Table 3.
Preclinical studies evaluating the efficacy of olorofim in animal models of invasive fungal infection.
| Reference | Infection Model Fungus (OLR MIC) Population |
Control | OLR Route OLR Dose TT Duration |
Measurement (Method) |
Efficacy |
|---|---|---|---|---|---|
| [11] | Invasive systemic infection through IV inoculation in a neutropenic murine model Aspergillus terreus (0.008 mg/L) 10 male neutropenic CD-1 mice per group |
Placebo IV excipient 1 mg/kg/day IV Amphotericin B |
Oral or IV 10 mg/kg/q12h 9 days |
Survival on day 10 (log-rank test) Renal fungal burden on death or on day 10 (CFU) |
Survival on day 10 vs. placebo Better survival rates in OLR-treated mice than in placebo-treated mice (p ≤ 0.0001). No significant difference in survival rates between the IV and oral route. |
|
Renal fungal burden on day 10 Reduction in fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001). | |||||
| [23] | CNS infection in a murine model Coccidioides immitis (0.016 mg/L) 10 male ICR mice per group |
Placebo oral excipient 25 mg/kg × 2/day oral fluconazole |
Oral 20 mg/kg/day in 2 or 3 administrations 40 mg/kg/day in 2 or 3 administrations 14 days |
Survival on day 30 (log-rank test) |
Survival on day 30 vs. placebo Significantly higher median survival time in OLR- and FLC-treated mice than in placebo-treated mice (p ≤ 0.0001), with no significant difference in the total survival rate compared to placebo for mice treated with OLR 20 mg/kg in 2 or 3 administrations nor mice treated with OLR 40 mg/kg in 2 administrations. Mice treated with OLR 40 mg/kg in 3 administrations presented the highest total survival rate (p = 0.0007). |
| [23] | CNS infection in a murine model Coccidioides immitis (0.016 mg/L) 10 male ICR mice per group |
Placebo oral excipient 25 mg/kg × 2/day oral fluconazole |
Oral 20 mg/kg/day in 2 or 3 administrations 40 mg/kg/day in 2 or 3 administrations 14 days |
Brain fungal burden on day 9 (CFU) Brain fungal burden at death or on day 30 for survivors (CFU) |
Brain fungal burden on day 9 vs. placebo Significant log10 reduction of median fungal burden in mice treated with FLC and OLR 40 mg/kg (p ≤ 0.0001) as compared to placebo-treated mice and other OLR regimens. |
|
Brain fungal burden on day 30 vs. placebo Only mice treated with OLR 40 mg/kg maintained a significant log10 reduction of the median fungal burden on day 30. Mice treated with FLC or other OLR regimens showed no significant differences with placebo-treated mice. | |||||
| [25] | Invasive sinopulmonary infection through nasal inoculation in a neutropenic murine model Aspergillus flavus 4 strains (0.03 mg/L) 10 male neutropenic CD-1 mice per group, per strain |
Placebo IV excipient 20 mg/kg/day oral posaconazole |
IV 24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h 3 days |
Survival on day 10 (log-rank test) Pulmonary histology on day 3 (GMS) |
Survival on day 10 vs. placebo Better apparent median survival time and total survival rates than placebo for OLR doses of 8 mg/kg/q8h and 15 mg/kg/q8h (p not mentioned). |
|
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where severe inflammation, necrosis, hemorrhage, edema, necrotizing vasculitis, vascular invasion, and thrombosis were observed. | |||||
| [26] | Invasive systemic infection through IV inoculation in a neutropenic murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 17 female neutropenic CD-1 mice per group: 10 for survival study, 3 for GM measurement and histology, 4 for fungal burden measurement |
Placebo IP PBS |
IP 15 mg/kg/q8h 9 days |
Survival on day 10 (log-rank test) Serum GM On day 3 and day 10 (EIA) Renal fungal burden on day 3 (qpCR) Renal histology on day 3 (GMS) |
Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
|
Serum GM on day 3 vs. placebo Lower serum GM levels in OLR-treated mice than in placebo-treated mice (p not mentioned). | |||||
|
Renal fungal burden on day 3 vs. placebo Three- to six-fold significant reduction of the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001 in the A. fumigatus model, p ≤ 0.05 in the A. nidulans and A. tanneri models). | |||||
|
Renal histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae, severe inflammatory infiltrations, and necrosis were observed. | |||||
