Unraveling Dilemmas and Lacunae in the Escalating Drug Resistance of Mycobacterium tuberculosis to Bedaquiline, Delamanid, and Pretomanid.

Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.

Therapeutic Failure and Acquired Bedaquiline and Delamanid Resistance in Treatment of Drug-Resistant TB.

New classes of antitubercular drugs, diarylquinolines and nitroimidazoles, have been associated with improved outcomes in the treatment of drug-resistant tuberculosis, but that success is threatened by emerging drug resistance. We report a case of bedaquiline and delamanid resistance in a 55-year-old woman in South Africa with extensively drug-resistant tuberculosis and known HIV.

Sugar and sugar-free liquid formulations of delamanid for patients with rifampicin-resistant TB.

BACKGROUND: Delamanid (DLM) tablets are recommended for the treatment of rifampicin-resistant TB. However, no liquid or dispersible tablet formulation of DLM is currently commercially available for patients with challenges ingesting these tablets. The aim of this study was to develop stable extemporaneous liquid formulations of DLM that can be stored at room temperature for several weeks.METHODS: DLM tablets were suspended in 1) simple syrup and 2) a specially formulated sugar-free vehicle. These suspensions containing DLM 5 mg/mL were stored in plastic prescription bottles at room temperature or 30°C for 30 days. These suspensions were evaluated for appearance, potency, pH, and microbial counts at Days 0, 15, and 30.RESULTS: The potency of DLM in each formulation remained at 98-104% of the theoretical concentration for 30 days. The appearance, pH, and microbial count did not change for the sugar-free formulation during the 30-day storage period. Microbial growth, however, was observed in the simple syrup formulation on Day 30 but not on Day 15.CONCLUSION: DLM can be formulated in sugar or sugar-free suspensions and stored at room temperature or 30°C for at least 15 and 30 days, respectively.

[Expert consensus on clinical application of delamanid].

Multidrug-resistant tuberculosis(MDR-TB) is a major problem in the prevention and treatment of tuberculosis worldwide, but the treatment success rate is low, and it is necessary to develop new anti-tuberculosis drugs and optimize treatment. Delamanid, a drug with good activity against MDR-TB, has been marketed in recent years. However, there is a lack of clinical medication guidance of delamanid for tuberculosis treatment. To standardize the rational application of delamanid in clinical practice, Chinese Tuberculosis Society organized experts in related fields to issue this consensus. This consensus described the molecular structure, anti-tuberculosis mechanism, pharmacodynamics/pharmacokinetics, drug resistance mechanism, and clinical research of delamanid, put forward recommendations for clinical application, and explained its suitable population, contraindications, methods of application, adverse events, and precautions, so as to provide a reference for clinicians to use delamanid.

Hierarchical Clustering and Target-Independent QSAR for Antileishmanial Oxazole and Oxadiazole Derivatives.

Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against Leishmania infantum, the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- (R2 = 0.90, R2pred = 0.82) and 4D-QSAR models (R2 = 0.80, R2pred = 0.64), which showed improved statistical robustness and predictive ability.

Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

Recently developed drugs for the treatment of drug-resistant tuberculosis: a research and development case study.

Two drugs with novel mechanisms of action, the diarylquinoline bedaquiline and the nitroimidazole delamanid-as well as pretomanid from the same class of drugs as delamanid-have recently become available to treat drug-resistant tuberculosis (DR-TB) after many decades of little innovation in the field of DR-TB treatment. Despite evidence of improved efficacy and reduced toxicity of multidrug regimens including the two agents, access to bedaquiline and delamanid has been limited in many settings with a high burden of DR-TB and consistently poor treatment outcomes. Aside from regulatory, logistic and cost barriers at country level, uptake of the novel agents was complicated by gaps in knowledge for optimal use in clinical practice after initial market approval. The main incentives of the current pharmaceutical research and development paradigm are structured around obtaining regulatory approval, which in turn requires efficacy and safety data generated by clinical trials. Recently completed and ongoing clinical trials did not answer critical questions of how to provide shorter, less toxic treatment DR-TB treatment regimens containing bedaquiline and delamanid and improve patient outcomes. Voluntary generation of evidence that is not part of this process-yet essential from a clinical or policy perspective-has been left to non-sponsor partners and researchers, often without collaborative efforts to improve post-regulatory approval access to life-saving drugs. Additionally, these efforts are currently not recognised in the value chain of the research and development process, and there are no incentives to make this critical research happen in a coordinated way.

Pharmacokinetics and Pharmacodynamics of Tedizolid.

Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.

Delamanid or pretomanid? A Solomonic judgement!

Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.

The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders.

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization.

Effectiveness of lotilaner against ticks of the genus Amblyomma spp. in three naturally infested cane toads (Rhinella horribilis).

