SSS07 / 3SBio, Pyxis Oncology, Danaher Corp - LARVOL DELTA

Therapeutic potential of Fosmanogepix (APX001) for intra-abdominal candidiasis: from lesion penetration to efficacy in a mouse model. (PubMed, Antimicrob Agents Chemother) - "Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated form of invasive candidiasis. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC."

Journal • Preclinical • Candidiasis • Hepatology • Infectious Disease

Safety and tolerability of a humanized rabbit monoclonal antibody (SSS07) in healthy adults: Randomized double-blind placebo-controlled single ascending dose trial. (PubMed, Int Immunopharmacol) - "SSS07 was generally safe and well tolerated in healthy Chinese volunteers. Higher immunogenicity was observed at low SSS07 concentration levels. The infections and administration site conditions might have been related to the immunogenicity and the degree of inhibition of TNF-α. However, the existence of ADA did not appear to affect the safety of the subjects throughout the follow-up period. These findings could support further investigations of treatments with humanized monoclonal antibodies."

Clinical • Journal • TNFA

Efficacy and Pharmacokinetics of Fosmanogepix (APX001) in the Treatment of Candida Endophthalmitis and Hematogenous Meningoencephalitis in Non-neutropenic Rabbits. (PubMed, Antimicrob Agents Chemother) - "Serum and CSF (1→3)-β-D-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and de-risk the clinical trials of candidemia and invasive candidiasis."

Clinical • Journal • PK/PD data • Candidiasis • CNS Disorders • Ocular Infections • Ocular Inflammation • Ophthalmology

Galactomannan is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis. (PubMed, Antimicrob Agents Chemother) - "Galactomannan (GM) detection in biological samples has been shown to predict therapeutic response by azoles and polyenes. In a murine invasive pulmonary aspergillosis model, fosmanogepix or posaconazole treatment resulted in a ∼6-7 log reduction in conidial equivalents (CE)/g lung tissue after 96 h versus placebo. Changes in GM levels in BAL and serum mirrored reductions in lung CE with significant decreases seen after 96 h or 72 h for fosmanogepix or posaconazole, respectively (P <0.02)."

Biomarker • Clinical • Journal

Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in vitro evaluation against Cryptococcus spp. (PubMed, Bioorg Med Chem Lett) - "Fosmanogepix (APX001) is a first-in-class prodrug molecule that is currently in Phase 2 clinical trials for invasive fungal infections. Several compounds demonstrated significantly (8- to 32-fold) improved antifungal activity against both Cryptococcus neoformans and C. gattii as compared to manogepix. Further in vitro characterization identified three analogs with a similar preliminary safety and in vitro profile to manogepix and superior activity against Cryptococcus spp."

Journal • Preclinical

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis. (PubMed, Antimicrob Agents Chemother) - "In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole resistant C. auris even when therapy is delayed."

Journal • Preclinical • Candidiasis • Neutropenia

An Efficacy and Safety Study of APX001 in Non-Neutropenic Patients With Candidemia (clinicaltrials.gov) - P2; N=21; Completed; Sponsor: Amplyx Pharmaceuticals; Active, not recruiting ➔ Completed; Trial primary completion date: Aug 2020 ➔ Mar 2020

Clinical • Trial completion • Trial primary completion date • Candidiasis

APEX: An Open-label Study of APX001 for Treatment of Patients With Candidemia/Invasive Candidiasis Caused by Candida Auris (clinicaltrials.gov) - P2; N=15; Recruiting; Sponsor: Amplyx Pharmaceuticals; Trial completion date: Jul 2020 ➔ Dec 2020; Trial primary completion date: May 2020 ➔ Nov 2020

Clinical • Trial completion date • Trial primary completion date • Candidiasis

In vitro activity of Manogepix (APX001A) and comparators against contemporary moulds; MEC comparison and preliminary experience with colorimetric MIC determination. (PubMed, Antimicrob Agents Chemother) - "Manogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections...Colorimetric MICs (measuring metabolic activity) were evaluated using three A. fumigatus and one A. flavus isolates with four inocula, 24-48h incubation and 1-3h XTT/MEN exposures.Manogepix modal MECs (range) (mg/L) against Aspergillus species were 0.03-0.06 (0.008-0.125) and unaffected by itraconazole resistance...Modal MEC/MICs were ≥3 two-fold dilutions apart without overlapping ranges comparing manogepix with amphotericin B, isavuconazole, and voriconazole against Aspergillus isolates. Manogepix and posaconazole MECs/MICs correlated for A. niger (Pearson r=0.711, P=0.0044)...The colorimetric method showed excellent agreement with the MECs when plates were inoculated with the lowest inoculum (1-2.5 x 10 CFU/mL), 24 h incubated and 1-3h XTT/MEN.Broad spectrum in vitro activity of manogepix against..."

Journal • Preclinical

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected During an International Surveillance Program (2017). (PubMed, Antimicrob Agents Chemother) - "isolates; corresponding anidulafungin, micafungin, and fluconazole MIC values were 16- to 64-fold higher...Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole)...The extended spectrum of APX001A was also notable for its potency against many less common, yet antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections."

