Mundipharma (United Kingdom)

ABSTRACTBackgroundInvasive candidiasis (IC), life‐threatening fungal infections with high economic burden, are often treated first‐line with daily intravenous echinocandins. A new once weekly echinocandin, rezafungin, demonstrated statistically non‐inferior efficacy and numerically shorter intensive care unit (ICU) stay compared to caspofungin in clinical trials, offering potential for earlier discharge.ObjectiveTo assess the cost‐effectiveness of rezafungin versus daily echinocandins for the treatment of IC from a UK healthcare perspective.MethodsAn economic model was developed including a short‐term decision tree (treatment duration ≤ 30 days) and a long‐term Markov model (for lifetime outcomes). Considering the impact IC has on a patient's life expectancy and quality of life, a cost‐utility analysis was performed. A cost‐minimisation analysis assuming similar efficacy among echinocandins was included as scenario analysis. Treatment response was assessed at days 5/14 with nonresponders switching to second‐line treatment. Patients with negative repeat blood cultures could step down to oral fluconazole. Rezafungin's weekly administration was estimated to lead to early discharge for 16% of patients. Risk of death was included. Efficacy and resource use estimates were from pooled trial data. Unit costs, utilities, long‐term mortality were from published literature and UK databases.ResultsRezafungin was estimated to be cost‐saving compared to daily echinocandins (discounted incremental costs: −£6028 to −£6727 vs. daily echinocandins). Quality‐adjusted life‐years (QALYs) were similar (incremental QALY: 0.03 vs. daily echinocandins), resulting in rezafungin being cost‐effective. Results were most sensitive to varying mortality and ICU length of stay.ConclusionOnce weekly rezafungin is a cost‐saving and cost‐effective treatment option in IC from the UK healthcare perspective.

ABSTRACTBackgroundThe global double‐blind, randomised, Phase 3 ReSTORE trial (NCT03667690) demonstrated noninferiority of rezafungin versus caspofungin for all‐cause mortality at Day 30 and global cure at Day 14 in patients with candidemia and/or invasive candidiasis.ObjectivesWe report outcomes for patients from China (ReSTORE China), comprising participants enrolled in the original ReSTORE trial (n = 11) and from an extended, China‐only phase (n = 47) implemented to fulfill Chinese regulatory requirements.MethodsPatients with candidemia/invasive candidiasis were randomised 1:1 to intravenous rezafungin (400 mg loading, then 200 mg once weekly) or caspofungin (70 mg loading, then 50 mg once daily) for ≤ 4 weeks. Primary endpoints were all‐cause mortality at Day 30 and global cure at Day 14 in the modified intent‐to‐treat population. Between October 2018 and March 2024, 58 patients were randomised and received study treatment (rezafungin n = 28 [modified intent‐to‐treat n = 27], caspofungin n = 30 [modified intent‐to‐treat n = 28]).ResultsAll‐cause mortality at Day 30 was 33.3% (9/27) for rezafungin versus 35.7% (10/28) for caspofungin (difference −2.4% [95% confidence interval −27.0–22.6]). Global cure at Day 14 was 48.1% (13/27) versus 46.4% (13/28), respectively (weighted difference 0.3% [95% confidence interval −25.4–26.3]). Day 5 and 14 mycological eradication rates were 70.4% and 63.0% for rezafungin versus 71.4% and 67.9% for caspofungin, respectively. Safety and tolerability profiles were similar between groups.ConclusionsRezafungin demonstrated similar efficacy and safety to caspofungin in the ReSTORE China cohort. These findings support the primary ReSTORE analysis and suggest that rezafungin could provide a new treatment option for candidemia/invasive candidiasis in China.Trial RegistrationClinicalTrials.gov identifier: NCT03667690

