag-immunocompromised","tag-isavuconazole","tag-ketoconazole","tag-liposomal-amb","tag-mef","tag-mold-infection","tag-new-antifungals","tag-nikkomycin","tag-olorofim","tag-opelconazole","tag-oritavancin","tag-oteseconazole","tag-pfizer","tag-pigw","tag-prolonged-half-life","tag-recurrent-vulvovaginal-candidiasis","tag-rezafungin","tag-rvvc","tag-tdm","tag-telavancin","tag-triazole","tag-vancomycin","tag-voriconazole"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/HR_SLIDER-The-Antifungal-Landscape-2.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-1rW","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":5569,"url":"https:\/\/allphasepharma.com\/dir\/2025\/10\/16\/5569\/the-antifungal-landscape-1\/","url_meta":{"origin":5576,"position":0},"title":"The Antifungal Landscape – 1","author":"Harald","date":"October 16, 2025","format":false,"excerpt":"Some newer azoles are still in development, but most only target candidiasis.\u00a0 Many years ago we saw development of nikkomycin (Nik Z), a drug mainly for coccidioidomycosis (Valley Fever).\u00a0 It has no appreciable activity against candida or aspergillus.\u00a0 Then there is ibrexafungerp, a promising new agent against C. albicans and\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/antigungals-table.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/antigungals-table.jpg?resize=350%2C200&ssl=1 1x, 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Below a table\u00a0which includes compound, sponsor\u00a0and development stage (Phase). It also indicates whether a drug has been\u00a0the topic of a\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"QIDP 4th edition","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1028,"url":"https:\/\/allphasepharma.com\/dir\/2014\/10\/05\/1028\/qidp-drugs-here-they-are-all-of-them\/","url_meta":{"origin":5576,"position":3},"title":"QIDP Drugs: Here They Are, All of Them","author":"Harald","date":"October 5, 2014","format":false,"excerpt":"For the latest QIDP listing, please click HERE As of Oct. 9, 2014, there were by my accounting 30 compounds with QIDP designation. Here is the break-down: \u00a0 31 compounds with QIDP designation 29 antibacterials, 2 \u00a0antifungals 22 systemically active, 9\u00a0for topical administration 13 in Phase 3, 9 in Phase\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":3257,"url":"https:\/\/allphasepharma.com\/dir\/2017\/03\/29\/3257\/fake-news-spectinomycin\/","url_meta":{"origin":5576,"position":4},"title":"The CDC and Spectinomycin","author":"Harald","date":"March 29, 2017","format":false,"excerpt":"Pfizer discontinued US distribution of spectinomycin (Trobicin\u00ae) in November 2005; remaining inventory expired in May 2006\u00a0[1]. Nonetheless, at the FDA website we still find a Package Insert for Trobicin updated as late as Aug 2012, a thin 6-page leaflet which seems to have survived from the 80s. The drug is\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/Spectino-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/Spectino-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/Spectino-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2205,"url":"https:\/\/allphasepharma.com\/dir\/2015\/12\/23\/2205\/qidp-antibiotics-2015-year-end-update\/","url_meta":{"origin":5576,"position":5},"title":"QIDP Antibiotics – 2015 Year-End Update","author":"Harald","date":"December 23, 2015","format":false,"excerpt":"Here an updated listing of all QIDP drugs we are aware of as of 12\/24\/2015. Today just\u00a0facts and numbers; we will provide an interpretation of the current landscape in upcoming blogs. There are\u00a058 drugs which garnered QIDP status and these are listed in the Main Table below. 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