Journal • Preclinical

APX001 protects immunosuppressed mice from scedosporiosis (ECCMID 2019) - "ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on days -2, and +3, relative to intratracheal infection with 3.0×107 cells of S. apiospermum. For survival studies, treatment with placebo (diluent control), APX001 (26, 52, 104, or 156 mg/kg, po), or liposomal amphotericin B (LAmB, 10 mg/kg, iv) began 16 h postinfection and continued for 7 or 11 days for APX and 4 days for LAmB... APX001A is cidal against S. apiospermum, S. boydii and L. prolificans in vitro. APX001 protected immunosuppressed mice from scedosporiosis due to S. apiospermum. Continued investigation of APX001 as a novel antifungal agent against scedosporiosis is warranted."

Preclinical

In vivo pharmacodynamic evaluation of the novel antifungal agent APX001 in a murine model of invasive pulmonary aspergillosis against wild-type and Cyp51 mutant Aspergillus fumigatus strains (ECCMID 2019) - "APX001 demonstrated potent in vivo efficacy against WT and triazole resistant AF clinical strains. AUC/MEC was the PK/PD index predictive of efficacy. Net cidal activity was observed for all strains and the exposure-response relationship was relatively steep as free drug AUC/MEC targets for stasis and 1-log kill differed by only 2-fold (48 and 89, respectively)."

PK/PD data • Preclinical • Neutropenia

A Drug-Drug Interaction Study of CYP3A4 Inhibition and Pan-CYP Induction on APX001 (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Amplyx Pharmaceuticals; Recruiting ➔ Completed

Clinical • Trial completion

Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs. (PubMed, Antimicrob Agents Chemother) - "Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001)...EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole and voriconazole...However, a 1-4 two-fold-dilution increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted."

Journal • Preclinical

Isolation of APX001A Resistant Strains and Characterization of Underlying Mechanisms in Candida spp (ASM Microbe 2018) - "Spontaneous mutations leading to elevated APX001A MIC values in Candida spp. occur at low frequencies, comparable to those obtained with other antifungals such as the echinocandins. A target mutation in GWT1 was identified."

Biosimilar

Efficacy of Oral APX001 in a Murine Model of Cryptococcal Meningitis (IDWeek 2017) - "o Combined therapy of APX001 with FCN significantly inhibited growth of C. neoformans H99 compared to untreated control mice (p<0.0001), and was significantly more active than monotherapy with APX001 or FCN (p<0.0001 and p<0.0003, respectively). o APX001 and FCN each, alone, significantly inhibited growth of C. neoformans H99 in brain tissue compared to untreated control mice (p<0.0001).no Combined therapy of APX001 with FCN performed somewhat better than FCN alone (p=0.0297), but no better than APX001 alone (p=0.2500)."

Preclinical • Infectious Disease

Fosmanogepix (APX001) is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus. (PubMed, Antimicrob Agents Chemother) - "Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first in class treatment for invasive mucormycosis."

Journal • Preclinical

An Efficacy and Safety Study of APX001 in Non-Neutropenic Patients With Candidemia (clinicaltrials.gov) - P2; N=20; Active, not recruiting; Sponsor: Amplyx Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an in vivo Model of Invasive Pulmonary Aspergillosis. (PubMed, Antimicrob Agents Chemother) - "Exposure-response relationships for all strains were similar and the median free drug AUC/MEC PK/PD targets for stasis and 1-log kill endpoint were 47.6 and 89.4, respectively. The present studies demonstrated in vitro and in vivo APX001A/APX001 potency against A. fumigatus These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints."

Journal • PK/PD data • Preclinical

A randomized controlled dose-escalation study of SSS07, a humanized rabbit anti-human TNF alpha antibody, in healthy Chinese adults. (PubMed, Int Immunopharmacol) - "A single-dose injection of SSS07 was safe and well-tolerated in healthy adults. Doses of SSS07 from 5 mg to 100 mg could not be regarded as nonlinear, based on dose-exposure proportionality analysis. A high incidence of anti-drug antibodies indicated strong immunogenicity, which may influence the pharmacokinetics profile and interfere with the TNF-α inhibition capability of SSS07."

Clinical • Journal

APX001 and Other Gwt1 inhibitor Prodrugs are Effective in Experimental Coccidioides immitis Pneumonia. (PubMed, Antimicrob Agents Chemother) - "In a survival experiment, both APX001 and APX2097-treated mice survived significantly longer than control and fluconazole treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis."

Journal

APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis. (PubMed, Antimicrob Agents Chemother) - "The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad spectrum, first in class treatment for invasive fungal infections."

Journal • Preclinical

AEGIS: An Open-label Study of APX001 for Treatment of Patients With Invasive Mold Infections Caused by Aspergillus Species or Rare Molds (clinicaltrials.gov) - P2; N=50; Recruiting; Sponsor: Amplyx Pharmaceuticals

Clinical • New P2 trial

Fosmanogepix (APX001) is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis. (PubMed, Antimicrob Agents Chemother) - "There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX, APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. The survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B dose (10-15 mg/kg). Our data support the continued development of fosmanogepix as a first in class treatment for infections caused by these rare molds."

Journal • Preclinical

A Drug-Drug Interaction Study of CYP3A4 Inhibition and Pan-CYP Induction on APX001 (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Amplyx Pharmaceuticals

New P1 trial