Aim: Compared with uncomplicated urinary tract infections (UTIs), complicated UTIs (cUTIs) including acute pyelonephritis (AP) present with significant morbidity, a higher risk of treatment failure and typically require longer courses of treatment, or alternative antibiotics. The emergence of drug-resistant organisms represents a considerable challenge in the treatment of patients with cUTIs/AP and has limited antibiotic options. Carbapenems are considered the current last line of therapy, however, carbapenem resistance represents a growing problem. Although several established and novel treatment options are available, direct comparative evidence is lacking. Methods: Randomized controlled trials (RCTs) were identified by systematic literature review of Embase®, MEDLINE® and Cochrane databases (database inception to 15th June 2022). Relevant conference proceedings (2020-2022) were also reviewed. Following feasibility assessment to verify network connectivity at an overall level, outcome specific networks were prepared. Bayesian network meta-analysis (NMA) was performed (using R version 4.2.1) to determine the relative efficacy of various treatments for cUTI/AP, including cefepime+enmetazobactam. Convergence was assessed by visual inspection of trace plots. The accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter. Published study results were included in the synthesis of the relative risk (RR) of efficacy end points, using a logit link with binomial likelihood distribution. Results: Feasibility assessment was conducted for 40 RCTs identified, to assess the viability of constructing a network of interlinked RCTs. Of those, 28 studies were included in the master NMA network. A fixed effects model (FEM) was selected due to low statistical heterogeneity, according to I2 values. For composite outcome at test of cure (TOC), ceftolozane+tazobactam, cefepime+enmetazobactam, cefiderocol, levofloxacin and plazomicin demonstrated significantly higher RRs versus carbapenems. For microbiological eradication at TOC, cefepime+enmetazobactam, plazomicin, cefiderocol, fosfomycin, meropenem+vaborbactam and ceftazidime+avibactam demonstrated significantly higher RRs versus carbapenems. RRs for cefepime+enmetazobactam were also significantly higher versus several established and novel treatment options for composite outcome, microbiological eradication and clinical cure. Conclusion: Against the backdrop of increasing bacterial resistance, these findings suggest that cefepime+enmetazobactam may represent an effective carbapenem-sparing treatment option in patients with cUTI including AP.

BackgroundRezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation.MethodsSTRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics.ResultsOf 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6–43.0) versus 38 (interquartile range, 15.9–211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117).ConclusionsRezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

<bold>Rationale</bold>: Timely initiation of therapy reduces risks of acute COPD exacerbations (AECOPD). This study examined whether prompt initiation of single inhaler triple therapy (SITT) with budesonide/glycopyrronium/formoterol fumarate (BGF) following an AECOPD also lowers risk of future AECOPD and severe cardiopulmonary (CP) events. <bold>Methods:</bold> This retrospective study used US claims data from patients with COPD who were ≥40 years with no prior SITT and either: ≥1 severe or ≥2 moderate AECOPD, or ≥1 moderate AECOPD while on non-SITT treatment (earliest event = index date); all patients initiated BGF within 1-year following index. Outcomes were annualized rates per person/year of AECOPD and severe CP events. Severe CP events included mortality, severe AECOPD and hospitalizations for HF, AMI, and cardiac arrest. Descriptive results were presented and stratified by BGF initiation: prompt (≤30 days), delayed (31–180 days), and very delayed (181–365 days). <bold>Results:</bold> 17613 patients qualified: 2192 prompt, 7230 delayed, and 8191 very delayed. The rate per person/year (95% CI) of post-index AECOPD increased as the time to BGF initiation increased: prompt 1.35 (1.30–1.40); delayed 1.77 (1.74–1.79); and very delayed 1.98 (1.95–2.00). Total severe CP event rates were: prompt 0.34 (0.32–0.37); delayed 0.39 (0.38–0.40); and very delayed 0.38 (0.37–0.39). <bold>Conclusion</bold>: Promptly initiating BGF was associated with 24% and 32% fewer subsequent AECOPD and 12.3% and 9.3% fewer severe CP events compared with delayed and very delayed groups. Proactive disease management with BGF may be warranted to prevent future AECOPD and CP events among patients with COPD.

BackgroundRezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE.MethodsReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated.ResultsThis analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [−13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [−16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [−0.2%, 40.2%]). Safety was comparable between treatments.ConclusionsThese findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Immune checkpoint inhibitors (CPIs) have been widely adopted in a number of early and advanced malignancies. Histone deacetylase inhibitors (HDACis) and alkylating agents (AAs) have been suggested to potentiate the actions of CPIs on tumor cells. We conducted a comprehensive literature review to explore the potential synergistic activity between CPIs, AAs, and HDACis. Clinical and non-clinical studies describing outcomes in patients with cancer receiving CPIs and either concomitant or sequential (pre- or post-CPI) AAs or HDACis were identified in PubMed using pre-defined search strings. Manual searches of key oncology congresses were similarly performed. All relevant articles and abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential. Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity. Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25–100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PerspectiveInhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.