| [26] | Invasive systemic infection through inhalation in a CGD murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 17 male gp91-/- phox CD-1 mice per group: 10 for survival study, 3 for GM measurement and histology, 4 for fungal burden measurement |
Placebo IP PBS |
IP 15 mg/kg/q8h 9 days |
Survival on day 10 (log-rank test) Serum GM On day 3 and day 10 (EIA) Pulmonary fungal burden on day 3 (qpCR) Pulmonary histology on day 3 (GMS) |
Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
|
Serum GM on day 3 vs. placebo Lower serum GM levels in OLR-treated mice than in placebo-treated mice (p not mentioned). | |||||
|
Pulmonary fungal burden on day 3 vs. placebo Eight- to twenty-two-fold significant reduction in the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.01 in the A. fumigatus model, p ≤ 0.001 in the A. nidulans model, p ≤ 0.0001 in the A. tanneri model). | |||||
|
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. | |||||
| [26] | Invasive systemic infection through inhalation in a CGD murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 14 male gp91-/- phox CD-1 mice per group |
Placebo IP PBS 20 mg/kg/day IP voriconazole |
IP 15 mg/kg/q8h 9 days |
Survival on day 10 (log-rank test) Pulmonary histology on day 3 (HE) |
Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice and VOR-treated mice as compared to placebo-treated mice (p not mentioned). VOR-treated mice seemed to have a better survival rate than OLR-treated mice in the A. fumigatus model. In the A. nidulans and A. tanneri models, OLR-treated mice seemed to have a better survival rate than VOR-treated mice. |
|
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. Few or no fungal elements in VOR-treated mice, except in the A. tanneri model, where abundant hyphae and extensive necrotic granulomas were observed, as in the placebo-treated mice. | |||||
| [27] | Invasive systemic infection through IV inoculation in a neutropenic murine model Scedosporium apiospermum (0.016 mg/L) Scedosporium boydii (0.016 mg/L) Lomentospora prolificans (0.03 mg/L) 17 female neutropenic CD-1 mice per group: 10 for survival study, 3 for BD measurement and histology, 4 for fungal burden measurement |
Placebo IP PBS |
IP 15 mg/kg/q8h 9 days |
Survival on day 10 (log-rank test) Serum BD on day 3 (colorimetric assay) Renal fungal burden on day 3 (qpCR) Renal histology on day 3 (GMS) |
Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
|
Serum BD on day 3 vs. placebo Significantly lower serum BD levels in OLR-treated mice than in placebo-treated mice (p ≤ 0.001 in the S. apiospermum and S. boydii models, p ≤ 0.0001 in the L. prolificans model). | |||||
|
Renal fungal burden on day 3 vs. placebo Four- to six-fold significant reduction in the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001 in the S. apiospermum and S. boydii models, p ≤ 0.01 in the L. prolificans model). | |||||
|
Renal histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. | |||||
| [28] | Dermatophytosis in an immunosuppressed guinea pig model Microsporum gypseum (0.03 mg/L) 9 albino female guinea pigs immunosuppressed by corticosteroids, divided into 3 groups |
Placebo topical PEG300 1% topical clotrimazole |
Topical 100 µL of 0.1 mg/mL of olorofim in PEG300 7 days |
Surface scrapings from inoculation site (optical microscopy) |
Scrapings on day 7 of TT vs. placebo No fungal elements in OLR-treated guinea pigs as compared to placebo-treated guinea pigs, which presented persistent alopecia and skin lesions. OLR-treated guinea pigs also presented an apparent reduction in skin lesions and faster capillary regrowth in comparison to CTZ-treated guinea pigs. |
AMB: amphotericin B. BD: 1,3-β-D-glucan. CFU: colony-forming unit. CGD: chronic granulomatous disease. CNS: central nervous system. CTZ: clotrimazole. EIA: enzyme immunoassay. FLC: fluconazole. GMS: Grocott–Gömöri Methenamine Silver stain. HE: Hematoxylin–Eosin stain. IP: intraperitoneal. IV: intravenous. MIC: minimal inhibitory concentration. NM: not mentioned. OLR: olorofim. PBS: phosphate-buffered saline. qPCR: quantitative real-time polymerase chain reaction. PSC: posaconazole. TT: treatment. VOR: voriconazole. WT: wild-type.