David Larwood, CEO of VFS, summed it up at the Cocci FDA workshop in 2020: “When the market opportunity is limited, finding investment becomes the key issue”. He mentioned other problems as well: “Very low patient numbers for disseminated disease, prolonged therapy, NI trial design, definition of clinical outcome”.[1]
Clearly, the cost of developing a new drug has become prohibitively expensive and often requires partnering. It is also clear, that the business model for Cocci is a spreadsheet full of red numbers.
In the world of infectious diseases, few indications are truly profitable by today’s standards, and these are defined by oncology and autoimmune drugs; none can even come close to the revenue-generating potential of a Keytruda or Humira. There are exceptions, as always, like the latest generation of HCV drugs that were clearly novel, life-saving, and profitable.
Big Pharma will partner with start-ups when their drugs meet certain criteria: true innovation, chance to be better, large addressable population, first to market, global market, long-term therapy not necessarily curative, reliable biomarkers for early derisking, feasible Phase 3 trials based on regulatory guidance, extension of indication. A long patent life with possibility for extension is also an important reason to invest.
Take GLP-1 agonists: they pretty much have a checkmark behind all these criteria. The same goes for statins, PD-1 inhibitors, and allergy / asthma medications.
A drug like nikkomycin (Nik Z) falls short in most of these categories: Few severe infections, small US and no global markets, soft outcome biomarkers and clinical benefit criteria, uncertain regulatory pathway, no remaining patent life. It would seem there is simply no way forward. Or is there?
Just this month, in Sept 2025, FDA released a Draft Guidance for developing drugs for disseminated coccidioidomycosis. Why for this indication, and why now? It’s anyone’s guess but there may have been some recent inquiries.
A new FDA Guidance takes much uncertainty out of the development pathway and is always welcome. But this Cocci Draft Guidance is a bit of a downer: it does not introduce anything that we have not seen before; it follows the well-known Feel / Function / Survive (F/F/S) mantra.
There is nothing wrong with the concept, but is it workable in this chronic disease?. Can any company ever enroll sufficient patient numbers for a NI trial with disseminated Cocci patients? Death is a relatively rare occurrence within a 1-2 years observation period, typical for such trials. How are we to assess the ‘Feel’ component? FDA seems to think that PRO tools could be developed to discern between ‘stable disease’, ‘slowly progressive disease’, and ‘slowly improving disease’.
Agree with reservations: PROs can work in the context of Orphan drug development.
Let’s have a look at a recently completed Omadacycline Phase 2b trial in NTM infection, an equally slowly progressive disease. In 2023 Paratek announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) had recommended a positive opinion for orphan medicinal product designation. Results were posted recently indicating that it does not take a huge study to assess this orphan population.[2] Only 66 patients were enrolled; clinical response, the primary efficacy outcome parameter, was based on a PRO, the NTM Symptom Assessment Questionnaire, at Day 84 Visit.
Here is another example. To assess treatment response in ALS patients, Neurofilament Light (NFL) was felt to be a useful biomarker. Levels in CSF and serum correlated reasonably well with disease activity. While the FDA was ambivalent about accepting this biomarker, an Ad Board convinced Regulators to make an exception and grant ‘conditional approval’ for the drug.[3] This helped a small start-up company execute a more definitive larger trial. When this study failed to confirm the earlier positive trend, the drug was withdrawn. Case closed. We feel this is the right course to take: give drugs a chance for rare diseases that cannot possibly be tested by the strictest of criteria, as long as there is no safety concern.
In Cocci, we only have serology as a potential objective biomarker, but it is not very good at assessing progression or improvement over time. Low sensitivity and specificity are issues, and so are reproducibility and accuracy. EIA, ID or CF tests are too coarse to serve as quantitative tools; textbooks still advise concurrent testing with a baseline sample in order to compensate for the biologic variability inherent with testing. What we need are tests that are sensitive to drug effect and/or disease progression.