The efficacy of lotilaner was evaluated in three tick-infested cane toads. A single oral administration of lotilaner eliminated all ticks from all three toads from Day (D)1. Environmental samples collected from toad enclosures were negative for ticks until D30.

L'efficacité du lotilaner a été évaluée chez trois crapauds buffle infestés de tiques. Une seule administration orale de lotilaner a éliminé toutes les tiques des trois crapauds à partir du jour (J)1. Les échantillons environnementaux prélevés dans les enclos des crapauds étaient négatifs pour les tiques jusqu'à J30.

Se evaluó la eficacia de lotilaner en tres sapos de caña infestados por garrapatas. Una sola administración oral de lotilaner eliminó todas las garrapatas de los tres sapos desde el día (D) 1. Las muestras ambientales recolectadas de los recintos de sapos fueron negativas para garrapatas hasta el D30.

A eficácia do lotialaner foi avaliada em três sapos-boi infestados por carrapatos. Uma única administração de lotialaner eliminou todos os carrapatos de todos os sapos no Dia (D) 1. Amostras ambientais coletadas dos terrários dos sapos foram todas negativas para carrapatos até o D30.

Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis.

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc values were <10 ms at the simulated maximum concentration (Cmax) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis.

PURPOSE: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective. MATERIALS AND METHODS: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed. RESULTS: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs. CONCLUSION: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib.

Recent Developments in Oxazole Derivatives as Anticancer Agents: Review on Synthetic Strategies, Mechanism of Action and SAR Studies.

BACKGROUND: Cancer is the world's third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requisite to expand novel anticancer agents with in vivo efficacy. OBJECTIVE: This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moiety, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs. METHODS: Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies. RESULTS: Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and Gquadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in nanomolar concentrations. CONCLUSION: Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs.

Aspects cliniques : Cancers HER2 et atteinte du système nerveux central, que faire en 2021 ?: Central nervous system metastases from HER2 positive breast cancers: what to do in 2021?

Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context.

Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials.

BACKGROUND: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.

Efficacy of tucatinib for HER2-positive metastatic breast cancer after HER2-targeted therapy: a network meta-analysis.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Lay abstract Although several therapies are used in HER2-positive metastatic breast cancer, direct head-to-head comparisons of these therapies are lacking. We conducted a network meta-analysis, a way of indirectly comparing the results of different clinical trials, to compare how long patients receiving therapy had no disease progression, and also how long patients survived. In terms of avoiding disease progression, tucatinib plus trastuzumab with capecitabine ranked highest, followed by T-DM1 monotherapy and neratinib plus capecitabine. In terms of survival, tucatinib plus trastuzumab with capecitabine ranked highest, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1. Tucatinib in combination with trastuzumab plus capecitabine and also T-DM1 monotherapy consistently demonstrated improved progression-free and overall survival outcomes compared with other therapies.

Collarette Elimination and Demodex Mite Eradication with Topical Lotilaner Ophthalmic Solution, 0.25.

Purpose: To evaluate the efficacy of topical lotilaner ophthalmic solution, 0.25%, in patients with Demodex blepharitis. Methods: Eighteen adults with Demodex blepharitis, defined as >10 collarettes on the upper lid and/or mite density of ≥1.5 mites per lash (upper and lower), were treated bid for 42 days with the topical lotilaner ophthalmic solution, 0.25%. Contact lens wear, artificial eyelashes, and lid structural abnormalities were among the exclusion criteria. No other antibacterial, antiparasitic, or anti-inflammatory treatment or lid hygiene products were permitted. One eye of each patient was selected for analysis and assessed on day 7, 14, 28, and 42. Collarettes were graded at each visit, and mite density was evaluated by microscopy at each visit except day 7. Outcome measures were collarette elimination (≤2 lashes with collarettes) and mite eradication (0 mites). Drop tolerability, adverse events, visual acuity, and slit-lamp biomicroscopy were assessed. Results: Collarette elimination was achieved in 13/18 participants (72.2%) by day 42. Mean collarette grade (upper lid) declined from 3.56 ± 0.17 to 0.28 ± 0.11. Mite eradication was achieved in 14/18 participants (77.8%) by day 42. Mean mite density decreased from 2.63 ± 0.39 to 0.12 ± 0.08 mites/lash. Participants reported good tolerability. Adverse events were mild and transient and did not result in treatment discontinuation. Conclusion: Six weeks of at-home topical therapy with the lotilaner ophthalmic solution, 0.25%, was effective in eliminating the most common objective signs of Demodex blepharitis, with a collarette elimination rate of 72% and mite eradication in 78% of eyes by day 42. ISRCTN registration #: 24398865.

Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial).

AIMS: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. METHODS: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. RESULTS: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. CONCLUSIONS: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. CLINICAL TRIAL REGISTRATION: NCT02614794.