In addition to a full roster of mycology experts, FDA invited leaders from pharma companies that were developing antifungals with activity against Cocci to the 2020 Public Workshop.[4] Here is the list of companies and the fate of their projects 5 years later:
- Scynexis (Ibrexafungerp – SCY-078)
- Study NCT03059992 enrolled mainly Candida, Aspergillus infections; too few patients with dimorphic fungi[5]
- CURRENT STATUS: no study activity for Cocci
- F2G (Olorofim)
- In-vitro data looked promising for the treatment of several rare fungal diseases, including Cocci
- CURRENT STATUS: In an uncontrolled Phase 2b study, 41 patients with Cocci were enrolled. None of them showed signs of clinical improvement, but most had stable disease by Day 42.[6] (see our last blog on Olorofim)
- Crozet Biopharma (vaccine for dogs)
- May work in humans too
- CURRENT STATUS: UNK
- Valley Fever Solutions (Nikkomycin Z)
- No progress as company is unable to attract funding
- CURRENT STATUS: completed and published Phase 1 results[7]
- Mycovia (VT-1598)
- VT-1598, a prior Viamet drug for Valley Fever
- CURRENT STATUS: in Phase 1 according to company website
- Mayne Pharma (SUBA-itraconazole)
- FDA approved since 2018 but not for Cocci
- SUBA-Itraconazole is a formulation of itraconazole with better oral bioavailability
- CURRENT STATUS: A comparison study with itraconazole included only 13 patients with Cocci[8]
It looks like the 2020 pipeline of antifungal candidates did not fare too well.
In the meantime, another antifungal project got underway and looks very promising. Fosmanogepix from Amplyx Pharmaceuticals has broad antifungal activity including (in-vitro at least!) for Cocci. The drug was acquired by Pfizer, then Basilea, a company known for its successful development of isavuconazole/Cresemba. They certainly have experience with antifungals. A big BARDA grant should help propel this program forward, mainly in the Candida and Aspergillus indications. Maybe this will incentivize Basilea to check on clinical activity against Cocci.
That’s good news – more on this drug another day!
ABBREVIATIONS
ALS Amyotrophic Lateral Sclerosis
BARDA Biomedical Advanced Research and Development Authority
CF complement fixation
COA Clinical Outcome Assessment
EIA enzyme immuno-assay
ID immunodiffusion
NFL Neurofilament light
NI non-inferiority
NTM non-tuberculous mycobacteria
PRO Patient Reported Outcome
VFS Valley Fever Solutions
REFERENCES
[1] Larwood J. Presentation for Valley Fever Solutions. FDA Workshop 2020 on coccidioides
[2] https://clinicaltrials.gov/study/NCT04922554?intr=Omadacycline&aggFilters=phase:2,status:com&rank=2&tab=results#outcome-measures
[3] Relyvrio (phenylbutarate + taurursodiol) by Amylyx Pharma
[4] https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/coccidioidomycosis-valley-fever-considerations-development-antifungal-drugs-08052020-08052020#event-materials
[5] Study to Evaluate the Efficacy and Safety of Ibrexafungerp in Patients With Fungal Diseases That Are Refractory to or Intolerant of Standard Antifungal Treatment (FURI). https://clinicaltrials.gov/study/NCT03059992?cond=Coccidioidomycosis&intr=Ibrexafungerp%20&rank=1&tab=results Accessed Sept. 28, 2025
[6] Maertens J. Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study. Lancet ID 2025, https://doi.org/10.1016/ S1473-3099(25)00224-5
[7] Nix D. Pharmacokinetics of nikkomycin Z following multiple doses in healthy subjects. AAC 69: 1, 2025
[8] Spec A. MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses—A Multicenter, Open-Label, Randomized Comparative Trial. Open Forum Infect Dis. 2024, 11
- Haboob هَبوب = blowing, from هب = blow, breathe
